CANIT0000001	11291838	Clinical research	Advanced renal carcinoma	Renal carcinoma	EFO:0002890	Kidney	TLR3 (O15455); 	TLR3; 	Poly-ICLC	N/A	Tumor vaccine	Poly-ICLC (NCIT:C1198); 	29	N/A	A phase II clinical trial	Poly ICLC at this dose and schedule is well tolerated and is inactive in renal carcinoma.	Toxicity included grade   3 anemia in 8 patients and grade 4 anemia in one patient. All patients were  anemic prior to entry with a median grade 2 anemia at baseline. Grade 4  neutropenia, thrombocytopenia and injection site pain occurred in one patient  each. Grade 3 fever, chills or fatigue occurred in four, three, and three  patients respectively. Any grade fever occurred in 10 patients (25.6%) and any  grade chills occurred in 9 patients (23.1%).	N/A	N/A	N/A	N/A	N/A	2001	 Toxicity and response evaluation of the interferon inducer poly ICLC administered  at low dose in advanced renal carcinoma and relapsed or refractory lymphoma: a  report of two clinical trials of the Eastern Cooperative Oncology Group.	 Invest New Drugs	 PURPOSE: Phase II studies were conducted to evaluate the safety and efficacy of  the interferon inducer Poly ICLC at low doses in advanced renal cancer and  relapsed or refractory lymphoma. PATIENTS AND METHODS: Twenty-nine patients with   advanced renal carcinoma and eleven patients with lymphoma were treated with poly  ICLC. Patients received 0.25 mg/m2 of poly ICLC intravenously twice weekly three   days apart until progression or unacceptable toxicity. RESULTS: There were no  objective responses. Six patients with renal carcinoma had stable disease as best  response with one patient receiving 62 weeks of therapy. Toxicity included grade   3 anemia in 8 patients and grade 4 anemia in one patient. All patients were  anemic prior to entry with a median grade 2 anemia at baseline. Grade 4  neutropenia, thrombocytopenia and injection site pain occurred in one patient  each. Grade 3 fever, chills or fatigue occurred in four, three, and three  patients respectively. Any grade fever occurred in 10 patients (25.6%) and any  grade chills occurred in 9 patients (23.1%). CONCLUSION: Poly ICLC at this dose  and schedule is well tolerated in both patient populations and is inactive in  renal carcinoma.
CANIT0000002	12439610	Basic research	Human embryonic kidney cell line 293 and Murine renal carcinoma cell lines	Renal carcinoma	EFO:0002890	Kidney	CD3E (P07766); 	CD3E; 	MVA-KT3 vaccine	N/A	Tumor vaccine	Ad-MIP1B vaccine (NCIT:C1467); Ad-IL-12 vaccine (DB06180); MVA-KT3 vaccine (NCIT:C25792); 	Cell lines/ animal models	N/A	Basic research	These data show that antigenic stimulation via the MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising approach to cancer gene therapy which is more likely to bypass tumor immunosuppression mechanisms.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2002 Dec	 The combination of a chemokine, cytokine and TCR-based T cell stimulus for  effective gene therapy of cancer.	 Cancer Immunol Immunother	 Cytotoxic T cells can recognize and kill tumor cells that present peptides  derived from tumor-associated antigens (TAA) on their surface when associated  with major histocompatibility complex (MHC) class I molecules. However, immune  responses to tumor-associated antigens are often suppressed by a tumor-induced  state of immune anergy. Previous work has attempted to overcome tumor-induced T  cell anergy by the direct injection of vectors carrying genes encoding one of a  variety of cytokines. Polyclonal stimulation of T cells, preferably via the TCR  complex, results in a cascade of cytokines associated with T cell activation and   thus may be better able to overcome T cell anergy. We have previously reported  the use of the highly attenuated MVA poxvirus to express on tumor cells, in vitro  and in vivo, antibodies specific for the CD3epsilon chain (KT3). When injected  into growing tumors, these constructs induce the activation of immune effector  cells and result in rejection of the tumor. A variety of recombinant adenovirus  (Ad) vectors expressing immunostimulatory and/or immunoattractant molecules have   now been produced. With this collection of viruses, we have carried out in vivo  analyses of combinations of vectors in tumor therapy experiments. For example, we  have tested, in murine tumor models, the combination of MVA-KT3 with Ad  expressing recently identified cytokines [for example interleukin-12 (IL-12),  IL-18] as well as chemokines (e.g. RANTES, MIP1beta). One combination,  MVA-KT3/Ad-IL-12/Ad-MIP1beta causes rejection of 100% of growing RENCA tumors.  Much attention has been focused on cancer gene therapy using gene transfer of  single agents. These data show that antigenic stimulation via the  MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising  approach to cancer gene therapy which is more likely to bypass tumor  immunosuppression mechanisms.
CANIT0000003	12439610	Basic research	Human embryonic kidney cell line 293 and Murine renal carcinoma cell lines	Renal carcinoma	EFO:0002890	Kidney	IL12R (P42701); 	IL12R; 	Ad-IL12 vaccine	N/A	Tumor vaccine	Ad-MIP1B vaccine (NCIT:C1467); Ad-IL-12 vaccine (DB06180); MVA-KT3 vaccine (NCIT:C25792); 	Cell lines/ animal models	N/A	Basic research	These data show that antigenic stimulation via the MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising approach to cancer gene therapy which is more likely to bypass tumor immunosuppression mechanisms.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2002 Dec	 The combination of a chemokine, cytokine and TCR-based T cell stimulus for  effective gene therapy of cancer.	 Cancer Immunol Immunother	 Cytotoxic T cells can recognize and kill tumor cells that present peptides  derived from tumor-associated antigens (TAA) on their surface when associated  with major histocompatibility complex (MHC) class I molecules. However, immune  responses to tumor-associated antigens are often suppressed by a tumor-induced  state of immune anergy. Previous work has attempted to overcome tumor-induced T  cell anergy by the direct injection of vectors carrying genes encoding one of a  variety of cytokines. Polyclonal stimulation of T cells, preferably via the TCR  complex, results in a cascade of cytokines associated with T cell activation and   thus may be better able to overcome T cell anergy. We have previously reported  the use of the highly attenuated MVA poxvirus to express on tumor cells, in vitro  and in vivo, antibodies specific for the CD3epsilon chain (KT3). When injected  into growing tumors, these constructs induce the activation of immune effector  cells and result in rejection of the tumor. A variety of recombinant adenovirus  (Ad) vectors expressing immunostimulatory and/or immunoattractant molecules have   now been produced. With this collection of viruses, we have carried out in vivo  analyses of combinations of vectors in tumor therapy experiments. For example, we  have tested, in murine tumor models, the combination of MVA-KT3 with Ad  expressing recently identified cytokines [for example interleukin-12 (IL-12),  IL-18] as well as chemokines (e.g. RANTES, MIP1beta). One combination,  MVA-KT3/Ad-IL-12/Ad-MIP1beta causes rejection of 100% of growing RENCA tumors.  Much attention has been focused on cancer gene therapy using gene transfer of  single agents. These data show that antigenic stimulation via the  MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising  approach to cancer gene therapy which is more likely to bypass tumor  immunosuppression mechanisms.
CANIT0000004	12439610	Basic research	Human embryonic kidney cell line 293 and Murine renal carcinoma cell lines	Renal carcinoma	EFO:0002890	Kidney	CCL4 (P13236); 	CCL4; 	Ad-MIP1beta vaccine	N/A	Tumor vaccine	Ad-MIP1B vaccine (NCIT:C1467); Ad-IL-12 vaccine (DB06180); MVA-KT3 vaccine (NCIT:C25792); 	Cell lines/ animal models	N/A	Basic research	These data show that antigenic stimulation via the MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising approach to cancer gene therapy which is more likely to bypass tumor immunosuppression mechanisms.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2002 Dec	 The combination of a chemokine, cytokine and TCR-based T cell stimulus for  effective gene therapy of cancer.	 Cancer Immunol Immunother	 Cytotoxic T cells can recognize and kill tumor cells that present peptides  derived from tumor-associated antigens (TAA) on their surface when associated  with major histocompatibility complex (MHC) class I molecules. However, immune  responses to tumor-associated antigens are often suppressed by a tumor-induced  state of immune anergy. Previous work has attempted to overcome tumor-induced T  cell anergy by the direct injection of vectors carrying genes encoding one of a  variety of cytokines. Polyclonal stimulation of T cells, preferably via the TCR  complex, results in a cascade of cytokines associated with T cell activation and   thus may be better able to overcome T cell anergy. We have previously reported  the use of the highly attenuated MVA poxvirus to express on tumor cells, in vitro  and in vivo, antibodies specific for the CD3epsilon chain (KT3). When injected  into growing tumors, these constructs induce the activation of immune effector  cells and result in rejection of the tumor. A variety of recombinant adenovirus  (Ad) vectors expressing immunostimulatory and/or immunoattractant molecules have   now been produced. With this collection of viruses, we have carried out in vivo  analyses of combinations of vectors in tumor therapy experiments. For example, we  have tested, in murine tumor models, the combination of MVA-KT3 with Ad  expressing recently identified cytokines [for example interleukin-12 (IL-12),  IL-18] as well as chemokines (e.g. RANTES, MIP1beta). One combination,  MVA-KT3/Ad-IL-12/Ad-MIP1beta causes rejection of 100% of growing RENCA tumors.  Much attention has been focused on cancer gene therapy using gene transfer of  single agents. These data show that antigenic stimulation via the  MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising  approach to cancer gene therapy which is more likely to bypass tumor  immunosuppression mechanisms.
CANIT0000005	12439610	Basic research	Human pulmonary carcinoma cell line A549 	Lung carcinoma	EFO:0001071	Lung	CD3E (P07766); 	CD3E; 	MVA-KT3 vaccine	N/A	Tumor vaccine	Ad-MIP1B vaccine (NCIT:C1467); Ad-IL-12 vaccine (DB06180); MVA-KT3 vaccine (NCIT:C25792); 	Cell lines/ animal models	N/A	Basic research	These data show that antigenic stimulation via the MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising approach to cancer gene therapy which is more likely to bypass tumor immunosuppression mechanisms.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2002 Dec	 The combination of a chemokine, cytokine and TCR-based T cell stimulus for  effective gene therapy of cancer.	 Cancer Immunol Immunother	 Cytotoxic T cells can recognize and kill tumor cells that present peptides  derived from tumor-associated antigens (TAA) on their surface when associated  with major histocompatibility complex (MHC) class I molecules. However, immune  responses to tumor-associated antigens are often suppressed by a tumor-induced  state of immune anergy. Previous work has attempted to overcome tumor-induced T  cell anergy by the direct injection of vectors carrying genes encoding one of a  variety of cytokines. Polyclonal stimulation of T cells, preferably via the TCR  complex, results in a cascade of cytokines associated with T cell activation and   thus may be better able to overcome T cell anergy. We have previously reported  the use of the highly attenuated MVA poxvirus to express on tumor cells, in vitro  and in vivo, antibodies specific for the CD3epsilon chain (KT3). When injected  into growing tumors, these constructs induce the activation of immune effector  cells and result in rejection of the tumor. A variety of recombinant adenovirus  (Ad) vectors expressing immunostimulatory and/or immunoattractant molecules have   now been produced. With this collection of viruses, we have carried out in vivo  analyses of combinations of vectors in tumor therapy experiments. For example, we  have tested, in murine tumor models, the combination of MVA-KT3 with Ad  expressing recently identified cytokines [for example interleukin-12 (IL-12),  IL-18] as well as chemokines (e.g. RANTES, MIP1beta). One combination,  MVA-KT3/Ad-IL-12/Ad-MIP1beta causes rejection of 100% of growing RENCA tumors.  Much attention has been focused on cancer gene therapy using gene transfer of  single agents. These data show that antigenic stimulation via the  MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising  approach to cancer gene therapy which is more likely to bypass tumor  immunosuppression mechanisms.
CANIT0000006	12439610	Basic research	Human pulmonary carcinoma cell line A549 	Lung carcinoma	EFO:0001071	Lung	IL12R (P42701); 	IL12R; 	Ad-IL12 vaccine	N/A	Tumor vaccine	Ad-MIP1B vaccine (NCIT:C1467); Ad-IL-12 vaccine (DB06180); MVA-KT3 vaccine (NCIT:C25792); 	Cell lines/ animal models	N/A	Basic research	These data show that antigenic stimulation via the MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising approach to cancer gene therapy which is more likely to bypass tumor immunosuppression mechanisms.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2002 Dec	 The combination of a chemokine, cytokine and TCR-based T cell stimulus for  effective gene therapy of cancer.	 Cancer Immunol Immunother	 Cytotoxic T cells can recognize and kill tumor cells that present peptides  derived from tumor-associated antigens (TAA) on their surface when associated  with major histocompatibility complex (MHC) class I molecules. However, immune  responses to tumor-associated antigens are often suppressed by a tumor-induced  state of immune anergy. Previous work has attempted to overcome tumor-induced T  cell anergy by the direct injection of vectors carrying genes encoding one of a  variety of cytokines. Polyclonal stimulation of T cells, preferably via the TCR  complex, results in a cascade of cytokines associated with T cell activation and   thus may be better able to overcome T cell anergy. We have previously reported  the use of the highly attenuated MVA poxvirus to express on tumor cells, in vitro  and in vivo, antibodies specific for the CD3epsilon chain (KT3). When injected  into growing tumors, these constructs induce the activation of immune effector  cells and result in rejection of the tumor. A variety of recombinant adenovirus  (Ad) vectors expressing immunostimulatory and/or immunoattractant molecules have   now been produced. With this collection of viruses, we have carried out in vivo  analyses of combinations of vectors in tumor therapy experiments. For example, we  have tested, in murine tumor models, the combination of MVA-KT3 with Ad  expressing recently identified cytokines [for example interleukin-12 (IL-12),  IL-18] as well as chemokines (e.g. RANTES, MIP1beta). One combination,  MVA-KT3/Ad-IL-12/Ad-MIP1beta causes rejection of 100% of growing RENCA tumors.  Much attention has been focused on cancer gene therapy using gene transfer of  single agents. These data show that antigenic stimulation via the  MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising  approach to cancer gene therapy which is more likely to bypass tumor  immunosuppression mechanisms.
CANIT0000007	12439610	Basic research	Human pulmonary carcinoma cell line A549 	Lung carcinoma	EFO:0001071	Lung	CCL4 (P13236); 	CCL4; 	Ad-MIP1beta vaccine	N/A	Tumor vaccine	Ad-MIP1B vaccine (NCIT:C1467); Ad-IL-12 vaccine (DB06180); MVA-KT3 vaccine (NCIT:C25792); 	Cell lines/ animal models	N/A	Basic research	These data show that antigenic stimulation via the MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising approach to cancer gene therapy which is more likely to bypass tumor immunosuppression mechanisms.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2002 Dec	 The combination of a chemokine, cytokine and TCR-based T cell stimulus for  effective gene therapy of cancer.	 Cancer Immunol Immunother	 Cytotoxic T cells can recognize and kill tumor cells that present peptides  derived from tumor-associated antigens (TAA) on their surface when associated  with major histocompatibility complex (MHC) class I molecules. However, immune  responses to tumor-associated antigens are often suppressed by a tumor-induced  state of immune anergy. Previous work has attempted to overcome tumor-induced T  cell anergy by the direct injection of vectors carrying genes encoding one of a  variety of cytokines. Polyclonal stimulation of T cells, preferably via the TCR  complex, results in a cascade of cytokines associated with T cell activation and   thus may be better able to overcome T cell anergy. We have previously reported  the use of the highly attenuated MVA poxvirus to express on tumor cells, in vitro  and in vivo, antibodies specific for the CD3epsilon chain (KT3). When injected  into growing tumors, these constructs induce the activation of immune effector  cells and result in rejection of the tumor. A variety of recombinant adenovirus  (Ad) vectors expressing immunostimulatory and/or immunoattractant molecules have   now been produced. With this collection of viruses, we have carried out in vivo  analyses of combinations of vectors in tumor therapy experiments. For example, we  have tested, in murine tumor models, the combination of MVA-KT3 with Ad  expressing recently identified cytokines [for example interleukin-12 (IL-12),  IL-18] as well as chemokines (e.g. RANTES, MIP1beta). One combination,  MVA-KT3/Ad-IL-12/Ad-MIP1beta causes rejection of 100% of growing RENCA tumors.  Much attention has been focused on cancer gene therapy using gene transfer of  single agents. These data show that antigenic stimulation via the  MHCI/TCR-CD3+cytokine+chemokine combination may provide a new and promising  approach to cancer gene therapy which is more likely to bypass tumor  immunosuppression mechanisms.
CANIT0000008	12481437	Basic research	Cell lines CT26 and B16F10 are from a chemically induced BALB/c colon carcinoma, BALB/c and C57BL/6 mice	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine	MVA-LacZ vaccine	Tumor vaccine	MVA-5T4 vaccine (NCIT:C49087); 	Cell lines/ animal models	N/A	Basic research	These data support the use of MVA-5T4 for tumor immunotherapy.	Mice vaccinated with MVA-m5T4 showed no signs of autoimmune toxicity.	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2002 Oct	 Attenuated recombinant vaccinia virus expressing oncofetal antigen  (tumor-associated antigen) 5T4 induces active therapy of established tumors.	 Mol Cancer Ther	 The human oncofetal antigen 5T4 (h5T4) is a transmembrane glycoprotein  overexpressed by a wide spectrum of cancers, including colorectal, ovarian, and  gastric, but with a limited normal tissue expression. Such properties make 5T4 an  excellent putative target for cancer immunotherapy. The murine homologue of 5T4  (m5T4) has been cloned and characterized, which allows for the evaluation of  immune intervention strategies in self-antigen in vivo tumor models. We have  constructed recombinant vaccinia viruses based on the highly attenuated and  modified vaccinia virus ankara (MVA strain), expressing h5T4 (MVA-h5T4), m5T4  (MVA-m5T4), and Escherichia coli LacZ (MVA-LacZ). Immunization of BALB/c and  C57BL/6 mice with MVA-h5T4 and MVA-m5T4 constructs induced antibody responses to   human and mouse 5T4, respectively. C57BL/6 and BALB/c mice vaccinated with  MVA-h5T4 were challenged with syngeneic tumor line transfectants, B16 melanoma,  and CT26 colorectal cells that express h5T4. MVA-h5T4-vaccinated mice showed  significant tumor retardation compared with mice vaccinated with MVA-LacZ or PBS.  In active treatment studies, inoculation with MVA-h5T4 was able to treat  established CT26-h5T4 lung tumor and to a lesser extent B16.h5T4 s.c. tumors.  Additionally, when C57BL/6 mice vaccinated with MVA-m5T4 were challenged with B16  cells expressing m5T4, resulting growth of the tumors was significantly retarded   compared with control animals. Furthermore, mice vaccinated with MVA-m5T4 showed   no signs of autoimmune toxicity. These data support the use of MVA-5T4 for tumor   immunotherapy.
CANIT0000009	12898638	Clinical research	MUC1-positive breast cancer	Breast cancer	MONDO:0007254	Breast	IL2R (A2N4P8); MUC1 (P15941); 	IL2R; MUC1	MVA-MUC1-IL2 vaccine	N/A	Tumor vaccine	MVA-MUC1-IL2 vaccine (NCIT:C2241); 	2	N/A	A phase I clinical trial 	Progressive disease	Tolerance of MVA-MUC1-IL2 vaccine (TG4010) was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. 	N/A	N/A	N/A	N/A	N/A	 2003 Aug	 Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1   as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.	 J Gene Med	 BACKGROUND: The MUC1 protein is a highly glycosylated mucin normally found at the  apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1  is expressed, but heavily underglycosylated, in different human tumors. TG4010 is  a viral suspension of a recombinant vaccinia vector (MVA) containing DNA  sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This  product was developed for use as a vaccine in cancer patients whose tumors  express the MUC1 antigen. The objective of the present study was to determine the  safety of the product and to define the dose of TG4010 to be used in further  clinical trials. MATERIALS AND METHODS: Thirteen patients with different solid  tumors were treated by repeated intramuscular injection with increasing doses of   TG4010 in two separate phase I studies, one in Europe (Basel-CR) and one in the  United States (UCLA-RF): a total of 6 patients were treated at a dose of 5 x  10(6) pfu, 3 patients at 5 x 10(7) pfu, and 4 patients at 10(8) pfu. Safety,  efficacy, and different immunological tests were the endpoints of the study.  RESULTS: Tolerance of TG4010 was excellent, and side effects mainly consisted of   injection site pain and influenza-like symptoms. There was no apparent  detrimental effect of repeated injections of the vaccinia virus. Four of thirteen  evaluable patients showed stabilization of their disease for 6 to 9 months. One  lung cancer patient who was initially progressing after the first injections  later showed a marked decrease in the size of his metastases that lasted for 14  months. Some T cell proliferative immune responses were seen in five patients.  CONCLUSIONS: The administration of TG4010 was generally well tolerated in  patients with metastatic tumors, and transient disease stabilization was observed  in several patients, warranting further clinical studies with the product.CI  - Copyright 2003 John Wiley & Sons, Ltd.
CANIT0000010	12898638	Clinical research	MUC1-positive gastric cancer	Gastric cancer	MONDO:0001056	Stomach	IL2R (A2N4P8); MUC1 (P15941); 	IL2R; MUC1	MVA-MUC1-IL2 vaccine	N/A	Tumor vaccine	MVA-MUC1-IL2 vaccine (NCIT:C2241); 	1	N/A	A phase I clinical trial 	Stable disease	Tolerance of MVA-MUC1-IL2 vaccine (TG4010) was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. 	N/A	N/A	N/A	N/A	N/A	 2003 Aug	 Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1   as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.	 J Gene Med	 BACKGROUND: The MUC1 protein is a highly glycosylated mucin normally found at the  apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1  is expressed, but heavily underglycosylated, in different human tumors. TG4010 is  a viral suspension of a recombinant vaccinia vector (MVA) containing DNA  sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This  product was developed for use as a vaccine in cancer patients whose tumors  express the MUC1 antigen. The objective of the present study was to determine the  safety of the product and to define the dose of TG4010 to be used in further  clinical trials. MATERIALS AND METHODS: Thirteen patients with different solid  tumors were treated by repeated intramuscular injection with increasing doses of   TG4010 in two separate phase I studies, one in Europe (Basel-CR) and one in the  United States (UCLA-RF): a total of 6 patients were treated at a dose of 5 x  10(6) pfu, 3 patients at 5 x 10(7) pfu, and 4 patients at 10(8) pfu. Safety,  efficacy, and different immunological tests were the endpoints of the study.  RESULTS: Tolerance of TG4010 was excellent, and side effects mainly consisted of   injection site pain and influenza-like symptoms. There was no apparent  detrimental effect of repeated injections of the vaccinia virus. Four of thirteen  evaluable patients showed stabilization of their disease for 6 to 9 months. One  lung cancer patient who was initially progressing after the first injections  later showed a marked decrease in the size of his metastases that lasted for 14  months. Some T cell proliferative immune responses were seen in five patients.  CONCLUSIONS: The administration of TG4010 was generally well tolerated in  patients with metastatic tumors, and transient disease stabilization was observed  in several patients, warranting further clinical studies with the product.CI  - Copyright 2003 John Wiley & Sons, Ltd.
CANIT0000011	12898638	Clinical research	MUC1-positive kidney cancer	Renal cell carcinoma	EFO:0000681	Kidney	IL2R (A2N4P8); MUC1 (P15941); 	IL2R; MUC1	MVA-MUC1-IL2 vaccine	N/A	Tumor vaccine	MVA-MUC1-IL2 vaccine (NCIT:C2241); 	4	N/A	A phase I clinical trial 	Stable disease or Progressive disease.	Tolerance of MVA-MUC1-IL2 vaccine (TG4010) was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. 	N/A	N/A	N/A	N/A	N/A	 2003 Aug	 Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1   as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.	 J Gene Med	 BACKGROUND: The MUC1 protein is a highly glycosylated mucin normally found at the  apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1  is expressed, but heavily underglycosylated, in different human tumors. TG4010 is  a viral suspension of a recombinant vaccinia vector (MVA) containing DNA  sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This  product was developed for use as a vaccine in cancer patients whose tumors  express the MUC1 antigen. The objective of the present study was to determine the  safety of the product and to define the dose of TG4010 to be used in further  clinical trials. MATERIALS AND METHODS: Thirteen patients with different solid  tumors were treated by repeated intramuscular injection with increasing doses of   TG4010 in two separate phase I studies, one in Europe (Basel-CR) and one in the  United States (UCLA-RF): a total of 6 patients were treated at a dose of 5 x  10(6) pfu, 3 patients at 5 x 10(7) pfu, and 4 patients at 10(8) pfu. Safety,  efficacy, and different immunological tests were the endpoints of the study.  RESULTS: Tolerance of TG4010 was excellent, and side effects mainly consisted of   injection site pain and influenza-like symptoms. There was no apparent  detrimental effect of repeated injections of the vaccinia virus. Four of thirteen  evaluable patients showed stabilization of their disease for 6 to 9 months. One  lung cancer patient who was initially progressing after the first injections  later showed a marked decrease in the size of his metastases that lasted for 14  months. Some T cell proliferative immune responses were seen in five patients.  CONCLUSIONS: The administration of TG4010 was generally well tolerated in  patients with metastatic tumors, and transient disease stabilization was observed  in several patients, warranting further clinical studies with the product.CI  - Copyright 2003 John Wiley & Sons, Ltd.
CANIT0000012	12898638	Clinical research	MUC1-positive mesothelioma	Mesothelioma	EFO:0000588	Soft tissue	IL2R (A2N4P8); MUC1 (P15941); 	IL2R; MUC1	MVA-MUC1-IL2 vaccine	N/A	Tumor vaccine	MVA-MUC1-IL2 vaccine (NCIT:C2241); 	1	N/A	A phase I clinical trial 	Stable disease and Progressive disease.	Tolerance of MVA-MUC1-IL2 vaccine (TG4010) was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. 	N/A	N/A	N/A	N/A	N/A	 2003 Aug	 Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1   as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.	 J Gene Med	 BACKGROUND: The MUC1 protein is a highly glycosylated mucin normally found at the  apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1  is expressed, but heavily underglycosylated, in different human tumors. TG4010 is  a viral suspension of a recombinant vaccinia vector (MVA) containing DNA  sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This  product was developed for use as a vaccine in cancer patients whose tumors  express the MUC1 antigen. The objective of the present study was to determine the  safety of the product and to define the dose of TG4010 to be used in further  clinical trials. MATERIALS AND METHODS: Thirteen patients with different solid  tumors were treated by repeated intramuscular injection with increasing doses of   TG4010 in two separate phase I studies, one in Europe (Basel-CR) and one in the  United States (UCLA-RF): a total of 6 patients were treated at a dose of 5 x  10(6) pfu, 3 patients at 5 x 10(7) pfu, and 4 patients at 10(8) pfu. Safety,  efficacy, and different immunological tests were the endpoints of the study.  RESULTS: Tolerance of TG4010 was excellent, and side effects mainly consisted of   injection site pain and influenza-like symptoms. There was no apparent  detrimental effect of repeated injections of the vaccinia virus. Four of thirteen  evaluable patients showed stabilization of their disease for 6 to 9 months. One  lung cancer patient who was initially progressing after the first injections  later showed a marked decrease in the size of his metastases that lasted for 14  months. Some T cell proliferative immune responses were seen in five patients.  CONCLUSIONS: The administration of TG4010 was generally well tolerated in  patients with metastatic tumors, and transient disease stabilization was observed  in several patients, warranting further clinical studies with the product.CI  - Copyright 2003 John Wiley & Sons, Ltd.
CANIT0000013	12898638	Clinical research	MUC1-positive NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	IL2R (A2N4P8); MUC1 (P15941); 	IL2R; MUC1	MVA-MUC1-IL2 vaccine	N/A	Tumor vaccine	MVA-MUC1-IL2 vaccine (NCIT:C2241); 	3	N/A	A phase I clinical trial 	Progressive disease	Tolerance of MVA-MUC1-IL2 vaccine (TG4010) was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. 	N/A	N/A	N/A	N/A	N/A	 2003 Aug	 Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1   as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.	 J Gene Med	 BACKGROUND: The MUC1 protein is a highly glycosylated mucin normally found at the  apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1  is expressed, but heavily underglycosylated, in different human tumors. TG4010 is  a viral suspension of a recombinant vaccinia vector (MVA) containing DNA  sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This  product was developed for use as a vaccine in cancer patients whose tumors  express the MUC1 antigen. The objective of the present study was to determine the  safety of the product and to define the dose of TG4010 to be used in further  clinical trials. MATERIALS AND METHODS: Thirteen patients with different solid  tumors were treated by repeated intramuscular injection with increasing doses of   TG4010 in two separate phase I studies, one in Europe (Basel-CR) and one in the  United States (UCLA-RF): a total of 6 patients were treated at a dose of 5 x  10(6) pfu, 3 patients at 5 x 10(7) pfu, and 4 patients at 10(8) pfu. Safety,  efficacy, and different immunological tests were the endpoints of the study.  RESULTS: Tolerance of TG4010 was excellent, and side effects mainly consisted of   injection site pain and influenza-like symptoms. There was no apparent  detrimental effect of repeated injections of the vaccinia virus. Four of thirteen  evaluable patients showed stabilization of their disease for 6 to 9 months. One  lung cancer patient who was initially progressing after the first injections  later showed a marked decrease in the size of his metastases that lasted for 14  months. Some T cell proliferative immune responses were seen in five patients.  CONCLUSIONS: The administration of TG4010 was generally well tolerated in  patients with metastatic tumors, and transient disease stabilization was observed  in several patients, warranting further clinical studies with the product.CI  - Copyright 2003 John Wiley & Sons, Ltd.
CANIT0000014	12898638	Clinical research	MUC1-positive pharynx cancer	Pharynx cancer	EFO:0005577	Head and neck	IL2R (A2N4P8); MUC1 (P15941); 	IL2R; MUC1	MVA-MUC1-IL2 vaccine	N/A	Tumor vaccine	MVA-MUC1-IL2 vaccine (NCIT:C2241); 	1	N/A	A phase I clinical trial 	Progressive disease	Tolerance of MVA-MUC1-IL2 vaccine (TG4010) was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. 	N/A	N/A	N/A	N/A	N/A	 2003 Aug	 Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1   as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.	 J Gene Med	 BACKGROUND: The MUC1 protein is a highly glycosylated mucin normally found at the  apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1  is expressed, but heavily underglycosylated, in different human tumors. TG4010 is  a viral suspension of a recombinant vaccinia vector (MVA) containing DNA  sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This  product was developed for use as a vaccine in cancer patients whose tumors  express the MUC1 antigen. The objective of the present study was to determine the  safety of the product and to define the dose of TG4010 to be used in further  clinical trials. MATERIALS AND METHODS: Thirteen patients with different solid  tumors were treated by repeated intramuscular injection with increasing doses of   TG4010 in two separate phase I studies, one in Europe (Basel-CR) and one in the  United States (UCLA-RF): a total of 6 patients were treated at a dose of 5 x  10(6) pfu, 3 patients at 5 x 10(7) pfu, and 4 patients at 10(8) pfu. Safety,  efficacy, and different immunological tests were the endpoints of the study.  RESULTS: Tolerance of TG4010 was excellent, and side effects mainly consisted of   injection site pain and influenza-like symptoms. There was no apparent  detrimental effect of repeated injections of the vaccinia virus. Four of thirteen  evaluable patients showed stabilization of their disease for 6 to 9 months. One  lung cancer patient who was initially progressing after the first injections  later showed a marked decrease in the size of his metastases that lasted for 14  months. Some T cell proliferative immune responses were seen in five patients.  CONCLUSIONS: The administration of TG4010 was generally well tolerated in  patients with metastatic tumors, and transient disease stabilization was observed  in several patients, warranting further clinical studies with the product.CI  - Copyright 2003 John Wiley & Sons, Ltd.
CANIT0000015	12898638	Clinical research	MUC1-positive SCLC	Small cell lung carcinoma	EFO:0000702	Lung	IL2R (A2N4P8); MUC1 (P15941); 	IL2R; MUC1	MVA-MUC1-IL2 vaccine	N/A	Tumor vaccine	MVA-MUC1-IL2 vaccine (NCIT:C2241); 	1	N/A	A phase I clinical trial 	Progressive disease	Tolerance of MVA-MUC1-IL2 vaccine (TG4010) was excellent, and side effects mainly consisted of injection site pain and influenza-like symptoms. There was no apparent detrimental effect of repeated injections of the vaccinia virus. 	N/A	N/A	N/A	N/A	N/A	 2003 Aug	 Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1   as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.	 J Gene Med	 BACKGROUND: The MUC1 protein is a highly glycosylated mucin normally found at the  apical surface of mucin-secreting epithelial cells in many types of tissues. MUC1  is expressed, but heavily underglycosylated, in different human tumors. TG4010 is  a viral suspension of a recombinant vaccinia vector (MVA) containing DNA  sequences coding for the human MUC1 antigen and interleukin-2 (IL-2). This  product was developed for use as a vaccine in cancer patients whose tumors  express the MUC1 antigen. The objective of the present study was to determine the  safety of the product and to define the dose of TG4010 to be used in further  clinical trials. MATERIALS AND METHODS: Thirteen patients with different solid  tumors were treated by repeated intramuscular injection with increasing doses of   TG4010 in two separate phase I studies, one in Europe (Basel-CR) and one in the  United States (UCLA-RF): a total of 6 patients were treated at a dose of 5 x  10(6) pfu, 3 patients at 5 x 10(7) pfu, and 4 patients at 10(8) pfu. Safety,  efficacy, and different immunological tests were the endpoints of the study.  RESULTS: Tolerance of TG4010 was excellent, and side effects mainly consisted of   injection site pain and influenza-like symptoms. There was no apparent  detrimental effect of repeated injections of the vaccinia virus. Four of thirteen  evaluable patients showed stabilization of their disease for 6 to 9 months. One  lung cancer patient who was initially progressing after the first injections  later showed a marked decrease in the size of his metastases that lasted for 14  months. Some T cell proliferative immune responses were seen in five patients.  CONCLUSIONS: The administration of TG4010 was generally well tolerated in  patients with metastatic tumors, and transient disease stabilization was observed  in several patients, warranting further clinical studies with the product.CI  - Copyright 2003 John Wiley & Sons, Ltd.
CANIT0000016	14687994	Clinical research	Patients with chronic lymphatic leukemia (CLL), cell lines	Chronic lymphocytic leukemia	EFO:0000095	Blood and lymph nodes	DENDRITIC CELL (N/A); 	DENDRITIC CELL; 	MVA virus vaccine	UVC-irradiation	Tumor vaccine	MVA vaccine (NCIT:C1572); 	5	5	N/A	Dendritic cell viability is decreased after phagocytosis of apoptotic tumor cells induced by vaccinia virus infection.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2003 Dec	 Dendritic cell viability is decreased after phagocytosis of apoptotic tumor cells  induced by staurosporine or vaccinia virus infection.	 Haematologica	 BACKGROUND AND OBJECTIVES: Dendritic cells (DC) primed with tumor antigens can  effectively mediate the regression of a variety of established solid malignancies  in both murine and human models. Several experimental studies indicate that  apoptotic bodies are an optimal source of tumor antigens for ex vivo priming of  DC. However, the clinical use of killed tumor cells as a source of antigens will   require an optimal methodology to induce effective tumor cell apoptosis. DESIGN  AND METHODS: The goal of this study was to compare the efficiency of three agents  for inducing neoplastic B lymphocyte apoptosis; staurosporine, infection by  modified vaccinia (MVA) viral particles and ultraviolet C (UVC) radiation.  RESULTS: The three methods were finely tuned to induce apoptosis in more than 90%  of tumor cells after 24 hours of exposure. However, the viability of  monocyte-derived DC, loaded with B-cell tumor apoptotic bodies induced by  staurosporine or MVA viral particles, decreased dramatically within 48 hours  after phagocytosis of the killed neoplastic cells. The persistence of the  apoptosis-inducing agents in the apoptotic bodies and not in the tumor  supernatant, was responsible for the observed damage to DC viability. In  contrast, DC viability was not affected after uptake of tumor cells killed  through UVC-irradiation. Furthermore, B-lymphoblastic cell line (LCL)-specific T   cells were reactivated by DC loaded with apoptotic bodies induced by UVC-rays.  INTERPRETATION AND CONCLUSIONS: Since the method used to induce tumor cell  apoptosis might be detrimental to DC viability, these findings should be  considered when designing anticancer vaccination programs.
CANIT0000017	14687994	Clinical research	Patients with follicular lymphoma (FL), cell lines	Follicular lymphoma	MONDO:0018906	Blood and lymph nodes	DENDRITIC CELL (N/A); 	DENDRITIC CELL; 	Staurosporine	UVC-irradiation	Immune checkpoint therapy	Staurosporine (DB02010); 	5	5	N/A	Dendritic cell viability is decreased after phagocytosis of apoptotic tumor cells induced by staurosporine.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2003 Dec	 Dendritic cell viability is decreased after phagocytosis of apoptotic tumor cells  induced by staurosporine or vaccinia virus infection.	 Haematologica	 BACKGROUND AND OBJECTIVES: Dendritic cells (DC) primed with tumor antigens can  effectively mediate the regression of a variety of established solid malignancies  in both murine and human models. Several experimental studies indicate that  apoptotic bodies are an optimal source of tumor antigens for ex vivo priming of  DC. However, the clinical use of killed tumor cells as a source of antigens will   require an optimal methodology to induce effective tumor cell apoptosis. DESIGN  AND METHODS: The goal of this study was to compare the efficiency of three agents  for inducing neoplastic B lymphocyte apoptosis; staurosporine, infection by  modified vaccinia (MVA) viral particles and ultraviolet C (UVC) radiation.  RESULTS: The three methods were finely tuned to induce apoptosis in more than 90%  of tumor cells after 24 hours of exposure. However, the viability of  monocyte-derived DC, loaded with B-cell tumor apoptotic bodies induced by  staurosporine or MVA viral particles, decreased dramatically within 48 hours  after phagocytosis of the killed neoplastic cells. The persistence of the  apoptosis-inducing agents in the apoptotic bodies and not in the tumor  supernatant, was responsible for the observed damage to DC viability. In  contrast, DC viability was not affected after uptake of tumor cells killed  through UVC-irradiation. Furthermore, B-lymphoblastic cell line (LCL)-specific T   cells were reactivated by DC loaded with apoptotic bodies induced by UVC-rays.  INTERPRETATION AND CONCLUSIONS: Since the method used to induce tumor cell  apoptosis might be detrimental to DC viability, these findings should be  considered when designing anticancer vaccination programs.
CANIT0000018	15328176	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	TYRO (P14679); 	TYRO; 	MVA-hTyr-transduced dendritic cells	N/A	Tumor vaccine	Dendritic cell based MVA-hTyr (NCIT:C28310); 	6	N/A	A phase I clinical trial 	Vaccination with MVA-hTyr-transduced dendritic cells is well tolerated, can possibly produce clinical responses, and activates tyrosinase- and vaccinia virus-specific T cells in vivo. These data suggest a broad utility of the MVA vector for targeting tumor-associated antigens to dendritic cells for tumor immunotherapy.	Treatment was well tolerated, except for low-grade fever (three of six patients), mild erythema at injection site (five of six), and vitiligo (two of six). 	N/A	N/A	N/A	N/A	N/A	 2004 Aug 15	 Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced,  CD34(+)-derived dendritic cell vaccination: a phase I trial in metastatic  melanoma.	 Clin Cancer Res	 PURPOSE: Six American Joint Committee on Cancer stage IV melanoma patients were  enrolled into a Phase I study of vaccination with autologous CD34(+)-derived  dendritic cells transduced with a modified vaccinia Ankara virus encoding human  tyrosinase gene (MVA-hTyr). EXPERIMENTAL DESIGN: Patients received a first  intravenous injection of 1 x 10(8) MVA-hTyr-transduced dendritic cells, followed   by three s.c. injections at a 14-day interval. RESULTS: Treatment was well  tolerated, except for low-grade fever (three of six patients), mild erythema at  injection site (five of six), and vitiligo (two of six). A partial response,  involving shrinkage of an s.c. nodule, later surgically removed, was observed in   1 patient, who then remained disease-free (>850 days). By human lymphocyte  antigen tetramer analysis, significant and often long-lasting increases in  frequency of T cells directed to tyrosinase(368-376) but not to gp100(209-217)  were documented in periphery of 4 of 5 HLA-A*0201+ patients, a few days after  vaccine administration. In addition, maturation phenotype of tyrosinase-specific   T cell shifted toward the T effector memory/T terminally differentiate stages  (CCR7(-)CD45RA(-/+)) in synchrony with the T-cell frequency peaks. By  enzyme-linked immunospot in peripheral blood of five HLA-A*0201+ patients, we  found that the vaccine could induce interferon gamma-releasing effector cells  directed to HLA-A*0201/tyrosinase(368-376) and to vaccinia virus  HLA-A*0201/H3L(184-192) epitopes. Moreover, an interferon gamma response after  vaccination was elicited even against the HLA-DRB1-1501/tyrosinase(386-406)  epitope in one out of two HLA-A* DRB1-01501+ patients. CONCLUSIONS: These results  indicate that vaccination with MVA-hTyr-transduced dendritic cells is well  tolerated, can possibly produce clinical responses, and activates tyrosinase- and  vaccinia virus-specific T cells in vivo. These data suggest a broad utility of  the MVA vector for targeting tumor-associated antigens to dendritic cells for  tumor immunotherapy.
CANIT0000019	15627214	Clinical research	Stage II melanoma	Melanoma	EFO:0000756	Skin	TYRO (P14679); 	TYRO; 	MVA-hTyr-transduced dendritic cells	N/A	Tumor vaccine	Dendritic cell based MVA-hTyr (NCIT:C28310); 	20	N/A	A phase I clinical trial 	We presume that modification of the antigen and/or prime-boost vaccination applying different approaches to antigen delivery may be required to induce an effective tyrosinase-specific immune response.	The delivery of MVA-hTyr was safe and did not cause any side effects above grade 2.	N/A	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	Frequency of MVA-specific CD4(+) T-cell 	Gene expression signature on/in immune cell	 2005 May	 A phase I vaccination study with tyrosinase in patients with stage II melanoma  using recombinant modified vaccinia virus Ankara (MVA-hTyr).	 Cancer Immunol Immunother	 A significant percentage of patients with stage II melanomas suffer a relapse  after surgery and therefore need the development of adjuvant therapies. In the  study reported here, safety and immunological response were analyzed after  vaccination in an adjuvant setting with recombinant modified vaccinia virus  Ankara carrying the cDNA for human tyrosinase (MVA-hTyr). A total of 20 patients   were included and vaccinated three times at 4-week intervals with 5x10(8) IU of  MVA-hTyr each time. The responses to the viral vector, to known HLA class  I-restricted tyrosinase peptides, and to dendritic cells transfected with  tyrosinase mRNA, were investigated by ELISpot assay on both ex vivo T cells and  on T cells stimulated in vitro prior to testing. The delivery of MVA-hTyr was  safe and did not cause any side effects above grade 2. A strong response to the  viral vector was achieved, indicated by an increase in the frequency of  MVA-specific CD4+ and CD8+ T cells and an increase in virus-specific antibody  titers. However, no tyrosinase-specific T-cell or antibody response was observed   with MVA-hTyr in any of the vaccinated patients. Although MVA-hTyr provides a  safe and effective antigen-delivery system, it does not elicit a measurable  immune response to its transgene product in patients with stage II melanoma after  repeated combined intradermal and subcutaneous vaccination. We presume that  modification of the antigen and/or prime-boost vaccination applying different  approaches to antigen delivery may be required to induce an effective  tyrosinase-specific immune response.
CANIT0000020	15627214	Clinical research	Stage II melanoma	Melanoma	EFO:0000756	Skin	TYRO (P14679); 	TYRO; 	MVA-hTyr-transduced dendritic cells	N/A	Tumor vaccine	Dendritic cell based MVA-hTyr (NCIT:C28310); 	20	N/A	A phase I clinical trial 	We presume that modification of the antigen and/or prime-boost vaccination applying different approaches to antigen delivery may be required to induce an effective tyrosinase-specific immune response.	The delivery of MVA-hTyr was safe and did not cause any side effects above grade 2.	N/A	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	Frequency of MVA-specific CD8(+) T-cell 	Gene expression signature on/in immune cell	 2005 May	 A phase I vaccination study with tyrosinase in patients with stage II melanoma  using recombinant modified vaccinia virus Ankara (MVA-hTyr).	 Cancer Immunol Immunother	 A significant percentage of patients with stage II melanomas suffer a relapse  after surgery and therefore need the development of adjuvant therapies. In the  study reported here, safety and immunological response were analyzed after  vaccination in an adjuvant setting with recombinant modified vaccinia virus  Ankara carrying the cDNA for human tyrosinase (MVA-hTyr). A total of 20 patients   were included and vaccinated three times at 4-week intervals with 5x10(8) IU of  MVA-hTyr each time. The responses to the viral vector, to known HLA class  I-restricted tyrosinase peptides, and to dendritic cells transfected with  tyrosinase mRNA, were investigated by ELISpot assay on both ex vivo T cells and  on T cells stimulated in vitro prior to testing. The delivery of MVA-hTyr was  safe and did not cause any side effects above grade 2. A strong response to the  viral vector was achieved, indicated by an increase in the frequency of  MVA-specific CD4+ and CD8+ T cells and an increase in virus-specific antibody  titers. However, no tyrosinase-specific T-cell or antibody response was observed   with MVA-hTyr in any of the vaccinated patients. Although MVA-hTyr provides a  safe and effective antigen-delivery system, it does not elicit a measurable  immune response to its transgene product in patients with stage II melanoma after  repeated combined intradermal and subcutaneous vaccination. We presume that  modification of the antigen and/or prime-boost vaccination applying different  approaches to antigen delivery may be required to induce an effective  tyrosinase-specific immune response.
CANIT0000021	1591717	Clinical research	Colorectal cancer patients	Colorectal cancer	EFO:0005842	Intestines	IL2R (A2N4P8); TLR3 (O15455); 	IL2R; TLR3	Poly-ICLC plus IL2	IL2	Tumor vaccine plus Immune cytokine	IL2 (NCIT:C24498); poly-ICLC (NCIT:C1198); 	5	25	A phase IB clinical trial 	This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 1992 Jun 1	 Polyinosinic-polycytidylic acid complexed with poly-L-lysine and  carboxymethylcellulose in combination with interleukin 2 in patients with cancer:  clinical and immunological effects.	 Cancer Res	 We have performed a phase IB study of polyinosinic-polycytidylic acid complexed  with poly-L-lysine and carboxymethylcellulose (poly-ICLC) in combination with  interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received   weekly or biweekly poly-ICLC by i.m. injection, at doses ranging from 0.01 to 1.0  mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with  biweekly i.m. poly-ICLC in combination with IL-2 (3 x 10(6) units/m2) given i.v.   by 24-h continuous infusion twice weekly, using a portable infusion pump. No  objective tumor responses were observed. Toxicity was moderate at all poly-ICLC  doses tested and increased only slightly following the addition of IL-2. No  increases in peripheral blood natural killer (NK) activity were observed after  treatment with poly-ICLC alone. However, high dose poly-ICLC (greater than or  equal to 0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than  that seen using the same dose of IL-2 in combination with lower poly-ICLC doses.   Increases in the number and percentage of CD56+ cells were evident only after  initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the  majority of patients, these increases were preferentially associated with the  subset of CD56+ cells coexpressing CD8, while the CD56+/CD16+ population was  elevated to a lesser extent. Moderate increases in serum neopterin levels and  2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells  were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No  induction of alpha or gamma interferon was detected. This study shows that the  addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance   NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity  without increases in the dose and, therefore, the toxicity of IL-2 treatment.
CANIT0000022	1591717	Clinical research	Melanoma patients	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); TLR3 (O15455); 	IL2R; TLR3	Poly-ICLC plus IL2	IL2	Tumor vaccine plus Immune cytokine	IL2 (NCIT:C24498); poly-ICLC (NCIT:C1198); 	6	25	A phase IB clinical trial 	This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 1992 Jun 1	 Polyinosinic-polycytidylic acid complexed with poly-L-lysine and  carboxymethylcellulose in combination with interleukin 2 in patients with cancer:  clinical and immunological effects.	 Cancer Res	 We have performed a phase IB study of polyinosinic-polycytidylic acid complexed  with poly-L-lysine and carboxymethylcellulose (poly-ICLC) in combination with  interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received   weekly or biweekly poly-ICLC by i.m. injection, at doses ranging from 0.01 to 1.0  mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with  biweekly i.m. poly-ICLC in combination with IL-2 (3 x 10(6) units/m2) given i.v.   by 24-h continuous infusion twice weekly, using a portable infusion pump. No  objective tumor responses were observed. Toxicity was moderate at all poly-ICLC  doses tested and increased only slightly following the addition of IL-2. No  increases in peripheral blood natural killer (NK) activity were observed after  treatment with poly-ICLC alone. However, high dose poly-ICLC (greater than or  equal to 0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than  that seen using the same dose of IL-2 in combination with lower poly-ICLC doses.   Increases in the number and percentage of CD56+ cells were evident only after  initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the  majority of patients, these increases were preferentially associated with the  subset of CD56+ cells coexpressing CD8, while the CD56+/CD16+ population was  elevated to a lesser extent. Moderate increases in serum neopterin levels and  2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells  were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No  induction of alpha or gamma interferon was detected. This study shows that the  addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance   NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity  without increases in the dose and, therefore, the toxicity of IL-2 treatment.
CANIT0000023	1591717	Clinical research	Renal cell patients	Renal cell carcinoma	EFO:0000681	Kidney	IL2R (A2N4P8); TLR3 (O15455); 	IL2R; TLR3	Poly-ICLC plus IL2	IL2	Tumor vaccine plus Immune cytokine	IL2 (NCIT:C24498); poly-ICLC (NCIT:C1198); 	5	25	A phase IB clinical trial 	This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 1992 Jun 1	 Polyinosinic-polycytidylic acid complexed with poly-L-lysine and  carboxymethylcellulose in combination with interleukin 2 in patients with cancer:  clinical and immunological effects.	 Cancer Res	 We have performed a phase IB study of polyinosinic-polycytidylic acid complexed  with poly-L-lysine and carboxymethylcellulose (poly-ICLC) in combination with  interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received   weekly or biweekly poly-ICLC by i.m. injection, at doses ranging from 0.01 to 1.0  mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with  biweekly i.m. poly-ICLC in combination with IL-2 (3 x 10(6) units/m2) given i.v.   by 24-h continuous infusion twice weekly, using a portable infusion pump. No  objective tumor responses were observed. Toxicity was moderate at all poly-ICLC  doses tested and increased only slightly following the addition of IL-2. No  increases in peripheral blood natural killer (NK) activity were observed after  treatment with poly-ICLC alone. However, high dose poly-ICLC (greater than or  equal to 0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than  that seen using the same dose of IL-2 in combination with lower poly-ICLC doses.   Increases in the number and percentage of CD56+ cells were evident only after  initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the  majority of patients, these increases were preferentially associated with the  subset of CD56+ cells coexpressing CD8, while the CD56+/CD16+ population was  elevated to a lesser extent. Moderate increases in serum neopterin levels and  2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells  were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No  induction of alpha or gamma interferon was detected. This study shows that the  addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance   NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity  without increases in the dose and, therefore, the toxicity of IL-2 treatment.
CANIT0000024	16456551	Clinical research	High-grade lesions (CIN 2 and CIN 3) associated with oncogenic papillomavirus	Cervical adenocarcinoma	EFO:0001416	Cervix	N/A (N/A); 	N/A; 	MVA E2 recombinant vaccinia virus	Conization	Tumor vaccine	MVA-HPV16 E2 vaccine (NCIT:C2419); 	34	20	A phase II clinical trial	Therapeutic vaccination with MVA E2 proved to be very effective in stimulating the immune system against papillomavirus, and in generating regression of high-grade lesion.	N/A	N/A	N/A	DNA viral load (NCIT:C51952); 	DNA viral load	Microbiota	 2006 Jun	 Regression of papilloma high-grade lesions (CIN 2 and CIN 3) is stimulated by  therapeutic vaccination with MVA E2 recombinant vaccine.	 Cancer Gene Ther	 Human papillomavirus (HPV) is the etiologic agent for cervical cancer. In Mexico,  a women dies every 2 h, and since 1990 the statistics have shown that the numbers  of deaths are increasing. We conducted a phase II clinical trial to evaluate the   potential use of the MVA E2 recombinant vaccinia virus in treating high-grade  lesions (CIN 2 and CIN 3) associated with oncogenic papillomavirus. Fifty-four  female patients with high degree lesions were treated either with an MVA E2  therapeutic vaccine or with conization. Thirty-four women received the  therapeutic vaccine, at a total of 10(7) virus particles per dose injected  directly into the uterus once every week over a 6-week period. Twenty control  patients were treated with conization. By colposcopy, 19 patients out of 34  showed no lesion, in three patients the lesions were reduced by 85-90%, in eight   other lesions had reduced by 60%, and in four more patients, they were reduced by  25%. Histological analysis showed total elimination of high-grade lesions in 20  out of 34 patients after treatment with MVA E2. Eleven patients had a 50%  reduction in lesion size. In two other patients, the lesion was reduced to CIN 2   and in one more patient the lesion was reduced to low grade (CIN 1). All patients  developed antibodies against the MVA E2 vaccine, and generated a specific  cytotoxic response against papilloma-transformed cells. DNA viral load was  significantly reduced in MVA E2-treated patients. Conization eliminated the  lesions in 80% of the patients, but patients did not develop cytotoxic activity  specific against cancer cells and did not eliminate the papillomavirus. In  addition, three patients treated with conization had recurrence of lesions 1 year  later. These results show that therapeutic vaccination with MVA E2 proved to be  very effective in stimulating the immune system against papillomavirus, and in  generating regression of high-grade lesion.
CANIT0000025	16740766	Clinical research	Metastatic colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine	N/A	Tumor vaccine	MVA-5T4 vaccine (NCIT:C49087); 	17	N/A	An open-label phase I/II clinical trial	Vaccination with TroVax is safe and well tolerated and that immune responses to 5T4 can be induced without any evidence of autoimmune toxicity. Furthermore, 5T4-specific antibody responses correlate with evidence of disease control.	Without any evidence of autoimmune toxicity	N/A	N/A	N/A	N/A	N/A	 2006 Jun 1	 Vaccination of colorectal cancer patients with modified vaccinia Ankara  delivering the tumor antigen 5T4 (TroVax) induces immune responses which  correlate with disease control: a phase I/II trial.	 Clin Cancer Res	 PURPOSE: The highly attenuated strain of vaccinia virus, modified vaccinia Ankara  (MVA), encoding the tumor antigen 5T4 (termed TroVax), has been evaluated in an  open-label phase I/II study in colorectal cancer patients. The primary objectives  were to assess the safety and immunogenicity of ascending doses of TroVax and to   determine the biodistribution of the vector. EXPERIMENTAL DESIGN: TroVax was  given to 22 patients with metastatic colorectal cancer. Seventeen patients  received doses of TroVax ranging from 5 x 10(7) up to 5 x 10(8) plaque-forming  units at 0, 4, and 8 weeks and were considered to be evaluable for assessment of   immunologic responses. Both antibody and cellular responses specific for the  tumor antigen 5T4 and the viral vector were monitored throughout the study.  RESULTS: TroVax was well tolerated in all patients with no serious adverse events  attributed to vaccination. Of 17 evaluable patients, 16 showed 5T4-specific  cellular responses whereas 14 had detectable antibody levels following  vaccination. TroVax was able to boost 5T4-specific immune responses in the  presence of MVA neutralizing antibodies. Periods of disease stabilization ranging  from 3 to 18 months were observed in five patients, all of whom mounted  5T4-specific immune responses. Furthermore, statistical analysis showed a  positive association between the development of a 5T4 (but not MVA) antibody  response and patient survival or time to disease progression. CONCLUSION: These  data indicate that vaccination with TroVax is safe and well tolerated and that  immune responses to 5T4 can be induced without any evidence of autoimmune  toxicity. Furthermore, 5T4-specific antibody responses correlate with evidence of  disease control.
CANIT0000026	17102977	Basic research	Prostate cancer	Prostate cancer	MONDO:0008315	Prostate	PPAP (P15309); 	PPAP; 	Prostatic acid phosphatase vaccine	N/A	Tumor vaccine	Prostatic acid phosphatase vaccine (NCIT:C74064); 	Cell lines/ animal models	N/A	Basic research	DNA vaccines provide a safe and effective method of generating  prostate antigen-specific T cell responses. These findings support the  investigation of PAP-specific DNA vaccines in human clinical trials.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2007 Jun	 Plasmid DNA vaccine encoding prostatic acid phosphatase is effective in eliciting  autologous antigen-specific CD8+ T cells.	 Cancer Immunol Immunother	 Prostatic acid phosphatase (PAP) is a prostate cancer tumor antigen and a  prostate-specific protein shared by rats and humans. Previous studies indicated  that Copenhagen rats immunized with a recombinant vaccinia virus expressing human  PAP (hPAP) developed PAP-specific cytotoxic T cells (CTL) with cross reactivity  to rat PAP (rPAP) and evidence of prostate inflammation. Viral delivery of  vaccine antigens is an active area of clinical investigation. However, a  potential difficulty with viral-based immunizations is that immune responses  elicited to the viral vector might limit the possibility of multiple  immunizations. In this paper, we investigate the ability of another genetic  immunization method, a DNA vaccine encoding PAP, to elicit antigen-specific CD8+   T cell immune responses. Specifically, Lewis rats were immunized with either a  plasmid DNA-based (pTVG-HP) or vaccinia-based (VV-HP) vaccine each encoding hPAP.  We determined that rats immunized with a DNA vaccine encoding hPAP developed a  Th1-biased immune response as indicated by proliferating PAP-specific CD4+ and  CD8+ cells and IFNG production. Rats immunized with vaccinia virus encoding  PAP did not develop a PAP-specific response unless boosted with a heterologous  vaccination scheme. Most importantly, multiple immunizations with a DNA vaccine  encoding the rat PAP homologue (pTVG-RP) could overcome peripheral self-tolerance  against rPAP and generate a Th1-biased antigen-specific CD4+ and CD8+ T cell  response. Overall, DNA vaccines provide a safe and effective method of generating  prostate antigen-specific T cell responses. These findings support the  investigation of PAP-specific DNA vaccines in human clinical trials.
CANIT0000027	17219151	Basic research	Balb/cJ and Hupki mice , A p53 null murine mammary adenocarcinoma cell line	Breast adenocarcinoma	EFO:0000304	Breast	P53 (P04637); 	P53; 	MVA-P53 vaccine	N/A	Tumor vaccine	MVA-P53 vaccine (NCIT:C116868); 	Cell lines/ animal models	N/A	Basic research	These studies demonstrate the potential of MVAp53 to overcome tolerance to p53 for cancer immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2007 Aug	 An MVA vaccine overcomes tolerance to human p53 in mice and humans.	 Cancer Immunol Immunother	 BACKGROUND: The cellular regulatory protein p53 is overexpressed by almost 50% of  all malignancies making it an attractive target for a vaccine approach to cancer.  A number of immunotherapy approaches targeting p53 have been evaluated  successfully in murine models, but translation of these preclinical findings to  the clinic has been unsuccessful. Prior studies in our laboratory employing  murine models demonstrated that a modified vaccinia virus Ankara (MVA) vaccine  expressing murine p53 could stimulate p53 specific immunity. Systemic  administration of the MVA vaccine was able to effect the rejection of established  tumors. To better understand the immunologic mechanisms that underlie the vaccine  function of human p53, we utilized a murine model in which the murine germ line  copy of p53 was replaced with a modified human one. These mice, referred to as  Hupki, were evaluated as a tolerant model to explore the capacity of MVA  expressing human p53 to overcome tolerance and reject human p53-expressing  tumors. RESULTS: MVAp53 immunization of Hupki mice resulted in the generation of   p53-specific CD8(+) T cells and the rejection of a highly aggressive murine  mammary carcinoma cell line 4T1(H-2d) transfected with human p53 (4T1p53). An  immunologic correlate of tumor protection was evaluated utilizing an overlapping   peptide library spanning the full length of human p53. This reagent was also used  in combination with MVAp53 to stimulate p53-specific CD8(+) T cell responses in  cancer patients. CONCLUSION: These studies demonstrate the potential of MVAp53 to  overcome tolerance to p53 for cancer immunotherapy.
CANIT0000028	17289891	Clinical research	Patients with colon cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	A pilot clinical trial 	Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. 	Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed.	N/A	N/A	N/A	N/A	N/A	 2007 Feb 1	 A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with  advanced malignancy.	 Clin Cancer Res	 PURPOSE: Eleven patients with progressive advanced malignancy after  administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal   antibody (ipilimumab). The primary end point was to determine drug toxicity.  Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of  CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.  EXPERIMENTAL DESIGN: Three patients with colon cancer, four with non-Hodgkin's  lymphoma, and four with prostate cancer were treated. The first dose was given at  3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total  of four cycles. RESULTS: Tumor regression was observed in two patients with  lymphoma; one of which obtained a partial response of 14-month duration.  Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One  drug-related grade 3 toxicity was observed. One patient died within 30 days of  treatment due to progressive colon cancer. No increase in vaccine-specific T-cell  responses was observed after therapy. Tregs as detected by expression of  CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above  baseline values at the time of the next infusion. CONCLUSIONS: Ipilimumab  treatment depressed Treg numbers at early time points in the treatment cycle but   was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in  these patients previously treated with a variety of investigational anticancer  vaccines. A partial response was observed in one patient with follicular  lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular  lymphoma is currently ongoing.
CANIT0000029	17671134	Clinical research	Colorectal cance	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine plus 5-fluorouracil	MVA-5T4 vaccine	Tumor vaccine plus Chemotherapy	MVA-5T4 vaccine (NCIT:C49087); 5-fluorouracil (DB00544); 	11	11	An open-label  phase II clinical trial	Potent 5T4-specific cellular and/or antibody responses were induced in all evaluable patients and were still detectable during the period in which chemotherapy was administered. These results suggest that TroVax can be added to chemotherapy regimens without any evidence of enhanced toxicity or reduced immunologic efficacy and may provide additional clinical benefit. 	Administration of TroVax alongside 5-fluorouracil, folinic acid, and oxaliplatin was safe and well tolerated with no serious adverse events attributed to TroVax.	N/A	N/A	MVA-5T4 response (NCIT:C49087); 	MVA-5T4 specific immune responses	Immune response	 2007 Aug 1	 Vaccination of colorectal cancer patients with modified vaccinia ankara encoding   the tumor antigen 5T4 (TroVax) given alongside chemotherapy induces potent immune  responses.	 Clin Cancer Res	 PURPOSE: The attenuated strain of vaccinia virus, modified vaccinia Ankara (MVA)   encoding the tumor antigen 5T4 (TroVax), has been evaluated in an open-label  phase II study in metastatic colorectal cancer patients. The primary objective  was to assess the safety and immunogenicity of TroVax injected before, during,  and after treatment with cycles of 5-fluorouracil, folinic acid, and oxaliplatin.  EXPERIMENTAL DESIGN: TroVax was administered to 17 patients with metastatic  colorectal cancer. In total, 11 patients were considered to be evaluable for  assessment of immunologic responses having received a total of six injections of   TroVax, administered before, during, and following completion of chemotherapy.  Antibody and cellular responses specific for 5T4 and MVA were monitored  throughout the study. RESULTS: Administration of TroVax alongside 5-fluorouracil,  folinic acid, and oxaliplatin was safe and well tolerated with no serious adverse  events attributed to TroVax. Ten of the 11 evaluable patients mounted  5T4-specific antibody responses with titers ranging from 10 to >1,000. IFNG  enzyme-linked immunospot responses specific for 5T4 were detected in 10 patients   with precursor frequencies exceeding 1 in 1,000 peripheral blood mononuclear  cells in 4 patients. Of the 11 evaluable patients, 6 had complete or partial  responses. 5T4-specific immune responses, but not MVA-specific immune responses,   correlated with clinical benefit. CONCLUSIONS: Potent 5T4-specific cellular  and/or antibody responses were induced in all evaluable patients and were still  detectable during the period in which chemotherapy was administered. These  results suggest that TroVax can be added to chemotherapy regimens without any  evidence of enhanced toxicity or reduced immunologic efficacy and may provide  additional clinical benefit.
CANIT0000030	17671134	Clinical research	Colorectal cance	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine plus folinic acid	MVA-5T4 vaccine	Tumor vaccine plus Chemotherapy	 MVA-5T4 vaccine (NCIT:C49087); folinic acid (DB00650); 	11	11	An open-label  phase II clinical trial	Potent 5T4-specific cellular and/or antibody responses were induced in all evaluable patients and were still detectable during the period in which chemotherapy was administered. These results suggest that TroVax can be added to chemotherapy regimens without any evidence of enhanced toxicity or reduced immunologic efficacy and may provide additional clinical benefit. 	Administration of TroVax alongside 5-fluorouracil, folinic acid, and oxaliplatin was safe and well tolerated with no serious adverse events attributed to TroVax.	N/A	N/A	MVA-5T4 response (NCIT:C49087); 	MVA-5T4 specific immune responses	Immune response	 2007 Aug 1	 Vaccination of colorectal cancer patients with modified vaccinia ankara encoding   the tumor antigen 5T4 (TroVax) given alongside chemotherapy induces potent immune  responses.	 Clin Cancer Res	 PURPOSE: The attenuated strain of vaccinia virus, modified vaccinia Ankara (MVA)   encoding the tumor antigen 5T4 (TroVax), has been evaluated in an open-label  phase II study in metastatic colorectal cancer patients. The primary objective  was to assess the safety and immunogenicity of TroVax injected before, during,  and after treatment with cycles of 5-fluorouracil, folinic acid, and oxaliplatin.  EXPERIMENTAL DESIGN: TroVax was administered to 17 patients with metastatic  colorectal cancer. In total, 11 patients were considered to be evaluable for  assessment of immunologic responses having received a total of six injections of   TroVax, administered before, during, and following completion of chemotherapy.  Antibody and cellular responses specific for 5T4 and MVA were monitored  throughout the study. RESULTS: Administration of TroVax alongside 5-fluorouracil,  folinic acid, and oxaliplatin was safe and well tolerated with no serious adverse  events attributed to TroVax. Ten of the 11 evaluable patients mounted  5T4-specific antibody responses with titers ranging from 10 to >1,000. IFNG  enzyme-linked immunospot responses specific for 5T4 were detected in 10 patients   with precursor frequencies exceeding 1 in 1,000 peripheral blood mononuclear  cells in 4 patients. Of the 11 evaluable patients, 6 had complete or partial  responses. 5T4-specific immune responses, but not MVA-specific immune responses,   correlated with clinical benefit. CONCLUSIONS: Potent 5T4-specific cellular  and/or antibody responses were induced in all evaluable patients and were still  detectable during the period in which chemotherapy was administered. These  results suggest that TroVax can be added to chemotherapy regimens without any  evidence of enhanced toxicity or reduced immunologic efficacy and may provide  additional clinical benefit.
CANIT0000031	17671134	Clinical research	Colorectal cance	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine plus oxaliplatin	MVA-5T4 vaccine	Tumor vaccine plus Chemotherapy	MVA-5T4 vaccine (NCIT:C49087); oxaliplatin (DB00526); 	11	11	An open-label  phase II clinical trial	Potent 5T4-specific cellular and/or antibody responses were induced in all evaluable patients and were still detectable during the period in which chemotherapy was administered. These results suggest that TroVax can be added to chemotherapy regimens without any evidence of enhanced toxicity or reduced immunologic efficacy and may provide additional clinical benefit. 	Administration of TroVax alongside 5-fluorouracil, folinic acid, and oxaliplatin was safe and well tolerated with no serious adverse events attributed to TroVax.	N/A	N/A	MVA-5T4 response (NCIT:C49087); 	MVA-5T4 specific immune responses	Immune response	 2007 Aug 1	 Vaccination of colorectal cancer patients with modified vaccinia ankara encoding   the tumor antigen 5T4 (TroVax) given alongside chemotherapy induces potent immune  responses.	 Clin Cancer Res	 PURPOSE: The attenuated strain of vaccinia virus, modified vaccinia Ankara (MVA)   encoding the tumor antigen 5T4 (TroVax), has been evaluated in an open-label  phase II study in metastatic colorectal cancer patients. The primary objective  was to assess the safety and immunogenicity of TroVax injected before, during,  and after treatment with cycles of 5-fluorouracil, folinic acid, and oxaliplatin.  EXPERIMENTAL DESIGN: TroVax was administered to 17 patients with metastatic  colorectal cancer. In total, 11 patients were considered to be evaluable for  assessment of immunologic responses having received a total of six injections of   TroVax, administered before, during, and following completion of chemotherapy.  Antibody and cellular responses specific for 5T4 and MVA were monitored  throughout the study. RESULTS: Administration of TroVax alongside 5-fluorouracil,  folinic acid, and oxaliplatin was safe and well tolerated with no serious adverse  events attributed to TroVax. Ten of the 11 evaluable patients mounted  5T4-specific antibody responses with titers ranging from 10 to >1,000. IFNG  enzyme-linked immunospot responses specific for 5T4 were detected in 10 patients   with precursor frequencies exceeding 1 in 1,000 peripheral blood mononuclear  cells in 4 patients. Of the 11 evaluable patients, 6 had complete or partial  responses. 5T4-specific immune responses, but not MVA-specific immune responses,   correlated with clinical benefit. CONCLUSIONS: Potent 5T4-specific cellular  and/or antibody responses were induced in all evaluable patients and were still  detectable during the period in which chemotherapy was administered. These  results suggest that TroVax can be added to chemotherapy regimens without any  evidence of enhanced toxicity or reduced immunologic efficacy and may provide  additional clinical benefit.
CANIT0000032	17289891	Clinical research	Patients with non-Hodgkin's lymphoma	Non-hodgkins lymphoma	EFO:0005952	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	4	N/A	A pilot clinical trial 	Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma.	Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed.	N/A	N/A	N/A	N/A	N/A	 2007 Feb 1	 A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with  advanced malignancy.	 Clin Cancer Res	 PURPOSE: Eleven patients with progressive advanced malignancy after  administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal   antibody (ipilimumab). The primary end point was to determine drug toxicity.  Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of  CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.  EXPERIMENTAL DESIGN: Three patients with colon cancer, four with non-Hodgkin's  lymphoma, and four with prostate cancer were treated. The first dose was given at  3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total  of four cycles. RESULTS: Tumor regression was observed in two patients with  lymphoma; one of which obtained a partial response of 14-month duration.  Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One  drug-related grade 3 toxicity was observed. One patient died within 30 days of  treatment due to progressive colon cancer. No increase in vaccine-specific T-cell  responses was observed after therapy. Tregs as detected by expression of  CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above  baseline values at the time of the next infusion. CONCLUSIONS: Ipilimumab  treatment depressed Treg numbers at early time points in the treatment cycle but   was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in  these patients previously treated with a variety of investigational anticancer  vaccines. A partial response was observed in one patient with follicular  lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular  lymphoma is currently ongoing.
CANIT0000033	17822323	Basic research	The metastatic murine lung tumour (A9) spontaneously arose from the primary tumour cells (TC1) (mice bearing HPV16 induced tumors )	Lung carcinoma	EFO:0001071	Lung	GM-CSF (P04141); 	GM-CSF; 	MVA-GM-CSF plus E7GGG.GUS	N/A	Tumor vaccine	HPV16 E7 with  E.coli B-glucuronidase DNA vaccine (NCIT:C39619); MVA-GM-CSF vaccine (NCIT:C2674); 	Cell lines/ animal models	N/A	Basic research	Delivery of MVA-GM-CSF changed the local tumor microenvironment and rendered tumors more attractive and better accessible to effector T cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	CD3 (P07766); T-Lymphocyte (NCIT:C12476); 	Intratumoral CD3(+) T-cell counts	Gene expression signature on/in immune cell	2007	 Combination of intratumoral injections of vaccinia virus MVA expressing GM-CSF  and immunization with DNA vaccine prolongs the survival of mice bearing HPV16  induced tumors with downregulated expression of MHC class I molecules.	 Neoplasma	 Downregulation of MHC class I molecules is believed to be often the cause of  tumor immune escape and at the same time it is the major obstacle to T-cell based  immunotherapy of tumors. In our experimental model, the C57BL/6 mice bearing  tumors induced by TC-1/A9 cells characterized by expression of HPV16 oncogenes  and downregulation of H-2b molecules were immunized with highly immunogenic  E7GGG.GUS DNA vaccine expressing the fused gene of modified HPV16 E7 (E7GGG) with  E.coli beta-glucuronidase (GUS). The DNA vaccine was administered by gene gun on   days 7 and 14 after s.c. injection of tumor cells. The tumors in situ were  injected with recombinant vaccinia virus MVA expressing the gene for murine  granulocyte-macrophage colony-stimulating factor (MVA-GM-CSF). Two doses of the  DNA vaccine combined with at least two consecutive local treatments with  MVA-GM-CSF were able to inhibit significantly the growth of tumors. We have shown  by ELISPOT-IFNG that in situ expression of the GM-CSF gene did not enhance  the E7 specific systemic Tcell response. We found that local injections of  MVA-GM-CSF induced an increase of intratumoral CD3+ T cell counts and that the  DNA vaccination resulted in up-regulation of MHC type I molecules on tumor cells   in vivo. We suppose that i.t. delivery of MVA-GM-CSF changed the local tumor  microenvironment and rendered tumors more attractive and better accessible to  effector T cells.
CANIT0000034	17289891	Clinical research	Patients with prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	4	N/A	A pilot clinical trial 	Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. 	Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed.	N/A	N/A	N/A	N/A	N/A	 2007 Feb 1	 A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with  advanced malignancy.	 Clin Cancer Res	 PURPOSE: Eleven patients with progressive advanced malignancy after  administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal   antibody (ipilimumab). The primary end point was to determine drug toxicity.  Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of  CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.  EXPERIMENTAL DESIGN: Three patients with colon cancer, four with non-Hodgkin's  lymphoma, and four with prostate cancer were treated. The first dose was given at  3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total  of four cycles. RESULTS: Tumor regression was observed in two patients with  lymphoma; one of which obtained a partial response of 14-month duration.  Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One  drug-related grade 3 toxicity was observed. One patient died within 30 days of  treatment due to progressive colon cancer. No increase in vaccine-specific T-cell  responses was observed after therapy. Tregs as detected by expression of  CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above  baseline values at the time of the next infusion. CONCLUSIONS: Ipilimumab  treatment depressed Treg numbers at early time points in the treatment cycle but   was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in  these patients previously treated with a variety of investigational anticancer  vaccines. A partial response was observed in one patient with follicular  lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular  lymphoma is currently ongoing.
CANIT0000035	17982122	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus peptide vaccinations	Intra-patient dose escalation of ipilimumab and randomized to receive peptides in accordance with HLA-A*0201 status	Immune checkpoint therapy plus Tumor vaccine 	Peptide-based vaccines (NCIT:C120475); ipilimumab (DB06186); 	54	85	N/A	In patients with metastatic melanoma, ipilimumab can induce durable objective clinical responses, which are related to the induction of immune-related adverse events.	The majority of patients (62%, 86 of 139) developed some form of IRAE, which was associated with a greater probability of objective antitumor response (P = 0.0004); all patients with CR had more severe IRAEs. There were no treatment-related deaths.	N/A	N/A	N/A	N/A	N/A	 2007 Nov 15	 Prognostic factors related to clinical response in patients with metastatic  melanoma treated by CTL-associated antigen-4 blockade.	 Clin Cancer Res	 PURPOSE: CTL-associated antigen 4 (CTLA-4) can inhibit T-cell activation and  helps maintain peripheral self-tolerance. Previously, we showed immune-related  adverse events (IRAE) and objective, durable clinical responses in patients with   metastatic melanoma treated with CTLA-4 blockade. We have now treated 139  patients in two trials and have sufficient follow-up to examine factors  associated with clinical response. EXPERIMENTAL DESIGN: A total of 139 patients  with metastatic melanoma were treated: 54 patients received ipilimumab in  conjunction with peptide vaccinations and 85 patients were treated with  intra-patient dose escalation of ipilimumab and randomized to receive peptides in  accordance with HLA-A*0201 status. RESULTS: Three patients achieved complete  responses (CR; ongoing at 29+, 52+, and 53+ months); an additional 20 patients  achieved partial responses (PR) for an overall objective response rate of 17%.  The majority of patients (62%, 86 of 139) developed some form of IRAE, which was   associated with a greater probability of objective antitumor response (P =  0.0004); all patients with CR had more severe IRAEs. Prior therapy with  IFNalpha-2b was a negative prognostic factor, whereas prior high-dose  interleukin-2 did not significantly affect the probability of response. There  were no significant differences in the rate of clinical response or development  of IRAEs between the two trials. The duration of tumor response was not affected   by the use of high-dose steroids for abrogation of treatment-related toxicities  (P = 0.23). There were no treatment-related deaths. CONCLUSION: In patients with   metastatic melanoma, ipilimumab can induce durable objective clinical responses,   which are related to the induction of IRAEs.
CANIT0000036	17295916	Basic research	Murine central nervous system tumor models	Central nervous system cancer	EFO:0000326	Nervous system	TLR3 (O15455); 	TLR3; 	Poly-ICLC	N/A	Tumor vaccine	Poly-ICLC (NCIT:C1198); 	Cell lines/ animal models	N/A	Basic research	These data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2007 Feb 12	 Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral  vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor  models.	 J Transl Med	 BACKGROUND: Toll-like receptor (TLR)3 ligands serve as natural inducers of  pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and  TLR3 is abundantly expressed by cells within the central nervous system (CNS). To  improve the efficacy of vaccine strategies directed against CNS tumors, we  evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic  (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC)  would enhance the anti-CNS tumor effectiveness of tumor peptide-based  vaccinations. METHODS: C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05  melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides  encoding CTL epitopes--mEphA2 (671-679), hgp100 (25-33) and mTRP-2 (180-188) for   GL261, or ovalbumin (OVA: 257-264) for M05. The mice also received intramuscular   (i.m.) injections with poly-ICLC. RESULTS: The combination of subcutaneous (s.c.)  peptide-based vaccination and i.m. poly-ICLC administration promoted systemic  induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation  antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs  based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4.  In addition, the combination treatment allowed expression of IFNG by CNS  tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the  absence of detectable autoimmunity. CONCLUSION: These data suggest that  poly-ICLC, which has been previously evaluated in clinical trials, can be  effectively combined with tumor Ag-specific vaccine strategies, thereby providing  a greater index of therapeutic efficacy.
CANIT0000037	18049334	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	61	N/A	A phase II clinical trial	There was a highly significant association between autoimmune events (AEs) and tumor regression (response rate=30% with AE, 0% without AE).	Thirty-three percent of patients experienced a grade III or IV immune-mediated toxicity. 	N/A	N/A	Autoimmune side effects (EFO:0005140); 	Autoimmune side effects	Adverse events	 2007 Nov-Dec	 Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell  cancer associated with enteritis and hypophysitis.	 J Immunother	 The inhibitory receptor CTLA4 has a key role in peripheral tolerance of T cells  for both normal and tumor-associated antigens. Murine experiments suggested that   blockade of CTLA4 might have antitumor activity and a clinical experience with  the blocking antibody ipilimumab in patients with metastatic melanoma did show  durable tumor regressions in some patients. Therefore, a phase II study of  ipilimumab was conducted in patients with metastatic renal cell cancer with a  primary end point of response by Response Evaluation Criteria in Solid Tumors  (RECIST) criteria. Two sequential cohorts received either 3 mg/kg followed by 1  mg/kg or all doses at 3 mg/kg every 3 weeks (with no intention of comparing  cohort response rates). Major toxicities were enteritis and endocrine  deficiencies of presumed autoimmune origin. One of 21 patients receiving the  lower dose had a partial response. Five of 40 patients at the higher dose had  partial responses (95% confidence interval for cohort response rate 4% to 27%)  and responses were seen in patients who had previously not responded to IL-2.  Thirty-three percent of patients experienced a grade III or IV immune-mediated  toxicity. There was a highly significant association between autoimmune events  (AEs) and tumor regression (response rate=30% with AE, 0% without AE). CTLA4  blockade with ipilimumab induces cancer regression in some patients with  metastatic clear cell renal cancer, even if they have not responded to other  immunotherapies. These regressions are highly associated with other  immune-mediated events of presumed autoimmune origin by mechanisms as yet  undefined.
CANIT0000038	17363537	Clinical research	Hormone-refractory prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	14	N/A	A pilot clinical trial 	A single dose of 3 mg/kg Ipilimumab, an anti-CTLA-4 antibody, given to patients with prostate cancer is safe and does not result in significant clinical autoimmunity. 	Treatment was well tolerated with clinical autoimmunity limited to one patient who developed grade 3 rash/pruritus requiring systemic corticosteroids. 	N/A	N/A	N/A	N/A	N/A	 2007 Mar 15	 A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with  hormone-refractory prostate cancer.	 Clin Cancer Res	 PURPOSE: Blockade of the T-cell inhibitory receptor CTL-associated antigen-4  (CTLA-4) augments and prolongs T-cell responses and is a strategy to elicit  antitumor immunity. The objectives of this pilot study were to establish the  pharmacokinetic and safety profile for a single dose of 3 mg/kg of the  anti-CTLA-4 antibody Ipilimumab (MDX-010, BMS-734016) and to assess if this  therapy resulted in prostate-specific antigen (PSA) modulation and the  development of polyclonal T-cell activation and/or clinical autoimmunity in  patients with hormone-refractory prostate cancer treated with Ipilimumab.  EXPERIMENTAL DESIGN: Patients with metastatic hormone-refractory prostate cancer   received a single 3 mg/kg i.v. dose of Ipilimumab. Serologic measures of  autoimmunity were obtained, and T-cell activation was evaluated by flow  cytometry. Pharmacokinetic sampling of plasma for MDX-CTLA-4, PSA measurement,  and diagnostic imaging were also undertaken. RESULTS: Fourteen patients were  treated: 12 patients received a single dose of Ipilimumab, and 2 patients were  re-treated with a second dose upon PSA progression. Two patients showed PSA  declines of > or =50%. Treatment was well tolerated with clinical autoimmunity  limited to one patient who developed grade 3 rash/pruritus requiring systemic  corticosteroids. The mean +/- SD Ipilimumab terminal elimination half-life was  12.5 +/- 5.3 days. CONCLUSIONS: A single dose of 3 mg/kg Ipilimumab, an  anti-CTLA-4 antibody, given to patients with prostate cancer is safe and does not  result in significant clinical autoimmunity. PSA-modulating effects observed  warrant further investigation.
CANIT0000039	18060404	Clinical research	Metastatic colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine plus 5-fluorouracil	 5-fluorouracil	Tumor vaccine plus Chemotherapy	MVA-5T4 vaccine (NCIT:C49087); 5-fluorouracil (DB00544); 	12	N/A	An open-label  phase II clinical trial	TroVax can be layered on top of chemotherapy regimens without any evidence of enhanced toxicity or reduced immunological or therapeutic efficacy.	Administration of TroVax alongside chemotherapy was safe and well tolerated with no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity. 	N/A	N/A	N/A	N/A	N/A	 2008 Jul	 Vaccination of colorectal cancer patients with TroVax given alongside  chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces  potent immune responses.	 Cancer Immunol Immunother	 Modified vaccinia Ankara (MVA) encoding the tumor antigen 5T4 (TroVax) has been  evaluated in an open label phase II study in metastatic colorectal cancer  patients. The primary objective was to assess the safety and immunogenicity of  TroVax injected before, during and after treatment with 5-fluorouracil,  leukovorin and irinotecan. TroVax was administered to 19 patients with metastatic  colorectal cancer. Twelve patients had blood samples taken following each of the   six injections and were considered to be evaluable for assessment of  immunological responses. Both antibody and cellular responses specific for the  tumor antigen 5T4 and the viral vector MVA were monitored throughout the study.  Administration of TroVax alongside chemotherapy was safe and well tolerated with   no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity.  Of the 12 patients who were evaluable for assessment of immune responses, ten  mounted 5T4-specific antibody responses with titers ranging from 10 to > 5,000.  IFNG ELISPOT responses specific for 5T4 were detected in 11 patients with  frequencies exceeding one in 1,000 PBMCs in five patients. Eight patients  presented with elevated circulating CEA concentrations, six of whom showed  decreases in excess of 50% during chemotherapy and four had CEA levels which  remained stable for > 1 month following completion of chemotherapy. Of the 19  intention to treat (ITT) patients, one had a CR, six had PRs and five had SD.  Potent 5T4-specific cellular and/or humoral immune responses were induced in all   12 evaluable patients and were detectable in most patients during the period in  which chemotherapy was administered. These data demonstrate that TroVax can be  layered on top of chemotherapy regimens without any evidence of enhanced toxicity  or reduced immunological or therapeutic efficacy.
CANIT0000040	18060404	Clinical research	Metastatic colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine plus irinotecan	Irinotecan	Tumor vaccine plus Chemotherapy	MVA-5T4 vaccine (NCIT:C49087); irinotecan (DB00762); 	12	N/A	An open-label  phase II clinical trial	TroVax can be layered on top of chemotherapy regimens without any evidence of enhanced toxicity or reduced immunological or therapeutic efficacy.	Administration of TroVax alongside chemotherapy was safe and well tolerated with no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity. 	N/A	N/A	N/A	N/A	N/A	 2008 Jul	 Vaccination of colorectal cancer patients with TroVax given alongside  chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces  potent immune responses.	 Cancer Immunol Immunother	 Modified vaccinia Ankara (MVA) encoding the tumor antigen 5T4 (TroVax) has been  evaluated in an open label phase II study in metastatic colorectal cancer  patients. The primary objective was to assess the safety and immunogenicity of  TroVax injected before, during and after treatment with 5-fluorouracil,  leukovorin and irinotecan. TroVax was administered to 19 patients with metastatic  colorectal cancer. Twelve patients had blood samples taken following each of the   six injections and were considered to be evaluable for assessment of  immunological responses. Both antibody and cellular responses specific for the  tumor antigen 5T4 and the viral vector MVA were monitored throughout the study.  Administration of TroVax alongside chemotherapy was safe and well tolerated with   no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity.  Of the 12 patients who were evaluable for assessment of immune responses, ten  mounted 5T4-specific antibody responses with titers ranging from 10 to > 5,000.  IFNG ELISPOT responses specific for 5T4 were detected in 11 patients with  frequencies exceeding one in 1,000 PBMCs in five patients. Eight patients  presented with elevated circulating CEA concentrations, six of whom showed  decreases in excess of 50% during chemotherapy and four had CEA levels which  remained stable for > 1 month following completion of chemotherapy. Of the 19  intention to treat (ITT) patients, one had a CR, six had PRs and five had SD.  Potent 5T4-specific cellular and/or humoral immune responses were induced in all   12 evaluable patients and were detectable in most patients during the period in  which chemotherapy was administered. These data demonstrate that TroVax can be  layered on top of chemotherapy regimens without any evidence of enhanced toxicity  or reduced immunological or therapeutic efficacy.
CANIT0000041	18060404	Clinical research	Metastatic colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine plus leukovorin	Leukovorin	Tumor vaccine plus Chemotherapy	MVA-5T4 vaccine (NCIT:C49087); leukovorin (DB00650); 	12	N/A	An open-label  phase II clinical trial	TroVax can be layered on top of chemotherapy regimens without any evidence of enhanced toxicity or reduced immunological or therapeutic efficacy.	Administration of TroVax alongside chemotherapy was safe and well tolerated with no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity. 	N/A	N/A	N/A	N/A	N/A	 2008 Jul	 Vaccination of colorectal cancer patients with TroVax given alongside  chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces  potent immune responses.	 Cancer Immunol Immunother	 Modified vaccinia Ankara (MVA) encoding the tumor antigen 5T4 (TroVax) has been  evaluated in an open label phase II study in metastatic colorectal cancer  patients. The primary objective was to assess the safety and immunogenicity of  TroVax injected before, during and after treatment with 5-fluorouracil,  leukovorin and irinotecan. TroVax was administered to 19 patients with metastatic  colorectal cancer. Twelve patients had blood samples taken following each of the   six injections and were considered to be evaluable for assessment of  immunological responses. Both antibody and cellular responses specific for the  tumor antigen 5T4 and the viral vector MVA were monitored throughout the study.  Administration of TroVax alongside chemotherapy was safe and well tolerated with   no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity.  Of the 12 patients who were evaluable for assessment of immune responses, ten  mounted 5T4-specific antibody responses with titers ranging from 10 to > 5,000.  IFNG ELISPOT responses specific for 5T4 were detected in 11 patients with  frequencies exceeding one in 1,000 PBMCs in five patients. Eight patients  presented with elevated circulating CEA concentrations, six of whom showed  decreases in excess of 50% during chemotherapy and four had CEA levels which  remained stable for > 1 month following completion of chemotherapy. Of the 19  intention to treat (ITT) patients, one had a CR, six had PRs and five had SD.  Potent 5T4-specific cellular and/or humoral immune responses were induced in all   12 evaluable patients and were detectable in most patients during the period in  which chemotherapy was administered. These data demonstrate that TroVax can be  layered on top of chemotherapy regimens without any evidence of enhanced toxicity  or reduced immunological or therapeutic efficacy.
CANIT0000042	18452610	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	12	N/A	N/A	Administration of CTLA4-blocking antibody tremelimumab to patients  with advanced melanoma results in a subset of patients with long-lived tumor  responses. T-cell activation and memory markers served as the only readout of the  pharmacodynamic effects of this antibody in peripheral blood.	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	T-cell activation or memory markers	Gene expression signature on/in immune cell	 2008 May 1	 Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated  antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of  patients with melanoma.	 J Transl Med	 BACKGROUND: CTLA4-blocking antibodies induce tumor regression in a subset of  patients with melanoma. Analysis of immune parameters in peripheral blood may  help define how responses are mediated. METHODS: Peripheral blood from  HLA-A*0201-positive patients with advanced melanoma receiving tremelimumab  (formerly CP-675,206) at 10 mg/kg monthly was repeatedly sampled during the first  4 cycles. Samples were analyzed by 1) tetramer and ELISPOT assays for reactivity   to CMV, EBV, MART1, gp100, and tyrosinase; 2) activation HLA-DR and memory CD45RO  markers on CD4+/CD8+ cells; and 3) real-time quantitative PCR of mRNA for FoxP3  transcription factor, preferentially expressed by T regulatory cells. The primary  endpoint was difference in MART1-specific T cells by tetramer assay.  Immunological data were explored for significant trends using clustering  analysis. RESULTS: Three of 12 patients eligible for immune monitoring had tumor   regression lasting > 2 years without relapse. There was no significant change in   percent of MART1-specific T cells by tetramer assay. Additionally, there was no  generalized trend toward postdosing changes in other antigen-specific CD8+ cell  populations, FoxP3 transcripts, or overall changes in surface expression of  T-cell activation or memory markers. Unsupervised hierarchical clustering based  on immune monitoring data segregated patients randomly. However, clustering  according to T-cell activation or memory markers separated patients with clinical  response and most patients with inflammatory toxicity into a common subgroup.  CONCLUSION: Administration of CTLA4-blocking antibody tremelimumab to patients  with advanced melanoma results in a subset of patients with long-lived tumor  responses. T-cell activation and memory markers served as the only readout of the  pharmacodynamic effects of this antibody in peripheral blood. CLINICAL TRIAL  REGISTRATION NUMBER: NCT00086489.
CANIT0000043	18582195	Clinical research	Healthy adults	Healthy adults	N/A	Other	N/A (N/A); 	N/A; 	Tuberculosis vaccine MVA85A	N/A	Tumor vaccine	Tuberculosis vaccine MVA85A (NCIT:C1572); 	24	N/A	N/A	The excellent safety profile and quantitative and qualitative immunogenicity data strongly support further trials assessing the efficacy of MVA85A as a boosting vaccine in countries where TB is endemic.	MVA85A vaccination was well tolerated and induced potent T cell responses, as measured by interferon (IFN)-gamma enzyme-linked immunospot assay, which exceeded prevaccination responses up to 364 days after vaccination. BCG-specific CD4+ T cells boosted by MVA85A were comprised of multiple populations expressing combinations of IFN-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, and IL-17, as measured by polychromatic flow cytometry. IFN-gamma-expressing and polyfunctional IFN-gamma+TNF-gamma+IL-2+ CD4+ T cells were boosted during the peak BCG-specific response, which occurred 7 days after vaccination.	N/A	N/A	N/A	N/A	N/A	 2008 Aug 15	 Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy  adults in South Africa.	 J Infect Dis	 BACKGROUND: The efficacy of bacille Calmette-Guerin (BCG) may be enhanced by  heterologous vaccination strategies that boost the BCG-primed immune response.  One leading booster vaccine, MVA85A (where MVA denotes modified vaccinia virus  Ankara), has shown promising safety and immunogenicity in human trials performed  in the United Kingdom. We investigated the safety and immunogenicity of MVA85A in  mycobacteria-exposed--but Mycobacterium tuberculosis-uninfected--healthy adults  from a region of South Africa where TB is endemic. METHODS: Twenty-four adults  were vaccinated with MVA85A. All subjects were monitored for 1 year for adverse  events and for immunological assessment. RESULTS: MVA85A vaccination was well  tolerated and induced potent T cell responses, as measured by interferon  (IFN)G enzyme-linked immunospot assay, which exceeded prevaccination  responses up to 364 days after vaccination. BCG-specific CD4+ T cells boosted by   MVA85A were comprised of multiple populations expressing combinations of  IFN-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, and IL-17, as  measured by polychromatic flow cytometry. IFN-gamma-expressing and polyfunctional  IFN-gamma+TNF-gamma+IL-2+ CD4+ T cells were boosted during the peak BCG-specific   response, which occurred 7 days after vaccination. CONCLUSION: The excellent  safety profile and quantitative and qualitative immunogenicity data strongly  support further trials assessing the efficacy of MVA85A as a boosting vaccine in   countries where TB is endemic. TRIAL REGISTRATION: ClinicalTrials.gov identifier:  NCT00460590.
CANIT0000044	18594319	Clinical research	Stage III/IV Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	IL2R (A2N4P8); MUC1 (P15941); 	IL2R; MUC1	MVA-MUC1-IL2 vaccine plus cisplatin and vinorelbine	MVA-MUC1-IL2 vaccine	Tumor vaccine plus Chemotherapy	Cisplatin and vinorelbine (DB00515; DB00361); MVA-MUC1-IL2 vaccine (NCIT:C2241); 	65	N/A	A multicenter, randomized phase II study	The combination of MVA-MUC1-IL2 vaccine (TG4010) with standard chemotherapy in advanced non-small cell lung cancer is feasible and shows encouraging results. A randomized study evaluating the addition of TG4010 to first line chemotherapy in this population is in progress.	MVA-MUC1-IL2 vaccine (TG4010) was well tolerated, mild to moderate injection site reactions, flu-like symptoms, and fatigue being the most frequent adverse reactions.	N/A	N/A	N/A	N/A	N/A	 2008 Jul	 A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in  patients with stage III/IV Non-small cell lung cancer.	 J Thorac Oncol	 BACKGROUND: TG4010 is a recombinant viral vector expressing both the  tumor-associated antigen MUC1 and Interleukine-2. This vector is based on the  modified virus of Ankara, a significantly attenuated strain of vaccinia virus.  TG4010 has been designed to induce or amplify a cellular immune response directed  against tumor cells expressing MUC1. METHODS: A multicenter, randomized phase II   study has explored two schedules of the combination of TG4010 with first line  chemotherapy in patients with stage IIIB/IV non-small cell lung cancer. In Arm 1,  TG4010 was combined upfront with cisplatin (100 mg/m day 1) and vinorelbine (25  mg/m day 1 and day 8). In Arm 2, patients were treated with TG4010 monotherapy  until disease progression, followed by TG4010 plus the same chemotherapy as in  Arm1. Response rate was evaluated according to RECIST. Median time to progression  and median overall survival were calculated according to the Kaplan-Meier method.  RESULTS: Sixty-five patients were enrolled, 44 in Arm 1 and 21 in Arm 2, in  accordance with the two stage Simon design of the statistical plan. In Arm 1,  partial response was observed in 13 patients out of 37 evaluable patients (29.5%   of the intent to treat population, 35.1% of the evaluable patients). In Arm 2,  two patients experienced stable disease for more than 6 months with TG4010 alone   (up to 211 days), in the subsequent combination with chemotherapy, one complete  and one partial response were observed out of 14 evaluable patients. Arm 2 did  not meet the criteria for moving forward to second stage. The median time to  progression was 4.8 months for Arm 1. The median overall survival was 12.7 months  for Arm 1 and 14.9 for Arm 2. One year survival rate was 53% for Arm 1 and 60%  for Arm 2. TG4010 was well tolerated, mild to moderate injection site reactions,   flu-like symptoms, and fatigue being the most frequent adverse reactions. A  MUC1-specific cellular immune response was observed in lymphocyte samples from  all responding patients evaluable for immunology. CONCLUSIONS: The combination of  TG4010 with standard chemotherapy in advanced non-small cell lung cancer is  feasible and shows encouraging results. A randomized study evaluating the  addition of TG4010 to first line chemotherapy in this population is in progress.
CANIT0000045	18612158	Clinical research	Breast cancer	Breast cancer	MONDO:0007254	Breast	HER2 (P04626); 	HER2; 	AE37 vaccine	N/A	Tumor vaccine	AE37 vaccine (NCIT:C91719); 	15	N/A	A phase I clinical trial 	AE37 is capable of eliciting HER-2/neu-specific immune responses without the use of an adjuvant. It's the first peptide vaccine to show potency in the absence of an immunoadjuvant.	The hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. 	N/A	N/A	N/A	N/A	N/A	 2008 Jul 10	 Results of the first phase I clinical trial of the novel II-key hybrid preventive  HER-2/neu peptide (AE37) vaccine.	 J Clin Oncol	 PURPOSE: HER-2/neu is overexpressed in breast cancer and is the source of  immunogenic peptides. CD4(+) T-helper peptides for HER-2/neu are being evaluated   in vaccine trials. The addition of Ii-Key, a four-amino-acid LRMK modification,  increases vaccine potency when compared with unmodified class II epitopes. We  present the results of the first human phase I trial of the Ii-Key hybrid  HER-2/neu peptide (AE37) vaccine in disease-free, node-negative breast cancer  patients. PATIENTS AND METHODS: The dose escalation trial included five dose  groups, to determine safety and optimal dose of the hybrid peptide (100 microg,  500 microg, 1,000 microg) and granulocyte-macrophage colony-stimulating factor  (GM-CSF; range, 0 to 250 microg). In the event of significant local toxicity,  GM-CSF (or peptide in absence of GM-CSF) was reduced by 50%. Immunologic response  was monitored by delayed-type hypersensitivity and [(3)H]thymidine proliferative   assays for both the hybrid AE37 (LRMK-positive HER-2/neu:776-790) and AE36  (unmodified HER-2/neu:776-790). RESULTS: All 15 patients completed the trial with  no grade 3 to 5 toxicities. Dose reductions occurred in 47% of patients. In the  second group (peptide, 500 microg; GM-CSF, 250 microg), all patients required  dose reductions, prompting peptide-only inoculations in the third group. The  vaccine induced dose-dependent immunologic responses in vitro and in vivo to  AE37, as well as AE36. CONCLUSION: The hybrid AE37 vaccine seems safe and well  tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting  HER-2/neu-specific immune responses, even without the use of an adjuvant. This  trial represents the first human experience with the Ii-Key modification, and to   our knowledge, AE37 is the first peptide vaccine to show potency in the absence  of an immunoadjuvant.
CANIT0000046	18665147	Case report	Melanoma metastases to the CNS	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Significant clinical benefit	N/A	N/A	N/A	N/A	N/A	N/A	 2008 Sep	 CTLA-4 blockade with ipilimumab induces significant clinical benefit in a female   with melanoma metastases to the CNS.	 Nat Clin Pract Oncol	 BACKGROUND: A 63-year-old female presented to her primary physician with numbness  and weakness in her left leg, which progressed over several days to involve her  entire lower extremities. MRI of the spine and brain revealed multiple  metastases. The patient received ipilimumab and after 3 months experienced  intermittent confusion and focal seizures. INVESTIGATIONS: Electroencephalogram  and MRI scans of the spine and brain, followed by surgical removal of a left  frontal cortical brain metastasis and subsequent histological and pathological  analyses. DIAGNOSIS: Metastatic melanoma from an unknown primary tumor.  MANAGEMENT: The patient was treated with ipilimumab on a compassionate-use  program and dexamethasone, celecoxib, and levetiracetam to treat the symptoms and  seizures. Postoperative stereotactic radiosurgery was initiated.
CANIT0000047	18698043	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	10	N/A	A multicentric phase II trial 	CTLA-4 blockade seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and our work suggests that memory T-cell resistance to Treg resulting from anti-CTLA-4 treatment might be a biological activity marker for tremelimumab in patients with melanoma.	N/A	N/A	N/A	Treg cells (CL:0000815); T-Lymphocyte (NCIT:C12476); 	Memory T-cell resistance to Treg	Cell percentage/counts in blood	 2008 Aug 15	 Ctla-4 blockade confers lymphocyte resistance to regulatory T-cells in advanced  melanoma: surrogate marker of efficacy of tremelimumab 	 Clin Cancer Res	 PURPOSE: Anti-CTL antigen-4 (CTLA-4) monoclonal antibody (mAb) has led to  encouraging antitumor activity associated with immune-related adverse events in  patients with heavily pretreated melanoma. However, mechanisms of action and  surrogate immunologic markers of efficacy have not been reported thus far.  EXPERIMENTAL DESIGN: We monitored the immune responses of 10 melanoma patients  included in a phase II clinical trial, which evaluated the efficacy of a second  line of therapy of tremelimumab anti-CTLA-4 mAb in patients with metastatic  melanoma. The frequency of blood leukocyte populations in association with T cell  and regulatory T cell (Treg) functions were evaluated. RESULTS: Prior to therapy,  patients with advanced melanoma presented with a severe CD4+ and CD8+ T cell  lymphopenia associated with blunted T-cell proliferative capacities that could be  assigned to Treg. Tremelimumab rapidly restored the effector and memory CD4+ and   CD8+ T-cell pool and TCR-dependent T-cell proliferation that became entirely  resistant to Treg-mediated suppression. Progression-free survival and overall  survival was directly correlated with the acquisition of a biological response  defined as the resistance of peripheral lymphocytes to Treg-inhibitory effects  (obtained in 7 of 10 patients). CONCLUSION: CTLA-4 blockade seems to be a  valuable strategy to revive reactive memory T cells anergized in the context of  stage IV melanoma, and our work suggests that memory T-cell resistance to Treg  resulting from anti-CTLA-4 treatment might be a biological activity marker for  tremelimumab in patients with melanoma.
CANIT0000048	18774925	Clinical research	Colorectal cancer 	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	47	N/A	A phase II/III clinical trial 	Objective response rates of approximately 2%	In Phase I and II studies, tremelimumab was well tolerated with predictable and manageable side effects. 	N/A	N/A	N/A	N/A	N/A	 2008 Oct	 Tremelimumab (CP-675,206): a fully human anticytotoxic T lymphocyte-associated  antigen 4 monoclonal antibody for treatment of patients with advanced cancers.	 Expert Opin Biol Ther	 Tremelimumab, a fully human monoclonal IgG2 antibody targeting cytotoxic T  lymphocyte-associated antigen 4 (CTLA4), is being developed by Pfizer for  treatment of patients with advanced cancers. Treatment with an anti-CTLA4 mAb  prevents normal downregulation of T cells and prolongs T cell activation, thereby  enhancing immune function. In Phase I and II studies, tremelimumab was well  tolerated with predictable and manageable side effects. Antitumor activity with  monotherapy was observed in patients with advanced melanoma and colorectal cancer  (objective response rates of approximately 10 and 2%, respectively), and most  objective responses were durable (defined as lasting > 180 days). Additional  Phase II and III studies in combination with other agents will assess antitumor  activity in multiple tumor types as well as attempt to identify patient  populations most likely to respond.
CANIT0000049	18774925	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	34	N/A	A phase II/III clinical trial 	Objective response rates of approximately 10%	In Phase I and II studies, tremelimumab was well tolerated with predictable and manageable side effects. 	N/A	N/A	N/A	N/A	N/A	 2008 Oct	 Tremelimumab (CP-675,206): a fully human anticytotoxic T lymphocyte-associated  antigen 4 monoclonal antibody for treatment of patients with advanced cancers.	 Expert Opin Biol Ther	 Tremelimumab, a fully human monoclonal IgG2 antibody targeting cytotoxic T  lymphocyte-associated antigen 4 (CTLA4), is being developed by Pfizer for  treatment of patients with advanced cancers. Treatment with an anti-CTLA4 mAb  prevents normal downregulation of T cells and prolongs T cell activation, thereby  enhancing immune function. In Phase I and II studies, tremelimumab was well  tolerated with predictable and manageable side effects. Antitumor activity with  monotherapy was observed in patients with advanced melanoma and colorectal cancer  (objective response rates of approximately 10 and 2%, respectively), and most  objective responses were durable (defined as lasting > 180 days). Additional  Phase II and III studies in combination with other agents will assess antitumor  activity in multiple tumor types as well as attempt to identify patient  populations most likely to respond.
CANIT0000050	18797818	Clinical research	Newly diagnosed supratentorial glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	TLR3 (O15455); 	TLR3; 	Poly-ICLC plus radiation	N/A	Tumor vaccine plus Radiotherapy	Radiotherapy (NCIT:C15313); poly-ICLC (NCIT:C1198); 	30	N/A	A phase II clinical trial	The combined therapy was relatively well-tolerated. This study  suggests a survival advantage compared to historical studies using RT without  chemotherapy but no survival advantage compared to RT with adjuvant nitrosourea  or non-temozolomide chemotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2009 Jan	 A phase II clinical trial of poly-ICLC with radiation for adult patients with  newly diagnosed supratentorial glioblastoma: a North American Brain Tumor  Consortium (NABTC01-05).	 J Neurooncol	 PURPOSE: This phase II study was designed to determine the overall survival time   of adults with supratentorial glioblastoma treated with the immune modulator,  polyinosinic-polycytidylic acid stabilized with polylysine and  carboxymethylcellulose (poly-ICLC), in combination with and following radiation  therapy (RT). METHODS AND MATERIALS: This was an open-label, single arm phase II   study. Patients were treated with RT in combination with poly-ICLC followed by  poly-ICLC as a single agent. Poly-ICLC was initiated 7-28 days after the surgical  procedure that established the diagnosis; radiotherapy began within 7 days of the  first dose of poly-ICLC and within 35 days of surgical diagnosis. Treatment with   poly-ICLC continued following the completion of RT to a maximum of 1 year or  until tumor progression. RESULTS: 31 patients were enrolled in this study. One  patient did not have a Glioblastoma mutiforme and was deemed ineligible. For the   30 eligible patients, time to progression was known for 27 patients and 3 were  censored. The estimated 6-month progression-free survival was 30% and the  estimated 1-year progression-free survival was 5%. Median time to progression was  as 18 weeks. The 1-year survival was 69% and the median survival was 65 weeks.  CONCLUSIONS: The combined therapy was relatively well-tolerated. This study  suggests a survival advantage compared to historical studies using RT without  chemotherapy but no survival advantage compared to RT with adjuvant nitrosourea  or non-temozolomide chemotherapy. Our results suggest that poly-ICLC has activity  against glioblastoma and may be worth further study in combination with agents  such as temozolomide.
CANIT0000051	18833005	Clinical research	Surgical resection of colorectal cancer liver metastases	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine	N/A	Tumor vaccine	MVA-5T4 vaccine (NCIT:C49087); 	20	N/A	N/A	The density of CD3 cells in colorectal cancer liver metastases are associated with longer survival. These observations warrant more studies to identify the precise underlying mechanisms.	N/A	N/A	N/A	CD3 (P07766); T-Lymphocyte (NCIT:C12476); 	CD3(+) T-cell density	Gene expression signature on/in immune cell	 2008 Nov-Dec	 An MVA-based vaccine targeting the oncofetal antigen 5T4 in patients undergoing  surgical resection of colorectal cancer liver metastases.	 J Immunother	 We investigated the use of a therapeutic vaccine, TroVax in patients undergoing  surgical resection of colorectal cancer liver metastases. Systemic immunity  generated by vaccination before and after resection of metastases was measured in  addition to assessing safety and analyzing the function and phenotype of  tumor-associated lymphocytes. Twenty patients were scheduled to receive 2 TroVax   vaccinations at 2-week intervals preoperatively and 2 postoperatively; if immune   responses were detected, 2 further vaccinations were offered. Blood was taken at   trial entry and 2 weeks after each vaccination; tumor biopsies were collected at   surgery. 5T4-specific cellular responses were assessed by lymphocyte  proliferation and enzyme-linked immunosorbent spot, with antibody responses by  enzyme-linked immunosorbent assay. Immunohistochemistry characterized the  phenotype of tumor-infiltrating lymphocytes. Seventeen of 19 colorectal cancer  patients showed 5T4 expression in the liver metastases or surrounding stroma and   18 mounted a 5T4-specific cellular and/or humoral response. In patients who  received at least 4 vaccinations and potentially curative surgery (n=15), those  with above median 5T4-specific proliferative responses or T-cell infiltration  into the resected tumor showed significantly longer survival compared with those   with below median responses. Seven of 8 patients who had preexisting  proliferative responses to 5T4 were longer-term survivors; these patients showed   significantly higher proliferative responses after vaccination than those who  subsequently died. These data suggest that the magnitude of 5T4 proliferative  responses and the density of CD3 cells in colorectal cancer liver metastases are   associated with longer survival. These observations warrant more studies to  identify the precise underlying mechanisms.
CANIT0000052	18833005	Clinical research	Surgical resection of colorectal cancer liver metastases	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine	N/A	Tumor vaccine	MVA-5T4 vaccine (NCIT:C49087); 	20	N/A	N/A	The magnitude of 5T4 proliferative responses in colorectal cancer liver metastases are associated with longer survival. These observations warrant more studies to identify the precise underlying mechanisms.	N/A	N/A	N/A	MVA-5T4 response (NCIT:C49087); 	MVA-5T4 specific immune responses	Immune response	 2008 Nov-Dec	 An MVA-based vaccine targeting the oncofetal antigen 5T4 in patients undergoing  surgical resection of colorectal cancer liver metastases.	 J Immunother	 We investigated the use of a therapeutic vaccine, TroVax in patients undergoing  surgical resection of colorectal cancer liver metastases. Systemic immunity  generated by vaccination before and after resection of metastases was measured in  addition to assessing safety and analyzing the function and phenotype of  tumor-associated lymphocytes. Twenty patients were scheduled to receive 2 TroVax   vaccinations at 2-week intervals preoperatively and 2 postoperatively; if immune   responses were detected, 2 further vaccinations were offered. Blood was taken at   trial entry and 2 weeks after each vaccination; tumor biopsies were collected at   surgery. 5T4-specific cellular responses were assessed by lymphocyte  proliferation and enzyme-linked immunosorbent spot, with antibody responses by  enzyme-linked immunosorbent assay. Immunohistochemistry characterized the  phenotype of tumor-infiltrating lymphocytes. Seventeen of 19 colorectal cancer  patients showed 5T4 expression in the liver metastases or surrounding stroma and   18 mounted a 5T4-specific cellular and/or humoral response. In patients who  received at least 4 vaccinations and potentially curative surgery (n=15), those  with above median 5T4-specific proliferative responses or T-cell infiltration  into the resected tumor showed significantly longer survival compared with those   with below median responses. Seven of 8 patients who had preexisting  proliferative responses to 5T4 were longer-term survivors; these patients showed   significantly higher proliferative responses after vaccination than those who  subsequently died. These data suggest that the magnitude of 5T4 proliferative  responses and the density of CD3 cells in colorectal cancer liver metastases are   associated with longer survival. These observations warrant more studies to  identify the precise underlying mechanisms.
CANIT0000053	18850068	Clinical research	Recurrent anaplastic gliomas	Anaplastic glioma	EFO:0002500	Brain	TLR3 (O15455); 	TLR3; 	Poly-ICLC	N/A	Tumor vaccine plus Chemotherapy	Poly-ICLC (NCIT:C1198); 	45	N/A	An open-labeled, single arm phase II study	Well tolerated, but poly-ICLC does not improve 6moPFS in patients with recurrent anaplastic gliomas but may be worth further study in combination with agents such as temozolomide.	N/A	N/A	N/A	N/A	N/A	N/A	 2009 Jan	 A North American brain tumor consortium phase II study of poly-ICLC for adult  patients with recurrent anaplastic gliomas.	 J Neurooncol	 This phase II study was designed to determine the objective response rate and  6-month progression free survival of adult patients with recurrent supratentorial  anaplastic glioma when treated with the immune modulator,  polyinosinic-polycytidylic acid stabilized with polylysine and  carboxymethylcellulose (poly-ICLC). This was an open-labeled, single arm phase II  study. Patients were treated with poly-ICLC alone. Patients may have had  treatment for no more than two prior relapses. Treatment with poly-ICLC continued  until tumor progression. Fifty five patients were enrolled in the study. Ten were  ineligible after central review of pathology. Eleven percent of patients (5 of  45) had a radiographic response. Time to progression was known for 39 patients  and 6 remain on treatment. The estimated 6-month progression free survival was  24%. The median survival time was 43 weeks. Poly-ICLC was well tolerated, but  there was no improvement in 6-month progression free survival compared to  historical database nor was there an encouraging objective radiographic response   rate. Based on this study, poly-ICLC does not improve 6moPFS in patients with  recurrent anaplastic gliomas but may be worth further study in combination with  agents such as temozolomide.
CANIT0000054	18931824	Clinical research	Prostate cancer with biochemical failure	Prostate cancer	MONDO:0008315	Prostate	IL2R (A2N4P8); MUC1 (P15941); 	IL2R; MUC1	MVA-MUC1-IL2 vaccine	N/A	Tumor vaccine	MVA-MUC1-IL2 vaccine (NCIT:C2241); 	40	N/A	A phase II clinical trial	Although the primary endpoint was not achieved, there is evidence of biologic activity of TG4010 in patients with PSA progression, further investigation in prostate cancer is warranted.	N/A	N/A	N/A	N/A	N/A	N/A	 2009 Aug	 MVA-MUC1-IL2 vaccine immunotherapy (TG4010) improves PSA doubling time in  patients with prostate cancer with biochemical failure.	 Invest New Drugs	 PURPOSE: TG4010 is a recombinant MVA vector expressing the tumor-associated  antigen MUC1 and IL2. We explored the effect two schedules of TG4010 on PSA in  men with PSA progression. PATIENTS AND METHODS: A randomized phase II trial was  conducted in 40 patients with PSA progression. Patients had PSA doubling times  less than 10 months, with no overt evidence of disease. Patients received either   weekly subcutaneous injection (sc) of TG4010 10(8) pfu for 6 weeks, then one  injection every 3 weeks or sc injection of TG4010 10(8) pfu every 3 weeks.  RESULTS: The primary endpoint of a 50% decrease in PSA values from baseline was  not observed. Nevertheless, 13 of 40 patients had a more than two fold  improvement in PSA doubling time. Ten patients had their PSA stabilized for over   8 months. Therapy was well tolerated. CONCLUSIONS: Although the primary endpoint   was not achieved, there is evidence of biologic activity of TG4010 in patients  with PSA progression, further investigation in prostate cancer is warranted.
CANIT0000055	19010868	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	5T4 (Q13641); IL12R (P42701); 	5T4; IL12R	IL2 plus MVA-5T4 vaccine	N/A	Tumor vaccine	MVA-5T4 vaccine (NCIT:C49087); IL2 (NCIT:C24498); 	25	N/A	A phase II clinical trial	TroVax in combination with IL-2 was safe  and well tolerated in all patients. The high frequency of 5T4-specific immune  responses and good clinical response rate are encouraging and warrant further  investigation.	MVA-5T4 (TroVax) was well tolerated with no serious adverse event attributed to vaccination. 	N/A	N/A	MVA-5T4 response (NCIT:C49087); 	MVA-5T4 specific immune responses	Immune response	 2008 Nov 15	 Vaccination of renal cell cancer patients with modified vaccinia ankara  delivering tumor antigen 5T4 (TroVax) administered with interleukin 2: a phase II  trial.	 Clin Cancer Res	 PURPOSE: The attenuated vaccinia virus modified vaccinia ankara (MVA) has been  engineered to deliver the tumor antigen 5T4 (TroVax). TroVax has been evaluated  in an open-label phase II trial in metastatic renal cell cancer patients in which  the vaccine was administered in combination with interleukin-2 (IL-2). The  safety, immunologic, and clinical efficacy of TroVax in combination with IL-2 was  determined. EXPERIMENTAL DESIGN: Twenty-five patients with metastatic renal cell   cancer were treated with TroVax plus IL-2. 5T4-specific cellular and humoral  responses were monitored throughout the study. Clinical responses were assessed  by measuring changes in tumor burden by computed tomography or magnetic resonance  imaging scan. RESULTS: TroVax was well tolerated with no serious adverse event  attributed to vaccination. Of 25 intention-to-treat patients, 21 mounted  5T4-specific antibody responses. Two patients showed a complete response for > 24  months and one a partial response for > 12 months. Six patients had disease  stabilization from 6 to > 21 months. Median progression-free survival (PFS) and  overall survival (OS) were > 3.37 months (range, 1.50- > 24.76) and > 12.87  months (range, 1.90- > 24.76), respectively. A statistically significant  relationship was detected between the magnitude of 5T4-specific antibody  responses and PFS and OS. CONCLUSION: TroVax in combination with IL-2 was safe  and well tolerated in all patients. The high frequency of 5T4-specific immune  responses and good clinical response rate are encouraging and warrant further  investigation.
CANIT0000056	19074257	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	15	N/A	N/A	CTLA-4 blockade enhanced NY-ESO-1 antigen-specific B cell and T cell immune responses in patients with durable objective clinical responses and stable disease. These data provide an immunologic rationale for the efficacy of anti-CTLA-4 therapy and call for immunotherapeutic designs that combine NY-ESO-1 vaccination with CTLA-4 blockade.	N/A	N/A	N/A	N/A	N/A	N/A	 2008 Dec 23	 CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in  metastatic melanoma patients with clinical benefit.	 Proc Natl Acad Sci U S A	 Blockade of inhibitory signals mediated by cytotoxic T lymphocyte-associated  antigen 4 (CTLA-4) has been shown to enhance T cell responses and induce durable   clinical responses in patients with metastatic melanoma. The functional impact of  anti-CTLA-4 therapy on human immune responses is still unclear. To explore this,   we analyzed immune-related adverse events and immune responses in metastatic  melanoma patients treated with ipilimumab, a fully human anti-CTLA-4 monoclonal  antibody. Fifteen patients were selected on the basis of availability of suitable  specimens for immunologic monitoring, and eight of these showed evidence of  clinical benefit. Five of the eight patients with evidence of clinical benefit  had NY-ESO-1 antibody, whereas none of seven clinical non-responders was  seropositive for NY-ESO-1. All five NY-ESO-1 seropositive patients had clearly  detectable CD4(+) and CD8(+) T cells against NY-ESO-1 following treatment with  ipilimumab. One NY-ESO-1 seronegative clinical responder also had a NY-ESO-1  CD4(+) and CD8(+) T cell response, possibly related to prior vaccination with  NY-ESO-1. Among five clinical non-responders analyzed, only one had a NY-ESO-1  CD4(+) T cell response and this patient did not have detectable anti-NY-ESO-1  antibody. Overall, NY-ESO-1-specific T cell responses increased in frequency and   functionality during anti-CTLA-4 treatment, revealing a polyfunctional response  pattern of IFN-gamma, MIP-1beta and TNF-alpha. We therefore suggest that CTLA-4  blockade enhanced NY-ESO-1 antigen-specific B cell and T cell immune responses in  patients with durable objective clinical responses and stable disease. These data  provide an immunologic rationale for the efficacy of anti-CTLA-4 therapy and call  for immunotherapeutic designs that combine NY-ESO-1 vaccination with CTLA-4  blockade.
CANIT0000057	19118070	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	7	N/A	N/A	Administration of tremelimumab was associated with massive intratumoral infiltrates of CD8(+) CTLs in patients with regressing tumors but had varying effects on intratumoral infiltrates of CD4(+) and FoxP3(+) cells or intratumoral expression of IDO.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Massive intratumoral -infiltrating CD8(+) T-cell 	Tumor-infiltrating immune cell	 2009 Jan 1	 Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in  patients with melanoma undergoing CTLA4 blockade.	 Clin Cancer Res	 PURPOSE: CTL-associated antigen 4 (CTLA4)-blocking monoclonal antibodies induce  long-term regression of metastatic melanoma in some patients, but the exact  mechanism is unknown. In this study, biopsies of selected accessible tumor  lesions from patients treated with tremelimumab were examined to further  elucidate the mechanism of its antitumor activity. EXPERIMENTAL DESIGN: Fifteen  tumor biopsies from 7 patients who had been treated with tremelimumab  (CP-675,206) were collected. Samples were analyzed for melanoma markers, immune  cell subset markers, the presence of the T regulatory-specific transcription  factor FoxP3 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO).   RESULTS: Clinically responding lesions had diffuse intratumoral infiltrates of  CD8(+) T cells that were markedly increased in cases where comparison with a  baseline biopsy was available. Nonregressing lesions had sparse, patchy CD8(+)  intratumoral infiltrates. Patients with regressing lesions had an increased  frequency of CD8(+) cells with or without a concomitant increase in CD4(+) cells.  Two of 3 responding patients with paired samples showed a slight increase in the   number of FoxP3(+) cells in the postdosing biopsies. In patients with regressing   lesions who had paired samples, the intensity of IDO staining in macrophages  and/or melanoma cells showed no clear pattern of change postdosing. CONCLUSIONS:   Administration of tremelimumab was associated with massive intratumoral  infiltrates of CD8(+) CTLs in patients with regressing tumors but had varying  effects on intratumoral infiltrates of CD4(+) and FoxP3(+) cells or intratumoral   expression of IDO.
CANIT0000058	19128501	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	5T4 (Q13641); IL12R (P42701); 	5T4; IL12R	MVA-5T4 vaccination followed by IL2	IL2	Tumor vaccine plus Immune cytokine	IL2 (NCIT:C24498); MVA-5T4 vaccine (NCIT:C49087); 	25	N/A	A phase II clinical trial	Vaccination with MVA-5T4 did not improve objective response rates of IL-2 therapy but did result in stable disease associated with an increase in the ratio of 5T4-specific effector to regulatory T cells in selected patients.	There were no serious vaccine-related adverse events.	N/A	N/A	5T4 (Q13641); T-Lymphocyte (NCIT:C12476); 	MVA-5T4 specific immune responses	Immune response	 2009 Jan 7	 Phase II trial of Modified Vaccinia Ankara (MVA) virus expressing 5T4 and high  dose Interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma.	 J Transl Med	 BACKGROUND: Interleukin-2 (IL-2) induces durable objective responses in a small  cohort of patients with metastatic renal cell carcinoma (RCC) but the antigen(s)   responsible for tumor rejection are not known. 5T4 is a non-secreted membrane  glycoprotein expressed on clear cell and papillary RCCs. A modified vaccinia  virus Ankara (MVA) encoding 5T4 was tested in combination with high-dose IL-2 to   determine the safety, objective response rate and effect on humoral and  cell-mediated immunity. METHODS: 25 patients with metastatic RCC who qualified  for IL-2 were eligible and received three immunizations every three weeks  followed by IL-2 (600,000 IU/kg) after the second and third vaccinations. Blood  was collected for analysis of humoral, effector and regulatory T cell responses.   RESULTS: There were no serious vaccine-related adverse events. While no objective  responses were observed, three patients (12%) were rendered disease-free after  nephrectomy or resection of residual metastatic disease. Twelve patients (48%)  had stable disease which was associated with improved median overall survival  compared to patients with progressive disease (not reached vs. 28 months, p =  0.0261). All patients developed 5T4-specific antibody responses and 13 patients  had an increase in 5T4-specific T cell responses. Although the baseline frequency  of Tregs was elevated in all patients, those with stable disease showed a trend  toward increased effector CD8+ T cells and a decrease in Tregs. CONCLUSION:  Vaccination with MVA-5T4 did not improve objective response rates of IL-2 therapy  but did result in stable disease associated with an increase in the ratio of  5T4-specific effector to regulatory T cells in selected patients. TRIAL  REGISTRATION NUMBER: ISRCTN83977250.
CANIT0000059	19139884	Case report	Metastatic melanoma unresponsive to prior systemic treatments	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	Case	These case reports highlight the potential for anti-CTLA-4-based therapy in previously treated patients with advanced melanoma. 	The patient achieving a partial response experienced no side effects while receiving ipilimumab. The other two patients developed immune-related adverse events (irAEs) including rash (one case; grade 2) and diarrhoea (both cases; grades 1 and 2, respectively); the histopathology of colon biopsy samples from both was suggestive of colitis, with an abundant CD8+ T-cell infiltrate. Nausea, vomiting and acute pancreatitis were also observed in one patient.	N/A	N/A	N/A	N/A	N/A	 2009 Aug	 Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in  patients with metastatic melanoma unresponsive to prior systemic treatments:  clinical and immunological evidence from three patient cases.	 Cancer Immunol Immunother	 The management of unresectable metastatic melanoma is a major clinical challenge   because of the lack of reliably effective systemic therapies. Blocking cytotoxic   T lymphocyte-associated antigen-4 (CTLA-4) has recently been proposed as a  strategy to enhance cell-mediated immune responses to cancer, and clinical trials  have demonstrated that anti-CTLA-4 therapy can produce durable outcomes with  different response patterns than cytotoxic chemotherapy. We enrolled eight out of  155 patients with advanced melanoma in a multicentre phase II trial that  evaluated the activity and tolerability of ipilimumab, a fully human, anti-CTLA-4  monoclonal antibody ( www.clinicaltrials.gov ; NCT00289627; CA184-008). Here we  report our experience with three of these patients, who experienced progressive  disease after a variety of previous therapies, including prior immunotherapies,  and who achieved good outcomes with ipilimumab. One patient had a partial  response ongoing at 17+ months on ipilimumab despite failure with four prior  therapies, and the other two patients showed durable stable disease, both still  ongoing at 17+ and 20+ months, respectively. The patient achieving a partial  response experienced no side effects while receiving ipilimumab. The other two  patients developed immune-related adverse events (irAEs) including rash (one  case; grade 2) and diarrhoea (both cases; grades 1 and 2, respectively); the  histopathology of colon biopsy samples from both was suggestive of colitis, with   an abundant CD8+ T-cell infiltrate. Nausea, vomiting and acute pancreatitis were   also observed in one patient. In addition, immunohistochemical findings of a  dense CD8+, TIA1+ and granzyme B+ lymphoid infiltrate within a biopsied lesion  provide indirect evidence of functional T-cell activation induced by treatment.  These case reports highlight the potential for anti-CTLA-4-based therapy in  previously treated patients with advanced melanoma. Moreover, because the  patterns of response to ipilimumab differ from chemotherapy, we need to  understand how and when patients may respond to treatment so that appropriate  clinical decisions can be made.
CANIT0000060	19147575	Clinical research	Metastatic, castration-resistant prostate cancer 	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); GM-CSF (P04141); 	CTLA-4; GM-CSF	Ipilimumab plus GM-CSF	N/A	Immune checkpoint therapy plus Tumor vaccine 	GM-CSF (DB05386); ipilimumab (DB06186); 	24	N/A	A phase I clinical trial 	These results show that this combination immunotherapy can induce the expansion not only of activated effector CD8 T cells in vivo but also of T cells that are specific for known tumor-associated antigens from the endogenous immune repertoire.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Effector CD8 T-cell 	Gene expression signature on/in immune cell	 2009 Jan 15	 Potentiating endogenous antitumor immunity to prostate cancer through combination  immunotherapy with CTLA4 blockade and GM-CSF.	 Cancer Res	 CTL-associated antigen 4 (CTLA4) is a costimulatory molecule expressed on  activated T cells that delivers an inhibitory signal to these T cells. CTLA4  blockade with antibody treatment has been shown to augment antitumor immunity in   animal models and is being developed as a treatment for cancer patients. As has  been seen in preclinical models, combining CTLA4 blockade and granulocyte  macrophage colony-stimulating factor (GM-CSF)-based immunotherapies can enhance  the antitumor efficacy of this approach. We therefore examined whether CTLA4  blockade could be combined with GM-CSF administration. We treated 24 patients  with metastatic, castration-resistant prostate cancer in a phase I trial where  sequential cohorts were treated with increasing doses of ipilimumab, a fully  human anti-CTLA4 antibody. Study subjects also received s.c. injections of GM-CSF  at a fixed dose. Of the six patients treated at the highest dose level, three had  confirmed PSA declines of >50%, including one patient that had a partial response  in visceral metastases. Expansion of activated, circulating CD25(+) CD69(+)  CD8(+) T cells occurred more frequently at higher doses of treatment and was  greater in magnitude than was seen in patients who received the same doses of  either ipilimumab or GM-CSF alone. By screening sera with protein arrays, we  showed that our treatment can induce antibody responses to NY-ESO-1. These  results show that this combination immunotherapy can induce the expansion not  only of activated effector CD8 T cells in vivo but also of T cells that are  specific for known tumor-associated antigens from the endogenous immune  repertoire.
CANIT0000061	19221742	Clinical research	Colorectal cancer liver metastasis	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine	N/A	Tumor vaccine	MVA-5T4 vaccine (NCIT:C49087); 	20	N/A	A phase II clinical trial	Responses to 5T4 protein or one or more peptide pools were pre-existing in 12/20 patients and subsequently 10 and 12 patients showed boosted and/or de novo responses, respectively. Cumulatively, 13/20 patients showed proliferative responses by week 13. We also assessed the levels of systemic T regulatory cells, plasma cytokine levels, phenotype of tumour-infiltrating lymphocytes including T regulatory cells and tumour HLA class I loss of expression. More than half of the patients showed phenotypes consistent with relative immune suppression and/or escape highlighting the complexity of positive and negative factors challenging any simple correlation with clinical outcome.	N/A	N/A	N/A	N/A	N/A	N/A	 2009 Oct	 Immune evasion mechanisms in colorectal cancer liver metastasis patients  vaccinated with TroVax (MVA-5T4).	 Cancer Immunol Immunother	 We have recently reported the results of a phase II trial in which two TroVax  [modified vaccinia ankara (MVA) encoding the tumour antigen 5T4] vaccinations  were given to patients both pre- and post-surgical resection of liver metastases   secondary to colorectal cancer (CRC). 5T4-specific cellular responses were  assessed at the entry and 2 weeks after each vaccination by proliferation of  fresh lymphocytes and ELISA for antibody responses; 18 from the 19 CRC patients  mounted a 5T4-specific cellular and/or humoral response. Here, we present a  comparison of individual and between patient responses over the course of the  treatments using cryopreserved peripheral blood mononuclear cells (PBMC) samples   from the baseline until after the fourth vaccination at 14 weeks. Assays used  were proliferation assay with 5T4-Fc fusion protein, overlapping 32mer 5T4  peptides, MVA-LacZ and MVA-5T4 infected autologous monocytes. Responses to 5T4  protein or one or more peptide pools were pre-existing in 12/20 patients and  subsequently 10 and 12 patients showed boosted and/or de novo responses,  respectively. Cumulatively, 13/20 patients showed proliferative responses by week  14. We also assessed the levels of systemic T regulatory cells, plasma cytokine  levels, phenotype of tumour-infiltrating lymphocytes including T regulatory cells  and tumour HLA class I loss of expression. More than half of the patients showed   phenotypes consistent with relative immune suppression and/or escape highlighting  the complexity of positive and negative factors challenging any simple  correlation with clinical outcome.
CANIT0000062	19242368	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	This report of acute grade 4 neutropenia associated with ipilimumab and clinically consistent with an autoimmune process emphasizes the importance of monitoring complete blood count during treatment with this new monoclonal antibody.	Neutropenia in a patient treated with ipilimumab	N/A	N/A	N/A	N/A	N/A	 2009 Apr	 Neutropenia in a patient treated with ipilimumab (anti-CTLA-4 antibody).	 J Immunother	 A 42-year-old white woman with a diagnosis of metastatic melanoma developed  severe neutropenia during treatment with ipilimumab (anticytotoxic  T-lymphocyte-associated antigen-4 antibody). Bone marrow aspiration and biopsy  specimens revealed marked myeloid hypoplasia, with unremarkable erythropoiesis  and megakaryopoiesis. The patient's neutropenia did not respond to therapy with a  combination of colony stimulating factors and steroids; however, it rapidly  improved after administration of intravenous immunoglobulin. Treatment with  ipilimumab has not been reported to be associated with hematologic toxicities,  and to our knowledge, no case of neutropenia has previously been reported. This  report of acute grade 4 neutropenia associated with ipilimumab and clinically  consistent with an autoimmune process emphasizes the importance of monitoring  complete blood count during treatment with this new monoclonal antibody.
CANIT0000063	19318477	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Several	N/A	A randomized, double-blind, phase II fixed-dose study	Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4.	N/A	N/A	N/A	Melan-A (Q16655); T-Lymphocyte (NCIT:C12476); 	Percentage of melan-A-specific cytotoxic T-cell 	Cell percentage/counts in blood	 2009 Apr 1	 Melan-A-specific cytotoxic T cells are associated with tumor regression and  autoimmunity following treatment with anti-CTLA-4.	 Clin Cancer Res	 PURPOSE: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory  interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical  trials in cancer patients with ipilimumab have shown promising antitumor  activity, particularly in patients with advanced melanoma. Often, tumor  regressions in these patients are correlated with immune-related side effects  such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are  believed to be immune-mediated, the antigenic targets for the cellular or humoral  immune response are not known. EXPERIMENTAL DESIGN: We enrolled patients with  advanced melanoma in a phase II study with ipilimumab. One of these patients  experienced a complete remission of his tumor. The specificity and functional  properties of CD8-positive T cells in his peripheral blood, in regressing tumor  tissue, and at the site of an immune-mediated skin rash were investigated.  RESULTS: Regressing tumor tissue was infiltrated with CD8-positive T cells, a  high proportion of which were specific for Melan-A. The skin rash was similarly  infiltrated with Melan-A-specific CD8-positive T cells, and a dramatic (>30-fold)  increase in Melan-A-specific CD8-positive T cells was apparent in peripheral  blood. These cells had an effector phenotype and lysed Melan-A-expressing tumor  cells. CONCLUSIONS: Our results show that Melan-A may be a major target for both   the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and   describe for the first time the antigen specificity of CD8-positive T cells that   mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4  antibody. These findings may allow a better integration of ipilimumab into other   forms of immunotherapy.
CANIT0000064	19457253	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	27	N/A	N/A	The anti-CTLA4  blocking antibody tremelimumab increases Th17 cells in peripheral blood of  patients with metastatic melanoma. The relation between increases in Th17 cells  and severe autoimmune toxicity after CTLA4 blockade may provide insights into the  pathogenesis of anti-CTLA4-induced toxicities.	The anti-CTLA4 blocking antibody tremelimumab increases Th17 cells in peripheral blood of patients with metastatic melanoma. The relation between increases in Th17 cells and severe autoimmune toxicity after CTLA4 blockade may provide insights into the pathogenesis of anti-CTLA4-induced toxicities.	N/A	N/A	Th17 cells (NCIT:C113815); 	Th17 cells in peripheral blood	Cell percentage/counts in blood	 2009 May 20	 CTLA4 blockade increases Th17 cells in patients with metastatic melanoma.	 J Transl Med	 BACKGROUND: Th17 cells are CD4+ cells that produce interleukin 17 (IL-17) and are  potent inducers of tissue inflammation and autoimmunity. We studied the levels of  this T cell subset in peripheral blood of patients treated with the anti-CTLA4  antibody tremelimumab since its major dose limiting toxicities are inflammatory  and autoimmune in nature. METHODS: Peripheral blood mononuclear cells (PBMC) were  collected before and after receiving tremelimumab within two clinical trials, one  with tremelimumab alone (21 patients) and another together with autologous  dendritic cells (DC) pulsed with the melanoma epitope MART-126-35 (6 patients).  Cytokines were quantified directly in plasma from patients and after in vitro  stimulation of PBMC. We also quantified IL-17 cytokine-producing cells by  intracellular cytokine staining (ICS). RESULTS: There were no significant changes  in 13 assayed cytokines, including IL-17, when analyzing plasma samples obtained   from patients before and after administration of tremelimumab. However, when PBMC  were activated in vitro, IL-17 cytokine in cell culture supernatant and Th17  cells, detected as IL-17-producing CD4 cells by ICS, significantly increased in  post-dosing samples. There were no differences in the levels of Th17 cells  between patients with or without an objective tumor response, but samples from  patients with inflammatory and autoimmune toxicities during the first cycle of  therapy had a significant increase in Th17 cells. CONCLUSION: The anti-CTLA4  blocking antibody tremelimumab increases Th17 cells in peripheral blood of  patients with metastatic melanoma. The relation between increases in Th17 cells  and severe autoimmune toxicity after CTLA4 blockade may provide insights into the  pathogenesis of anti-CTLA4-induced toxicities.
CANIT0000065	19474123	Case report	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	Case	Presumed ipilimumab-induced hypophysitis	We present the imaging findings in 3 patients with presumed ipilimumab-induced hypophysitis. the 3 patients presented with hypophysitis, which was attributed to an autoimmune process based on the documented relationship of the drug to other autoimmune phenomena and significant and rapid improvement with discontinuation of the drug and addition of steroids.	N/A	N/A	N/A	N/A	N/A	 2009 Oct	 Ipilimumab-induced hypophysitis: MR imaging findings.	 AJNR Am J Neuroradiol	 Ipilimumab is a promising new immunotherapeutic antineoplastic agent with  clinical activity in the treatment of metastatic melanoma and renal cell  carcinoma. With advances in immunotherapy, however, a host of new side effects  related to the mechanism of action of these drugs has appeared. At our  institution, 3 patients presented with hypophysitis, which was attributed to an  autoimmune process based on the documented relationship of the drug to other  autoimmune phenomena and significant and rapid improvement with discontinuation  of the drug and addition of steroids. We present the imaging findings in 3  patients with presumed ipilimumab-induced hypophysitis.
CANIT0000066	19507029	Clinical research	Refractory melanoma or prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	N/A	We performed immunohistochemical analysis of colon biopsies from ipilimumab recipients to determine if colitis correlates with depletion of intramucosal FOXP3(+) regulatory T cells (Tregs), which normally express CTLA4. However, we found no evidence of FOXP2(+) T cell depletion in any of the nine patients who developed colitis.	Refractory colitis	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2010 May	 Refractory colitis following anti-CTLA4 antibody therapy: analysis of mucosal  FOXP3+ T cells.	 Dig Dis Sci	 Ipilimumab is a humanized antibody to CTLA4 and is used to treat cancers  refractory to conventional treatment. We treated 21 patients with refractory  melanoma or prostate cancer with anti-CTLA4 antibody (ipilimumab), with  subsequent development of significant colitis in nine cases. Two of these nine  did not respond rapidly to high-dose (2 mg kg(-1) day(-1)) glucocorticoids or  infliximab. They required additional immunosuppression, and one ultimately died  of opportunistic infection, representing a more refractory course than has  previously been described complicating ipilimumab therapy. Both patients had  received radiation to the pelvis for prostate cancer less than 1 year prior to  receiving ipilimumab. We performed immunohistochemical analysis of colon biopsies  from ipilimumab recipients to determine if colitis correlates with depletion of  intramucosal FOXP3(+) regulatory T cells (Tregs), which normally express CTLA4.  However, we found no evidence of FOXP3(+) T cell depletion in any of the nine  patients who developed colitis.
CANIT0000067	19538054	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	Case	Treatment with infliximab, mesalamine, and hydrocortisone enemas may produce a rapid improvement in ipilimumab-induced colitis and avoid the administration of systemic steroids.	Anti-CTLA4 antibody (ipilimumab) induced immune-related colitis	N/A	N/A	N/A	N/A	N/A	 2009 Jun	 Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced  immune-related colitis.	 Cancer Biother Radiopharm	 The anti-CTLA4 antibody, ipilimumab, has shown clinical activity against  melanoma. Diarrhea due to immune-related colitis is the most frequent serious  toxicity and, if untreated, may lead to intestinal perforation. Diarrhea  treatment guidelines were developed based on clinical experience in over 2000  patients treated with ipilimumab, and these safety guidelines recommend systemic   steroids as the first choice for the treatment of severe diarrhea. In this  article, we present an alternative approach to the control of immune-related  colitis by using the antitumor necrosis factor antibody, infliximab. Patients  with metastatic melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 doses,   then every 3 months. Those who developed grade 2 diarrhea were treated with  infliximab 5 mg/kg weeks 0 and 2 with mesalamine and loperamide. Steroids were  given only for refractory cases requiring hospitalization. Of the first 3 cases  of ipilimumab-induced diarrhea, 2 proved refractory and required hospitalization,  but 1 recovered quickly without systemic steroids. We then added hydrocortisone  enemas daily to the above regimen, and the next 3 patients recovered from grade 2  ipilimumab-induced colitis without difficulty. Treatment with infliximab,  mesalamine, and hydrocortisone enemas may produce a rapid improvement in  ipilimumab-induced colitis and avoid the administration of systemic steroids.
CANIT0000068	19561532	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	5T4 (Q13641); INAR1 (P17181); 	5T4; INAR1	MVA-5T4 vaccine plus IFNA	MVA-5T4 vaccine	Tumor vaccine plus Immune cytokine	IFNA (DB00018); MVA-5T4 vaccine (NCIT:C49087); 	15	13	A phase II clinical trial	Despite the high frequency of 5T4-specific immune responses, it is not possible to conclude that patients are receiving clinical benefit. The results are encouraging and warrant further investigation.	MVA-5T4 administered alone or in combination with IFN-alpha was well tolerated in all patients. 	N/A	N/A	N/A	N/A	N/A	 2009 Sep	 Vaccination of renal cell cancer patients with modified vaccinia Ankara  delivering the tumor antigen 5T4 (TroVax) alone or administered in combination  with interferon-alpha (IFN-alpha): a phase 2 trial.	 J Immunother	 Attenuated vaccinia virus, modified vaccinia Ankara (MVA) has been engineered to   deliver the tumor antigen 5T4 (TroVax). MVA-5T4 has been evaluated in an  open-label phase 2 trial in metastatic renal cell cancer patients in which the  vaccine was administered alone or in combination with interferon-alpha-2b  (IFN-alpha). The safety, immunologic, and clinical efficacy of MVA-5T4 with or  without IFN-alpha was determined. Twenty-eight patients with metastatic renal  cell cancer were treated with MVA-5T4 alone (13) or plus IFN-alpha (15). The  5T4-specific cellular and humoral responses were monitored throughout the study.   Clinical responses were assessed by measuring changes in tumor burden by computed  tomography or magnetic resonance imaging scan. MVA-5T4 was well tolerated with no  serious adverse event attributed to vaccination. Of 23 intent-to-treat patients  tested for immune responses postvaccination, 22 (96%) mounted 5T4-specific  antibody and/or cellular responses. One patient treated with MVA-5T4 plus  IFN-alpha showed a partial response for >7 months, whereas an additional 14  patients (7 receiving MVA-5T4 plus IFN and 7 receiving MVA-5T4 alone) showed  periods of disease stabilization ranging from 1.73 to 9.60 months. Median  progression free survival and overall survival for all intent-to-treat patients  was 3.8 months (range: 1 to 11.47 mo) and 12.1 months (range: 1 to 27 mo),  respectively. MVA-5T4 administered alone or in combination with IFN-alpha was  well tolerated in all patients. Despite the high frequency of 5T4-specific immune  responses, it is not possible to conclude that patients are receiving clinical  benefit. The results are encouraging and warrant further investigation.
CANIT0000069	19671877	Clinical research	Unresectable stage III or IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus prophylactic budesonide	Ipilimumab plus placebo	Immune checkpoint therapy plus Chemotherapy	 prophylactic budesonide (DB01222); ipilimumab (DB06186); 	58	57	A randomized, double-blind, placebo-controlled, phase II study	Ipilimumab shows activity in advanced melanoma, with encouraging survival and manageable adverse events. Budesonide should not be used prophylactically for grade >or=2 diarrhea associated with ipilimumab therapy.	Budesonide did not affect the rate of grade >or=2 diarrhea, which occurred in 32.7% and 35.0% of patients in groups ipilimumab with prophylactic budesonide and ipilimumab without prophylactic budesonide, respectively. 	N/A	N/A	N/A	N/A	N/A	 2009 Sep 1	 A randomized, double-blind, placebo-controlled, phase II study comparing the  tolerability and efficacy of ipilimumab administered with or without prophylactic  budesonide in patients with unresectable stage III or IV melanoma.	 Clin Cancer Res	 PURPOSE: Diarrhea (with or without colitis) is an immune-related adverse event  (irAE) associated with ipilimumab. A randomized, double-blind,  placebo-controlled, multicenter, multinational phase II trial was conducted to  determine whether prophylactic budesonide (Entocort EC), a nonabsorbed oral  steroid, reduced the rate of grade >or=2 diarrhea in ipilimumab-treated patients   with advanced melanoma. EXPERIMENTAL DESIGN: Previously treated and  treatment-naive patients (N = 115) with unresectable stage III or IV melanoma  received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) with daily  blinded budesonide (group A) or placebo (group B) through week 16. The first  scheduled tumor evaluation was at week 12; eligible patients received maintenance  treatment starting at week 24. Diarrhea was assessed using Common Terminology  Criteria for Adverse Events (CTCAE) 3.0. Patients kept a diary describing their  bowel habits. RESULTS: Budesonide did not affect the rate of grade >or=2  diarrhea, which occurred in 32.7% and 35.0% of patients in groups A and B,  respectively. There were no bowel perforations or treatment-related deaths. Best   overall response rates were 12.1% in group A and 15.8% in group B, with a median   overall survival of 17.7 and 19.3 months, respectively. Within each group, the  disease control rate was higher in patients with grade 3 to 4 irAEs than in  patients with grade 0 to 2 irAEs, although many patients with grade 1 to 2 irAEs   experienced clinical benefit. Novel patterns of response to ipilimumab were  observed. CONCLUSIONS: Ipilimumab shows activity in advanced melanoma, with  encouraging survival and manageable adverse events. Budesonide should not be used  prophylactically for grade >or=2 diarrhea associated with ipilimumab therapy.
CANIT0000070	19789309	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	MART-1 peptide-dendritic cell vaccination plus tremelimumab	MART-1 peptide-dendritic cell vaccination	Immune checkpoint therapy plus Tumor vaccine 	Dendritic cell vaccine (NCIT:C28310); tremelimumab (DB11771); 	16	N/A	A phase I open-label, single site clinical trial	The combination of MART-1 peptide-pulsed DC and  tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.Exploratory gene expression analysis suggested that immune-related gene  signatures, in particular for B-cell function, may be important in predicting  response.	Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly.	N/A	N/A	N/A	Immune-related gene signatures, in particular for B-cell function	Gene expression signature on/in immune cell	 2009 Oct 1	 Dendritic cell vaccination combined with CTLA4 blockade in patients with  metastatic melanoma.	 Clin Cancer Res	 PURPOSE: Tumor antigen-loaded dendritic cells (DC) are believed to activate  antitumor immunity by stimulating T cells, and CTL-associated antigen 4  (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T  cells. The combination was tested in a phase I clinical trial in patients with  advanced melanoma. EXPERIMENTAL DESIGN: Autologous DC were pulsed with  MART-1(26-35) peptide and administered with a dose escalation of the  CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose   levels. Primary end points were safety and immune effects; clinical efficacy was   a secondary end point. RESULTS: Dose-limiting toxicities of grade 3 diarrhea and   grade 2 hypophysitis developed in two of three patients receiving tremelimumab at  10 mg/kg monthly. Four patients had an objective tumor response, two partial  responses and two complete responses, all melanoma free between 2 and 4 years  after study initiation. There was no difference in immune monitoring results  between patients with an objective tumor response and those without a response.  Exploratory gene expression analysis suggested that immune-related gene  signatures, in particular for B-cell function, may be important in predicting  response. CONCLUSION: The combination of MART-1 peptide-pulsed DC and  tremelimumab results in objective and durable tumor responses at the higher range  of the expected response rate with either agent alone.
CANIT0000071	19789309	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	MART-1 peptide-dendritic cell vaccination plus tremelimumab	Tremelimumab	Immune checkpoint therapy plus Tumor vaccine 	Dendritic cell vaccine (NCIT:C28310); tremelimumab (DB11771); 	16	N/A	A phase I open-label, single site clinical trial	The combination of MART-1 peptide-pulsed DC and  tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.Exploratory gene expression analysis suggested that immune-related gene  signatures, in particular for B-cell function, may be important in predicting  response.	Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly.	N/A	N/A	N/A	Immune-related gene signatures, in particular for B-cell function	Gene expression signature on/in immune cell	 2009 Oct 1	 Dendritic cell vaccination combined with CTLA4 blockade in patients with  metastatic melanoma.	 Clin Cancer Res	 PURPOSE: Tumor antigen-loaded dendritic cells (DC) are believed to activate  antitumor immunity by stimulating T cells, and CTL-associated antigen 4  (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T  cells. The combination was tested in a phase I clinical trial in patients with  advanced melanoma. EXPERIMENTAL DESIGN: Autologous DC were pulsed with  MART-1(26-35) peptide and administered with a dose escalation of the  CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose   levels. Primary end points were safety and immune effects; clinical efficacy was   a secondary end point. RESULTS: Dose-limiting toxicities of grade 3 diarrhea and   grade 2 hypophysitis developed in two of three patients receiving tremelimumab at  10 mg/kg monthly. Four patients had an objective tumor response, two partial  responses and two complete responses, all melanoma free between 2 and 4 years  after study initiation. There was no difference in immune monitoring results  between patients with an objective tumor response and those without a response.  Exploratory gene expression analysis suggested that immune-related gene  signatures, in particular for B-cell function, may be important in predicting  response. CONCLUSION: The combination of MART-1 peptide-pulsed DC and  tremelimumab results in objective and durable tumor responses at the higher range  of the expected response rate with either agent alone.
CANIT0000072	19808874	Clinical research	Relapsed/refractory B-cell lymphoma	B-cell non-hodgkins lymphoma	EFO:1001938	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	18	N/A	A phase I clinical trial 	Blockade of CTLA-4 signaling with the use of ipilimumab is well tolerated at the doses used and has antitumor activity in patients with B-cell lymphoma.	Eighteen patients were treated, 12 at the lower dose level and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to it, including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia.	N/A	N/A	N/A	N/A	N/A	 2009 Oct 15	 Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with  relapsed and refractory B-cell non-Hodgkin lymphoma.	 Clin Cancer Res	 PURPOSE: The growth of non-Hodgkin lymphomas can be influenced by tumor-immune  system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative  regulator of T-cell activation that serves to dampen antitumor immune responses.   Blocking anti-CTLA-4 monoclonal antibodies improves host resistance to  immunogenic tumors, and the anti-CTLA-4 antibody ipilimumab (MDX-010) has  clinical activity against melanoma, prostate, and ovarian cancers. EXPERIMENTAL  DESIGN: We did a phase I trial of ipilimumab in patients with relapsed/refractory  B-cell lymphoma to evaluate safety, immunologic activity, and potential clinical   efficacy. Treatment consisted of ipilimumab at 3 mg/kg and then monthly at 1  mg/kg x 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly x   4 months (dose level 2). RESULTS: Eighteen patients were treated, 12 at the lower  dose level and 6 at the higher dose level. Ipilimumab was generally well  tolerated, with common adverse events attributed to it, including diarrhea,  headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia.  Two patients had clinical responses; one patient with diffuse large B-cell  lymphoma had an ongoing complete response (>31 months), and one with follicular  lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%),  T-cell proliferation to recall antigens was significantly increased (>2-fold)  after ipilimumab therapy. CONCLUSIONS: Blockade of CTLA-4 signaling with the use   of ipilimumab is well tolerated at the doses used and has antitumor activity in  patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in  combination with other agents in B-cell lymphoma patients is therefore warranted.
CANIT0000073	20004617	Clinical research	Pretreated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	217	N/A	A randomised, double-blind, multicentre, phase II, dose-ranging study	Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with  advanced melanoma, lending support to further studies at a dose of 10 mg/kg.	Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group).	N/A	N/A	N/A	N/A	N/A	 2010 Feb	 Ipilimumab monotherapy in patients with pretreated advanced melanoma: a  randomised, double-blind, multicentre, phase 2, dose-ranging study.	 Lancet Oncol	 BACKGROUND: Ipilimumab is a human monoclonal antibody that blocks cytotoxic  T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We   aimed to ascertain the antitumour efficacy of ipilimumab in patients with  advanced melanoma. METHODS: We undertook a randomised, double-blind, phase 2  trial in 66 centres from 12 countries. 217 patients with previously treated stage  III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of  ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3  weeks for four cycles (induction) followed by maintenance therapy every 3 months.  Randomisation was done with a permuted block procedure, stratified on the basis  of type of previous treatment. The primary endpoint was best overall response  rate (the proportion of patients with a complete or partial response, according  to modified WHO criteria). Efficacy analyses were done by intention to treat,  whereas safety analyses included patients who received at least one dose of  ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640.  FINDINGS: The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10  mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015;  trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of   71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg,  respectively; the most common grade 3-4 adverse events were gastrointestinal  immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none  in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3  mg/kg group, none in the 0.3 mg/kg group). INTERPRETATION: Ipilimumab elicited a   dose-dependent effect on efficacy and safety measures in pretreated patients with  advanced melanoma, lending support to further studies at a dose of 10 mg/kg.  FUNDING: Bristol-Myers Squibb.CI  - Copyright 2010 Elsevier Ltd. All rights reserved.
CANIT0000074	20043222	Clinical research	HLA-A2 positive patients with stage III/IV melanoma	Melanoma	EFO:0000756	Skin	HLA-A1 (P04439); HLA-A2 (P04439); 	HLA-A1; HLA-A2	MVA-HLA.A2 or A1 epitopes vaccine	N/A	Tumor vaccine	MVA-HLA.A2/A1 epitopes vaccine (NCIT:C1572); 	41	N/A	N/A	DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune  responses with patient outcomes encourages further investigation.	High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions.	N/A	N/A	N/A	N/A	N/A	 2010 Jun	 Clinical and immunological responses in metastatic melanoma patients vaccinated  with a high-dose poly-epitope vaccine.	 Cancer Immunol Immunother	 BACKGROUND: Safety and cellular immunogenicity of rising doses and varying  regimens of a poly-epitope vaccine were evaluated in advanced metastatic  melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia  virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes  from five melanoma antigens. METHODS: Forty-one HLA-A2 positive patients with  stage III/IV melanoma were enrolled. Patient groups received one or two doses of   DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued  eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell   responses were evaluated using ex-vivo tetramer and IFNG ELISPOT assays.  Safety and clinical responses were monitored. RESULTS: Prime-boost DNA/MVA  induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected  by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31  (32%) patients. T cell responder rates were <50% with low-dose DNA/MVA, or MVA  alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing  evidence of clinical benefit-one PR (24 months+), five SD (5 months+) and two  mixed responses-seven had associated immune responses. Melan-A-tetramer+ immunity  was associated with a median 8-week increase in time-to-progression (P = 0.037)  and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose  vaccine was well tolerated. The only significant toxicities were flu-like  symptoms and injection-site reactions. CONCLUSIONS: DNA.Mel3 and MVA.Mel3 in a  prime-boost protocol generated high rates of immune response to melanoma antigen   epitopes. The treatment was well tolerated and the correlation of immune  responses with patient outcomes encourages further investigation.
CANIT0000075	20082117	Clinical research	Chemotherapy-na ve patients with advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus dacarbazine	Ipilimumab	Immune checkpoint therapy plus Target therapy	Dacarbazine (DB00851); ipilimumab (DB06186); 	35	37	A phase II multicenter study	Ipilimumab therapy resulted in clinically meaningful responses in  advanced melanoma patients, and the results support further investigations of  ipilimumab in combination with DTIC.	Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% grade 3, respectively.	N/A	N/A	N/A	N/A	N/A	 2011 Jun	 A phase II multicenter study of ipilimumab with or without dacarbazine in  chemotherapy-naive patients with advanced melanoma.	 Invest New Drugs	 OBJECTIVE: Ipilimumab is a fully human, anti-cytotoxic T-lymphocyte antigen-4  (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced  melanoma. We evaluated the safety and efficacy of ipilimumab alone and in  combination with dacarbazine (DTIC) in patients with unresectable, metastatic  melanoma. METHODS: Chemotherapy-naive patients were randomized in this  multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for  four doses either alone or with up to six 5-day courses of DTIC at 250  mg/m(2)/day. The primary efficacy endpoint was objective response rate. RESULTS:   Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35;  ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8-30.3)  with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7-18.2) with ipilimumab alone.   At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32)  and ipilimumab alone (n = 32), respectively, median overall survival was 14.3  months (95% CI, 10.2-18.8) and 11.4 months (95% CI, 6.1-15.6); 12-month,  24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab  plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group,  respectively. Immune-related adverse events were, in general, medically  manageable and occurred in 65.7% of patients in the combination group versus  53.8% in the monotherapy group, with 17.1% and 7.7% >/=grade 3, respectively.  CONCLUSION: Ipilimumab therapy resulted in clinically meaningful responses in  advanced melanoma patients, and the results support further investigations of  ipilimumab in combination with DTIC.
CANIT0000076	20143434	Clinical research	Advanced refractory melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	53	N/A	N/A	The results confirm that ipilimumab is clinically active in patients with advanced refractory melanoma. The ALC after 2 ipilimumab treatments appears to correlate with clinical benefit and OS, and should be prospectively validated.	Grade 3/4 immune-related adverse events were noted in 29% of patients, with the most common immune-related adverse events being pruritus (43%), rash (37%), and diarrhea (33%).	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2010 Apr 1	 Single-institution experience with ipilimumab in advanced melanoma patients in  the compassionate use setting: lymphocyte count after 2 doses correlates with  survival.	 Cancer	 BACKGROUND: : Ipilimumab is a monoclonal antibody that antagonizes cytotoxic T  lymphocyte antigen-4, a negative regulator of the immune system. The authors  report on advanced refractory melanoma patients treated in a compassionate use  trial of ipilimumab at the Memorial Sloan-Kettering Cancer Center. METHODS: :  Patients with advanced refractory melanoma were treated in a compassionate use  trial with ipilimumab 10 mg/kg every 3 weeks for 4 doses. Those with evidence of   clinical benefit at Week 24 (complete response [CR], partial response [PR], or  stable disease [SD]) then received ipilimumab every 12 weeks. RESULTS: : A total   of 53 patients were enrolled, with 51 evaluable. Grade 3/4 immune-related adverse  events were noted in 29% of patients, with the most common immune-related adverse  events being pruritus (43%), rash (37%), and diarrhea (33%). On the basis of  immune-related response criteria, the response rate (CR + PR) was 12% (95%  confidence interval [CI], 5%-25%), whereas 29% had SD (95% CI, 18%-44%). The  median progression-free survival was 2.6 months (95% CI, 2.3-5.2 months), whereas  the median overall survival (OS) was 7.2 months (95% CI, 4.0-13.3 months).  Patients with an absolute lymphocyte count (ALC) > micro =1000/microL after 2  ipilimumab treatments (Week 7) had a significantly improved clinical benefit rate  (51% vs 0%; P = .01) and median OS (11.9 vs 1.4 months; P < .001) compared with  those with an ALC <1000/microL. CONCLUSIONS: : The results confirm that  ipilimumab is clinically active in patients with advanced refractory melanoma.  The ALC after 2 ipilimumab treatments appears to correlate with clinical benefit   and OS, and should be prospectively validated. Cancer 2010. (c) 2010 American  Cancer Society.
CANIT0000077	20147741	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	155	N/A	A multicenter single-arm phase II	Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.	Adverse events (AEs) were largely immune related, occurring mainly in the skin and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs were manageable and generally reversible with corticosteroids	N/A	N/A	N/A	N/A	N/A	 2010 Aug	 Efficacy and safety of ipilimumab monotherapy in patients with pretreated  advanced melanoma: a multicenter single-arm phase II study.	 Ann Oncol	 BACKGROUND: This phase II study evaluated the safety and activity of ipilimumab,   a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4, in patients with   advanced melanoma. PATIENTS AND METHODS: Patients with previously treated,  unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3  weeks for four cycles (induction) followed by maintenance therapy every 3 months.  The primary end point was best overall response rate (BORR) using modified World   Health Organization (WHO) criteria. We also carried out an exploratory analysis  of proposed immune-related response criteria (irRC). RESULTS: BORR was 5.8% with   a disease control rate (DCR) of 27% (N = 155). One- and 2-year survival rates  (95% confidence interval) were 47.2% (39.5% to 55.1%) and 32.8% (25.4% to 40.5%),  respectively, with a median overall survival of 10.2 months (7.6-16.3). Of 43  patients with disease progression by modified WHO criteria, 12 had disease  control by irRC (8% of all treated patients), resulting in a total DCR of 35%.  Adverse events (AEs) were largely immune related, occurring mainly in the skin  and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs  were manageable and generally reversible with corticosteroids. CONCLUSION:  Ipilimumab demonstrated clinical activity with encouraging long-term survival in   a previously treated advanced melanoma population.
CANIT0000078	20179239	Clinical research	Metastatic gastric and esophageal adenocarcinomas	Esophageal adenocarcinoma	EFO:0000478	Esophagus	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	18	N/A	A phase II clinical trial	Baseline interleukin-2 release after T-cell activation was higher in patients with clinical benefit and toxicity.	Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis.	N/A	N/A	IL2 (P60568); T-Lymphocyte (NCIT:C12476); 	Baseline IL2 release after T-cell activation	Gene expression signature in serum	 2010 Mar 1	 Modulation of lymphocyte regulation for cancer therapy: a phase II trial of  tremelimumab in advanced gastric and esophageal adenocarcinoma.	 Clin Cancer Res	 PURPOSE: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of  T-cell activation, is targeted by the antibody tremelimumab to release  potentially useful antitumor activity. EXPERIMENTAL DESIGN: This phase II trial  investigated tremelimumab as a second-line treatment for patients with metastatic  gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months  until symptomatic disease progression. Safety, clinical efficacy, and immunologic  activity were evaluated. RESULTS: Eighteen patients received tremelimumab. Most  drug-related toxicity was mild; however, there was a single death due to bowel  perforation that complicated colitis. Four patients had stable disease with  clinical benefit; one patient achieved a partial response after eight cycles  (25.4 months) and remains well on study at 32.7 months. Markers of regulatory  phenotype, forkhead box protein 3 and CTLA4, doubled transiently in  CD4(+)CD25(high) lymphocytes in the first month after tremelimumab before  returning to baseline. In contrast, CTLA4 increased in CD4(+)CD25(low/negative)  lymphocytes throughout the cycle of treatment. De novo proliferative responses to  tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5   of 13) were detected. Patients with a posttreatment carcinoembryonic antigen  proliferative response had median survival of 17.1 months compared with 4.7  months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell  activation was higher in patients with clinical benefit and toxicity. CONCLUSION:  Despite the disappointing response rate of tremelimumab, one patient had a  remarkably durable benefit for this poor-prognosis disease. In vitro evidence of   enhanced proliferative responses to relevant tumor-associated antigens suggests  that combining CTLA4 blockade with antigen-targeted therapy may warrant further  investigation.
CANIT0000079	20179239	Clinical research	Metastatic gastric and esophageal adenocarcinomas	Esophageal adenocarcinoma	EFO:0000478	Esophagus	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	18	N/A	A phase II clinical trial	Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17.1 months compared with 4.7 months for nonresponders (P = 0.004).	Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis.	N/A	N/A	Carcinoembryonic antigen (P06731); 	Posttreatment carcinoembryonic antigen proliferative response	Immune response	 2010 Mar 1	 Modulation of lymphocyte regulation for cancer therapy: a phase II trial of  tremelimumab in advanced gastric and esophageal adenocarcinoma.	 Clin Cancer Res	 PURPOSE: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of  T-cell activation, is targeted by the antibody tremelimumab to release  potentially useful antitumor activity. EXPERIMENTAL DESIGN: This phase II trial  investigated tremelimumab as a second-line treatment for patients with metastatic  gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months  until symptomatic disease progression. Safety, clinical efficacy, and immunologic  activity were evaluated. RESULTS: Eighteen patients received tremelimumab. Most  drug-related toxicity was mild; however, there was a single death due to bowel  perforation that complicated colitis. Four patients had stable disease with  clinical benefit; one patient achieved a partial response after eight cycles  (25.4 months) and remains well on study at 32.7 months. Markers of regulatory  phenotype, forkhead box protein 3 and CTLA4, doubled transiently in  CD4(+)CD25(high) lymphocytes in the first month after tremelimumab before  returning to baseline. In contrast, CTLA4 increased in CD4(+)CD25(low/negative)  lymphocytes throughout the cycle of treatment. De novo proliferative responses to  tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5   of 13) were detected. Patients with a posttreatment carcinoembryonic antigen  proliferative response had median survival of 17.1 months compared with 4.7  months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell  activation was higher in patients with clinical benefit and toxicity. CONCLUSION:  Despite the disappointing response rate of tremelimumab, one patient had a  remarkably durable benefit for this poor-prognosis disease. In vitro evidence of   enhanced proliferative responses to relevant tumor-associated antigens suggests  that combining CTLA4 blockade with antigen-targeted therapy may warrant further  investigation.
CANIT0000080	20179239	Clinical research	Metastatic gastric and esophageal adenocarcinomas	Gastric adenocarcinoma	EFO:0000503	Stomach	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	18	N/A	A phase II clinical trial	Baseline interleukin-2 release after T-cell activation was higher in patients with clinical benefit and toxicity.	Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis.	N/A	N/A	IL2 (P60568); T-Lymphocyte (NCIT:C12476); 	Baseline IL2 release after T-cell activation	Gene expression signature in serum	 2010 Mar 1	 Modulation of lymphocyte regulation for cancer therapy: a phase II trial of  tremelimumab in advanced gastric and esophageal adenocarcinoma.	 Clin Cancer Res	 PURPOSE: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of  T-cell activation, is targeted by the antibody tremelimumab to release  potentially useful antitumor activity. EXPERIMENTAL DESIGN: This phase II trial  investigated tremelimumab as a second-line treatment for patients with metastatic  gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months  until symptomatic disease progression. Safety, clinical efficacy, and immunologic  activity were evaluated. RESULTS: Eighteen patients received tremelimumab. Most  drug-related toxicity was mild; however, there was a single death due to bowel  perforation that complicated colitis. Four patients had stable disease with  clinical benefit; one patient achieved a partial response after eight cycles  (25.4 months) and remains well on study at 32.7 months. Markers of regulatory  phenotype, forkhead box protein 3 and CTLA4, doubled transiently in  CD4(+)CD25(high) lymphocytes in the first month after tremelimumab before  returning to baseline. In contrast, CTLA4 increased in CD4(+)CD25(low/negative)  lymphocytes throughout the cycle of treatment. De novo proliferative responses to  tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5   of 13) were detected. Patients with a posttreatment carcinoembryonic antigen  proliferative response had median survival of 17.1 months compared with 4.7  months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell  activation was higher in patients with clinical benefit and toxicity. CONCLUSION:  Despite the disappointing response rate of tremelimumab, one patient had a  remarkably durable benefit for this poor-prognosis disease. In vitro evidence of   enhanced proliferative responses to relevant tumor-associated antigens suggests  that combining CTLA4 blockade with antigen-targeted therapy may warrant further  investigation.
CANIT0000081	20179239	Clinical research	Metastatic gastric and esophageal adenocarcinomas	Gastric adenocarcinoma	EFO:0000503	Stomach	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	18	N/A	A phase II clinical trial	Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17.1 months compared with 4.7 months for nonresponders (P = 0.004).	Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis.	N/A	N/A	Carcinoembryonic antigen (P06731); 	Posttreatment carcinoembryonic antigen proliferative response	Immune response	 2010 Mar 1	 Modulation of lymphocyte regulation for cancer therapy: a phase II trial of  tremelimumab in advanced gastric and esophageal adenocarcinoma.	 Clin Cancer Res	 PURPOSE: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of  T-cell activation, is targeted by the antibody tremelimumab to release  potentially useful antitumor activity. EXPERIMENTAL DESIGN: This phase II trial  investigated tremelimumab as a second-line treatment for patients with metastatic  gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months  until symptomatic disease progression. Safety, clinical efficacy, and immunologic  activity were evaluated. RESULTS: Eighteen patients received tremelimumab. Most  drug-related toxicity was mild; however, there was a single death due to bowel  perforation that complicated colitis. Four patients had stable disease with  clinical benefit; one patient achieved a partial response after eight cycles  (25.4 months) and remains well on study at 32.7 months. Markers of regulatory  phenotype, forkhead box protein 3 and CTLA4, doubled transiently in  CD4(+)CD25(high) lymphocytes in the first month after tremelimumab before  returning to baseline. In contrast, CTLA4 increased in CD4(+)CD25(low/negative)  lymphocytes throughout the cycle of treatment. De novo proliferative responses to  tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5   of 13) were detected. Patients with a posttreatment carcinoembryonic antigen  proliferative response had median survival of 17.1 months compared with 4.7  months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell  activation was higher in patients with clinical benefit and toxicity. CONCLUSION:  Despite the disappointing response rate of tremelimumab, one patient had a  remarkably durable benefit for this poor-prognosis disease. In vitro evidence of   enhanced proliferative responses to relevant tumor-associated antigens suggests  that combining CTLA4 blockade with antigen-targeted therapy may warrant further  investigation.
CANIT0000082	20371685	Clinical research	Glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	TLR3 (O15455); 	TLR3; 	Radiotherapy plus temozolomide plus poly-ICLC	Radiation  plus temozolomide	Tumor vaccine plus Radiotherapy	Temozolomide (DB00853); radiotherapy (NCIT:C15313); cilengitide (DB11890); poly-ICLC (NCIT:C1198); talampanel (DB04982); 	281	84	A phase II/III clinical trial 	Newly  diagnosed glioblastoma treated recently with RT + TMZ and talampanel, poly-ICLC, or cilengitide had significantly longer survival than similar patients treated  with only RT + TMZ accrued internationally from 2000 to 2002.	N/A	N/A	N/A	N/A	N/A	N/A	 2010 Apr 15	 Survival of patients with newly diagnosed glioblastoma treated with radiation and  temozolomide in research studies in the United States.	 Clin Cancer Res	 PURPOSE: Novel agents are currently combined with radiation and temozolomide (RT   + TMZ) in newly diagnosed glioblastoma using overall survival as the primary end   point. Results of these phase II studies are typically compared with the phase  III European Organization for Research and Treatment of Cancer (EORTC) survival  data that resulted in RT + TMZ becoming standard therapy. EXPERIMENTAL DESIGN:  The New Approaches to Brain Tumor Therapy (NABTT) Consortium assigned 365  patients with glioblastoma to four single-cohort studies with similar eligibility  criteria. Patients received RT + TMZ with talampanel (n = 72), poly-ICLC (n =  97), or cilengitide (n = 112) or RT + TMZ alone with monitoring of CD4 counts (n   = 84). Overall survival of those ages 18 to 70 years with glioblastoma was  compared with published EORTC data. RESULTS: NABTT and EORTC patients had  comparable performance status and debulking surgery. Median, 12-month, and  24-month survival rates for the EORTC patients (n = 287) and the comparable NABTT  patients receiving RT + TMZ and novel agents (n = 244) are 14.6 versus 19.6  months, 61% versus 81%, and 27% versus 37%, respectively. This represents a 37%  reduction in odds of death (P < 0.0001) through 2 years of follow-up. NABTT and  EORTC patients receiving only RT + TMZ had similar survival. CONCLUSIONS: Newly  diagnosed glioblastoma treated recently with RT + TMZ and talampanel, poly-ICLC,   or cilengitide had significantly longer survival than similar patients treated  with only RT + TMZ accrued internationally from 2000 to 2002. These differences  could result from the novel agents or changing patterns of care. Until the  reasons for these different survival rates are clarified, comparisons of outcomes  from phase II studies with published RT + TMZ survival data should be interpreted  with caution.
CANIT0000083	20460488	Clinical research	Urothelial carcinoma of the bladder	Bladder cancer	EFO:0000292	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	12	N/A	N/A	Our trial shows that anti-CTLA-4 therapy has a tolerable safety profile in the presurgical setting and that a preoperative model can be used to obtain biological data on human immune responses, which can efficiently guide the monitoring of patients treated in the metastatic disease setting. An increased frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy, correlates with increased likelihood of clinical benefit consisting of overall survival.	Most drug-related adverse events consisted of grade 1/2 toxicities.	N/A	N/A	ICOS (Q9Y6W8); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	Frequency of CD4(+)ICOShi T-cell 	Gene expression signature on/in immune cell	 2010 May 15	 Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting  of a presurgical clinical trial.	 Clin Cancer Res	 PURPOSE: Cytotoxic T lymphocyte associated antigen (CTLA-4) blockade is being  explored in numerous clinical trials as an immune-based therapy for different  malignancies. Our group conducted the first preoperative clinical trial with the   anti-CTLA-4 antibody ipilimumab in 12 patients with localized urothelial  carcinoma of the bladder. EXPERIMENTAL DESIGN: Six patients were treated with 3  mg/kg/dose of anti-CTLA-4 and six patients were treated with 10 mg/kg/dose of  antibody. Primary end points of the study were safety and immune monitoring.  RESULTS: Most drug-related adverse events consisted of grade 1/2 toxicities. All   patients had measurable immunologic pharmacodynamic effects, consisting of an  increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic  circulation. To determine if CD4+ICOShi T cells could be a correlative marker for  clinical outcome after treatment with anti-CTLA-4, a cohort of metastatic  melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells  and survival. Data from this small cohort of patients indicated that an increased  frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy,   correlates with increased likelihood of clinical benefit consisting of overall  survival. CONCLUSIONS: Our trial shows that anti-CTLA-4 therapy has a tolerable  safety profile in the presurgical setting and that a preoperative model can be  used to obtain biological data on human immune responses, which can efficiently  guide the monitoring of patients treated in the metastatic disease setting.CI  - Copyright (c) 2010 AACR.
CANIT0000084	20466887	Clinical research	HER-2/neu(+) prostate cancer	Prostate cancer	MONDO:0008315	Prostate	HER2 (P04626); 	HER2; 	AE36 vaccine	N/A	Tumor vaccine	AE36 vaccine (NCIT:C2537); 	32	N/A	A phase I clinical trial 	AE37 vaccine is safe and can induce HER-2/neu-specific cellular immune responses in patients with castrate-sensitive and castrate-resistant prostate cancer, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer.  Additionally, significant decreases could be detected in circulating Treg frequencies, plasma HER-2/neu, and serum transforming growth factor-beta levels. Patients with less extensive disease developed better immunologic responses on vaccination.	Toxicities beyond grade 2 were not observed. 	N/A	N/A	Treg cells (CL:0000815); T-Lymphocyte (NCIT:C12476); 	Circulating Treg frequencies	Cell percentage/counts in blood	 2010 Jul 1	 Results from a phase I clinical study of the novel Ii-Key/HER-2/neu(776-790)  hybrid peptide vaccine in patients with prostate cancer.	 Clin Cancer Res	 PURPOSE: Active immunotherapy is emerging as a potential therapeutic approach for  prostate cancer. We conducted the first phase I trial of an  Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine (AE37) with recombinant  granulocyte macrophage colony-stimulating factor as adjuvant in patients with  HER-2/neu(+) prostate cancer. The primary end points of the study were to  evaluate toxicity and monitor patients' immune responses to the vaccine.  EXPERIMENTAL DESIGN: Thirty-two HER-2/neu(+), castrate-sensitive, and  castrate-resistant prostate cancer patients were enrolled. Of these, 29 patients   completed all six vaccination cycles with AE37. Immunologic responses in the  total patient population were monitored by delayed-type hypersensitivity and  IFNG ELISPOT and intracellular staining. Regulatory T-cell (Treg) frequency   and plasma HER-2/neu and transforming growth factor-beta levels were also  determined. Immunologic responses were also analyzed among groups of patients  with different clinical characteristics. Local/systemic toxicities were monitored  throughout the study. RESULTS: Toxicities beyond grade 2 were not observed.  Seventy-five percent of patients developed augmented immunity to the AE37 vaccine  and 65% to the unmodified AE36 peptide as detected in the IFN-gamma-based ELISPOT  assay. Intracellular IFNG analyses revealed that AE37 elicited both CD4(+)  and CD8(+) T-cell responses. Eighty percent of the patients developed a positive   delayed-type hypersensitivity reaction to AE36. Additionally, significant  decreases could be detected in circulating Treg frequencies, plasma HER-2/neu,  and serum transforming growth factor-beta levels. Patients with less extensive  disease developed better immunologic responses on vaccination. CONCLUSION: AE37  vaccine is safe and can induce HER-2/neu-specific cellular immune responses in  patients with castrate-sensitive and castrate-resistant prostate cancer, thus  emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of  prostate cancer.
CANIT0000085	20466887	Clinical research	HER-2/neu(+) prostate cancer	Prostate cancer	MONDO:0008315	Prostate	HER2 (P04626); 	HER2; 	AE36 vaccine	N/A	Tumor vaccine	AE36 vaccine (NCIT:C2537); 	32	N/A	A phase I clinical trial 	AE37 vaccine is safe and can induce HER-2/neu-specific cellular immune responses in patients with castrate-sensitive and castrate-resistant prostate cancer, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer.  Additionally, significant decreases could be detected in circulating Treg frequencies, plasma HER-2/neu, and serum transforming growth factor-beta levels. Patients with less extensive disease developed better immunologic responses on vaccination.	Toxicities beyond grade 2 were not observed. 	N/A	N/A	HER2 (P04626); 	Serum HER2 expression levels	Gene expression signature in serum	 2010 Jul 1	 Results from a phase I clinical study of the novel Ii-Key/HER-2/neu(776-790)  hybrid peptide vaccine in patients with prostate cancer.	 Clin Cancer Res	 PURPOSE: Active immunotherapy is emerging as a potential therapeutic approach for  prostate cancer. We conducted the first phase I trial of an  Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine (AE37) with recombinant  granulocyte macrophage colony-stimulating factor as adjuvant in patients with  HER-2/neu(+) prostate cancer. The primary end points of the study were to  evaluate toxicity and monitor patients' immune responses to the vaccine.  EXPERIMENTAL DESIGN: Thirty-two HER-2/neu(+), castrate-sensitive, and  castrate-resistant prostate cancer patients were enrolled. Of these, 29 patients   completed all six vaccination cycles with AE37. Immunologic responses in the  total patient population were monitored by delayed-type hypersensitivity and  IFNG ELISPOT and intracellular staining. Regulatory T-cell (Treg) frequency   and plasma HER-2/neu and transforming growth factor-beta levels were also  determined. Immunologic responses were also analyzed among groups of patients  with different clinical characteristics. Local/systemic toxicities were monitored  throughout the study. RESULTS: Toxicities beyond grade 2 were not observed.  Seventy-five percent of patients developed augmented immunity to the AE37 vaccine  and 65% to the unmodified AE36 peptide as detected in the IFN-gamma-based ELISPOT  assay. Intracellular IFNG analyses revealed that AE37 elicited both CD4(+)  and CD8(+) T-cell responses. Eighty percent of the patients developed a positive   delayed-type hypersensitivity reaction to AE36. Additionally, significant  decreases could be detected in circulating Treg frequencies, plasma HER-2/neu,  and serum transforming growth factor-beta levels. Patients with less extensive  disease developed better immunologic responses on vaccination. CONCLUSION: AE37  vaccine is safe and can induce HER-2/neu-specific cellular immune responses in  patients with castrate-sensitive and castrate-resistant prostate cancer, thus  emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of  prostate cancer.
CANIT0000086	20466887	Clinical research	HER-2/neu(+) prostate cancer	Prostate cancer	MONDO:0008315	Prostate	HER2 (P04626); 	HER2; 	AE36 vaccine	N/A	Tumor vaccine	AE36 vaccine (NCIT:C2537); 	32	N/A	A phase I clinical trial 	AE37 vaccine is safe and can induce HER-2/neu-specific cellular immune responses in patients with castrate-sensitive and castrate-resistant prostate cancer, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer.  Additionally, significant decreases could be detected in circulating Treg frequencies, plasma HER-2/neu, and serum transforming growth factor-beta levels. Patients with less extensive disease developed better immunologic responses on vaccination.	Toxicities beyond grade 2 were not observed. 	N/A	N/A	TGFB (P01137); 	Serum TGFB expression levels	Gene expression signature in serum	 2010 Jul 1	 Results from a phase I clinical study of the novel Ii-Key/HER-2/neu(776-790)  hybrid peptide vaccine in patients with prostate cancer.	 Clin Cancer Res	 PURPOSE: Active immunotherapy is emerging as a potential therapeutic approach for  prostate cancer. We conducted the first phase I trial of an  Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine (AE37) with recombinant  granulocyte macrophage colony-stimulating factor as adjuvant in patients with  HER-2/neu(+) prostate cancer. The primary end points of the study were to  evaluate toxicity and monitor patients' immune responses to the vaccine.  EXPERIMENTAL DESIGN: Thirty-two HER-2/neu(+), castrate-sensitive, and  castrate-resistant prostate cancer patients were enrolled. Of these, 29 patients   completed all six vaccination cycles with AE37. Immunologic responses in the  total patient population were monitored by delayed-type hypersensitivity and  IFNG ELISPOT and intracellular staining. Regulatory T-cell (Treg) frequency   and plasma HER-2/neu and transforming growth factor-beta levels were also  determined. Immunologic responses were also analyzed among groups of patients  with different clinical characteristics. Local/systemic toxicities were monitored  throughout the study. RESULTS: Toxicities beyond grade 2 were not observed.  Seventy-five percent of patients developed augmented immunity to the AE37 vaccine  and 65% to the unmodified AE36 peptide as detected in the IFN-gamma-based ELISPOT  assay. Intracellular IFNG analyses revealed that AE37 elicited both CD4(+)  and CD8(+) T-cell responses. Eighty percent of the patients developed a positive   delayed-type hypersensitivity reaction to AE36. Additionally, significant  decreases could be detected in circulating Treg frequencies, plasma HER-2/neu,  and serum transforming growth factor-beta levels. Patients with less extensive  disease developed better immunologic responses on vaccination. CONCLUSION: AE37  vaccine is safe and can induce HER-2/neu-specific cellular immune responses in  patients with castrate-sensitive and castrate-resistant prostate cancer, thus  emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of  prostate cancer.
CANIT0000087	20479064	Clinical research	Advanced breast cancer	Breast cancer	MONDO:0007254	Breast	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab plus exemestane	Tremelimumab 	Immune checkpoint therapy plus Chemotherapy	Exemestane (DB00990); tremelimumab (DB11771); 	26	N/A	A phase I clinical trial 	Tremelimumab plus exemestane is  tolerable in patients with hormone-responsive advanced breast cancer. Treatment  is associated with increased ICOS+ T cells, which likely signals immune  activation secondary to CTL-associated antigen 4 blockade.	Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxicities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane.	N/A	N/A	Treg cells (CL:0000815); FOXP3 (Q9BZS1); ICOS (Q9Y6W8); T-Lymphocyte (NCIT:C12476); 	Ratio of ICOS(+) T-cell to FoxP3(+) regulatory T-cell .	Gene expression signature on/in immune cell	 2010 Jul 1	 Tremelimumab in combination with exemestane in patients with advanced breast  cancer and treatment-associated modulation of inducible costimulator expression  on patient T cells.	 Clin Cancer Res	 PURPOSE: Tremelimumab is a fully human monoclonal antibody specific for  CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but  has not been evaluated in patients with breast cancer. EXPERIMENTAL DESIGN: In a   phase 1 study, 26 patients with advanced, hormone-responsive breast cancer  received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane  25 mg daily. The objectives were to determine safety and the maximum tolerated  dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor  response, pharmacokinetics, and immune pharmacodynamics. RESULTS: Most  treatment-related adverse events were mild to moderate with the most common being  diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue  (23%). Dose-limiting toxicities were transient serum transaminase elevations (one  patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane  was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed  grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was  observed between tremelimumab and exemestane. The best overall response was  stable disease for >or=12 weeks in 11 patients (42%). Treatment was associated in  most patients with increased peripheral CD4+ and CD8+ T cells expressing  inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells  to FoxP3+ regulatory T cells. CONCLUSIONS: Tremelimumab plus exemestane is  tolerable in patients with hormone-responsive advanced breast cancer. Treatment  is associated with increased ICOS+ T cells, which likely signals immune  activation secondary to CTL-associated antigen 4 blockade.
CANIT0000088	20498386	Clinical research	Refractory metastatic colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	47	N/A	A single-arm, multicenter, phase II trial	Tremelimumab did not demonstrate clinically meaningful single-agent activity in this patient population, although the number of survivors at 6 months and the one patient with confirmed partial response are potentially interesting.	Grade 3/4 treatment-related adverse events (AEs) were diarrhea (n = 5; 11%), ulcerative colitis (n = 1; 2%), fatigue (n = 1; 2%), autoimmune thrombocytopenia (n = 1; 2%), and hypokalemia (n = 1; 2%), which resolved spontaneously or with interventions. Six patients discontinued because of an AE; two were considered treatment related.	N/A	N/A	N/A	N/A	N/A	 2010 Jul 20	 Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal  antibody, tremelimumab, in patients with refractory metastatic colorectal cancer.	 J Clin Oncol	 PURPOSE: Safety and efficacy of tremelimumab (CP-675,206), a fully human  anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody,  were assessed in patients with treatment-refractory colorectal cancer. PATIENTS  AND METHODS: A single-arm, multicenter, phase II trial was conducted in patients   with Eastern Cooperative Oncology Group performance status <or= 1 and measurable   colorectal carcinoma for whom standard treatments for metastatic disease had  failed. Patients received 15 mg/kg tremelimumab intravenously every 90 days until  progression. Primary end point was objective response status (per Response  Evaluation Criteria in Solid Tumors). Secondary end points included safety,  duration of response, progression-free survival, and overall survival. RESULTS:  Forty-seven patients who had received extensive prior therapies (all had received  fluoropyrimidines, oxaliplatin, and irinotecan; most [91%] had also received  cetuximab) were treated. Grade 3/4 treatment-related adverse events (AEs) were  diarrhea (n = 5; 11%), ulcerative colitis (n = 1; 2%), fatigue (n = 1; 2%),  autoimmune thrombocytopenia (n = 1; 2%), and hypokalemia (n = 1; 2%), which  resolved spontaneously or with interventions. Six patients discontinued because  of an AE; two were considered treatment related. Of 45 response-evaluable  patients, 44 did not reach second dose (43 progressive disease; one  discontinuation). Twenty-one patients (45%) lived >or= 180 days after enrollment.  One patient (2%; 90% CI, < 1% to 10%) had a stable pelvic mass and substantial  regression in an adrenal mass (partial response). This patient received five  tremelimumab doses; response duration was 6 months (enrollment to disease  progression, 15 months). CONCLUSION: Tremelimumab did not demonstrate clinically   meaningful single-agent activity in this patient population, although the number   of survivors at 6 months and the one patient with confirmed partial response are   potentially interesting. Further study of tremelimumab in combination with other   agents may be warranted.
CANIT0000089	20532500	Clinical research	Mesothelioma and non-small cell lung cancer	Mesothelioma	EFO:0000588	Soft tissue	WT1 (P19544); 	WT1; 	WT1 peptide cancer vaccine	N/A	Tumor vaccine	WT1 vaccine (NCIT:C104738); 	12	N/A	N/A	This multivalent WT1 peptide analog vaccine induces immune responses in a high proportion of patients with thoracic malignancies with minimal toxicity. A randomized trial testing this vaccine as adjuvant therapy in MPM is planned.	N/A	N/A	N/A	N/A	N/A	N/A	 2010 Oct	 WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients  with mesothelioma and non-small cell lung cancer.	 Cancer Immunol Immunother	 BACKGROUND: The transcription factor, WT1, is highly overexpressed in malignant  pleural mesothelioma (MPM) and immunohistochemical stains for WT1 are used  routinely to aid in its diagnosis. Using computer prediction analysis we designed  analog peptides derived from WT1 sequences by substituting amino acids at key  HLA-A0201 binding positions. We tested the safety and immunogenicity of a WT1  vaccine comprised of four class I and class II peptides in patients with thoracic  neoplasms expressing WT1. METHODS: Therapy consisted of six subcutaneous  vaccinations administered with Montanide adjuvant on weeks 0, 4, 6, 8, 10, and  12, with 6 additional monthly injections for responding patients. Injection sites  were pre-stimulated with GM-CSF (70 mcg). Immune responses were evaluated by DTH,  CD4 T-cell proliferation, CD8 T-cell interferon gamma release, intracellular  cytokine staining, WT1 peptide MHC-tetramer staining, and cytotoxicity against  WT1 positive tumor cells. RESULTS: Nine patients with MPM and 3 with NSCLC were  vaccinated, with 8 patients receiving at least 6 vaccinations; in total, 10  patients were evaluable for immune response. Six out of nine patients tested  demonstrated CD4 T-cell proliferation to WT1 specific peptides, and five of the  six HLA-A0201 patients tested mounted a CD8 T-cell response. Stimulated T cells  were capable of cytotoxicity against WT-1 positive cells. Vaccination also  induced polyfunctional CD8 T cell responses. CONCLUSIONS: This multivalent WT1  peptide analog vaccine induces immune responses in a high proportion of patients   with thoracic malignancies with minimal toxicity. A randomized trial testing this  vaccine as adjuvant therapy in MPM is planned.
CANIT0000090	20593249	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2011 Dec	 Continuous systemic corticosteroids do not affect the ongoing regression of  metastatic melanoma for more than two years following ipilimumab therapy.	 Med Oncol	 Malignant melanoma is an aggressive skin cancer with no effective therapies  currently approved for advanced disease. In the case presented, a 55-year-old  female patient diagnosed with widespread disease from amelanotic desmoplastic  melanoma was treated with 10 mg/kg ipilimumab as part of a phase II clinical  trial (CA184-008). Prior to ipilimumab, three chemotherapeutic regimens had  failed. Ipilimumab acts as a T-cell potentiator via blockade of cytotoxic  T-lymphocyte antigen-4, a negative regulator of T-cell activation. Response to  ipilimumab treatment was rapid, with a substantial drop in tumor volume within 12  weeks of treatment initiation. Based on the appearance of a new subcutaneous  lesion, reinduction with ipilimumab was performed at Week 30. Following  reinduction, the appearance of another small new lesion made the patient  ineligible, as per protocol, for further dosing despite stabilization of her  remaining lesions. Ipilimumab-associated immune-related adverse events were  manageable with the use of treatment guidelines. It is of remarkable  immunotherapeutic importance that no new lesions emerged and gradual tumor  regression is still ongoing more than 2 years following the last dose of  ipilimumab, despite daily administration of systemic corticosteroids to manage  drug-induced AEs. The ongoing clinical response is maintained without any further  antineoplastic treatment.
CANIT0000091	20713164	Clinical research	Relapsed malignancy following allogeneic hematopoietic stem cell transplantation (allo-HSCT)	Leukemia	EFO:0000565	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	29	N/A	A phase I clinical trial 	There was no significant change in Treg cell numbers after ipilimumab infusion.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2011 May	 CTLA-4 blockade following relapse of malignancy after allogeneic stem cell  transplantation is associated with T cell activation but not with increased  levels of T regulatory cells.	 Biol Blood Marrow Transplant	 Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a key negative regulator   of T cell activation and proliferation. Ipilimumab is a human monoclonal antibody  that specifically blocks the binding of CTLA-4 to its ligand. To test the  hypothesis that blockade of CTLA-4 by ipilimumab could augment  graft-versus-malignancy (GVM) effects without a significant impact on  graft-versus-host disease (GVHD), we conducted a phase I clinical trial of  ipilimumab infusion in patients with relapsed malignancy following allogeneic  hematopoietic stem cell transplantation (allo-HSCT). Here, we report the analysis  of peripheral blood T lymphocyte reconstitution, T regulatory cell (Treg)  expression, and T cell activation markers after a single dose of ipilimumab in 29  patients. Peripheral blood samples were collected from all patients before and  after ipilimumab infusion. Lymphocyte immunophenotyes, including levels of  CD4(+)CD25(high) cells and T cell activation markers, were analyzed in all cases.  Levels of CD4(+)CD25(high)Foxp3(+) cells and intracellular CTLA-4 in CD4(+) T  cells also were evaluated in the last 11 cases. We found lower baseline levels of  CD4(+) and CD45RO(+) T cells in patients compared with normal controls. More than  50% of the patients had abnormally low lymphocyte counts (CD4 or/and CD8 T  cells), and some had no circulating B lymphocytes. The percentages of both  CD4(+)CD25(high) and CD4(+)CD25(high)Foxp3(+) T cells were significantly higher  in patients before ipilimumab infusion than in healthy donors. Twenty of 29  patients exhibited an elevated level of CD4(+)CD25(low) activated T cells at  baseline, compared with only 3 of 26 healthy donors. Both CD4(+) and CD8(+) T  lymphocyte counts were significantly increased after ipilimumab infusion. There  was no consistent change in absolute lymphocyte count or in the number of T cells  expressing the activation marker CD69. However, increases in CD4(+)CD25(low) T  cells were seen in 20 of 29 patients and increases in CD4(+)HLA-DR(+) T cells  were seen in the last 10 patients in the first 60 days after ipilimumab infusion.  Although the percentages of both CD4(+)CD25(high) and CD4(+)CD25(high)Foxp3(+) T   cells decreased significantly during the observation period, the absolute cell  counts did not change. Intracellular CTLA-4 expression in CD4(+)CD25(lo/-) T  cells increased significantly after ipilimumab infusion. We conclude that CTLA-4   blockade by a single infusion of ipilimumab increased CD4(+) and CD4(+)HLA-DR(+)   T lymphocyte counts and intracellular CTLA-4 expression at the highest dose  level. There was no significant change in Treg cell numbers after ipilimumab  infusion. These data demonstrate that significant changes in T cell populations  occur on exposure to a single dose of ipilimumab. Further studies with multiple  doses are needed to explore this phenomenon further and to correlate changes in  lymphocyte subpopulations with clinical events.CI  - Copyright (c) 2011 American Society for Blood and Marrow Transplantation.  Published by Elsevier Inc. All rights reserved.
CANIT0000092	20842054	Clinical research	Locally advanced or metastatic pancreatic adenocarcinoma	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	27	N/A	A phase II trial of single agent	Single agent Ipilimumab at 3.0 mg/kg/dose is ineffective for the treatment of advanced pancreas cancer.	N/A	N/A	N/A	N/A	N/A	N/A	 2010 Oct	 Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or  metastatic pancreatic adenocarcinoma.	 J Immunother	 New, effective therapies are needed for pancreatic ductal adenocarcinoma.  Ipilimumab can mediate an immunologic tumor regression in other histologies. This  phase II trial evaluated the efficacy of Ipilimumab for advanced pancreatic  cancer. Subjects were adults with locally advanced or metastatic pancreas  adenocarcinoma with measurable disease, good performance status, and minimal  comorbidities. Ipilimumab was administered intravenously (3.0 mg/kg every 3 wk; 4  doses/course) for a maximum of 2 courses. Response rate by response evaluation  criteria in solid tumors criteria and toxicity were measured. Twenty-seven  subjects were enrolled (metastatic disease: 20 and locally advanced: 7) with  median age of 55 years (27 to 68 y) and good performance status (26 with Eastern   Cooperative Oncology Group performance status =0 to 1). Three subjects  experienced >/= grade 3 immune-mediated adverse events (colitis:1,  encephalitis:1, hypohysitis:1). There were no responders by response evaluation  criteria in solid tumors criteria but a subject experienced a delayed response  after initial progressive disease. In this subject, new metastases after 2 doses   of Ipilimumab established progressive disease. But continued administration of  the agent per protocol resulted in significant delayed regression of the primary   lesion and 20 hepatic metastases. This was reflected in tumor markers  normalization, and clinically significant improvement of performance status.  Single agent Ipilimumab at 3.0 mg/kg/dose is ineffective for the treatment of  advanced pancreas cancer. However, a significant delayed response in one subject   of this trial suggests that immunotherapeutic approaches to pancreas cancer  deserve further exploration.
CANIT0000093	20853321	Basic research	Cases of colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	Cell lines and 3	N/A	Basic research	Tremelimumab therapy may benefit from previous or concomitant Treg depletion.	T(reg) depletion and CTLA-4 blockade  synergistically enhanced specific cytotoxicity raised in culture against  autologous EBV-transformed cell lines.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); T-Lymphocyte (NCIT:C12476); 	Previous or concomitant T(reg) depletion	Cell percentage/counts in blood	 2011 Jul 15	 Synergistic effects of CTLA-4 blockade with tremelimumab and elimination of  regulatory T lymphocytes in vitro and in vivo.	 Int J Cancer	 Anti-CTLA-4 monoclonal antibodies (mAb) that block the interaction of CTLA-4 with  CD80 and CD86 such as tremelimumab and ipilimumab are currently being tested in  the clinic for cancer treatment exploiting their properties to de-repress  tumor-specific cellular immunity. Addition of the fully human anti-CTLA-4  (tremelimumab) to cultures of human T cells with allogenic dendritic cells (DCs)   did not increase proliferation. Magnetic bead-mediated elimination of CD4(+)  CD25(+) regulatory T cells (T(reg)) before setting up those alloreactive cultures  also largely failed to increase primary proliferation. In contrast, predepletion   of CD4(+) CD25(+) T(reg) and culture in the presence of tremelimumab  synergistically resulted in increased proliferation and DC:T-cell aggregation.  These effects were much more prominent in CD4 than in CD8 T cells. The synergy  mechanism can be traced to enhanced CTLA-4 expression in effector cells as a  result of T(reg) elimination, thereby offering more targets to the blocking  antibody. Human T cells and allogenic DCs (derived both from healthy donors and  advanced cancer patients) were coinjected in the peritoneum of Rag2(-/-)  IL-2Rgamma(-/-) mice. In these conditions, tremelimumab injected intravenously  did not significantly enhance alloreactive proliferation unless T(reg) cells had   been predepleted. Synergistic effects in vivo were again largely restricted to  the CD4 T-cell compartment. In addition, T(reg) depletion and CTLA-4 blockade  synergistically enhanced specific cytotoxicity raised in culture against  autologous EBV-transformed cell lines. Taken together, these experiments indicate  that tremelimumab therapy may benefit from previous or concomitant T(reg)  depletion.CI  - Copyright (c) 2010 UICC.
CANIT0000094	20853321	Basic research	Cases of melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	Cell lines and 2	N/A	Basic research	Tremelimumab therapy may benefit from previous or concomitant Treg depletion.	T(reg) depletion and CTLA-4 blockade  synergistically enhanced specific cytotoxicity raised in culture against  autologous EBV-transformed cell lines.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); T-Lymphocyte (NCIT:C12476); 	Previous or concomitant T(reg) depletion	Cell percentage/counts in blood	 2011 Jul 15	 Synergistic effects of CTLA-4 blockade with tremelimumab and elimination of  regulatory T lymphocytes in vitro and in vivo.	 Int J Cancer	 Anti-CTLA-4 monoclonal antibodies (mAb) that block the interaction of CTLA-4 with  CD80 and CD86 such as tremelimumab and ipilimumab are currently being tested in  the clinic for cancer treatment exploiting their properties to de-repress  tumor-specific cellular immunity. Addition of the fully human anti-CTLA-4  (tremelimumab) to cultures of human T cells with allogenic dendritic cells (DCs)   did not increase proliferation. Magnetic bead-mediated elimination of CD4(+)  CD25(+) regulatory T cells (T(reg)) before setting up those alloreactive cultures  also largely failed to increase primary proliferation. In contrast, predepletion   of CD4(+) CD25(+) T(reg) and culture in the presence of tremelimumab  synergistically resulted in increased proliferation and DC:T-cell aggregation.  These effects were much more prominent in CD4 than in CD8 T cells. The synergy  mechanism can be traced to enhanced CTLA-4 expression in effector cells as a  result of T(reg) elimination, thereby offering more targets to the blocking  antibody. Human T cells and allogenic DCs (derived both from healthy donors and  advanced cancer patients) were coinjected in the peritoneum of Rag2(-/-)  IL-2Rgamma(-/-) mice. In these conditions, tremelimumab injected intravenously  did not significantly enhance alloreactive proliferation unless T(reg) cells had   been predepleted. Synergistic effects in vivo were again largely restricted to  the CD4 T-cell compartment. In addition, T(reg) depletion and CTLA-4 blockade  synergistically enhanced specific cytotoxicity raised in culture against  autologous EBV-transformed cell lines. Taken together, these experiments indicate  that tremelimumab therapy may benefit from previous or concomitant T(reg)  depletion.CI  - Copyright (c) 2010 UICC.
CANIT0000095	20881001	Clinical research	Metastatic renal cancer patients	Renal carcinoma	EFO:0002890	Kidney	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine	Placebo	Tumor vaccine	 MVA-5T4 vaccine (NCIT:C49087); 	365	368	A randomized, double-blind, placebo-controlled phase III study	MVA-5T4 in combination with SOC was well tolerated, but no difference in survival was observed in the overall study population. Exploratory analyses indicate that a number of pretreatment  hematologic factors that could identify patients who derive significant benefit  from this vaccine. Therefore, there may be subsets of patients who could gain significant benefit from MVA-5T4, but such results would need to be confirmed in future randomized clinical studies.	No significant difference in the incidence of adverse events or serious adverse events was observed. 	N/A	N/A	Hematologic factors (N/A); 	Serum hematologic factors levels	Gene expression signature in serum	 2010 Nov 15	 Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized,  double-blind, placebo-controlled phase III study.	 Clin Cancer Res	 PURPOSE: The TroVax Renal Immunotherapy Survival Trial was a randomized,  placebo-controlled phase III study that investigated whether modified vaccinia  Ankara encoding the tumor antigen 5T4 (MVA-5T4) prolonged survival of patients  receiving first-line standard-of-care (SOC) treatment for metastatic renal cell  cancer. EXPERIMENTAL DESIGN: Patients with metastatic clear cell renal cancer,  prior nephrectomy, and good or intermediate prognosis were randomized 1:1 to  receive up to 13 immunizations of MVA-5T4/placebo in combination with either  sunitinib, interleukin-2 or interferon-alpha. The primary end point was overall  survival. Secondary end points included progression-free survival, overall  response rate, and safety. RESULTS: Seven hundred thirty-three patients were  recruited (365 MVA-5T4 and 368 placebo). Treatment arms were well balanced for  SOC and prognosis. No significant difference in the incidence of adverse events  or serious adverse events was observed. No significant difference in overall  survival was evident in the two treatment arms (median 20.1 months MVA-5T4 versus  19.2 months placebo; P = 0.55). The magnitude of the 5T4-specific antibody  response induced by vaccination with MVA-5T4 was associated with enhanced patient  survival. Furthermore, exploratory analyses suggested a number of pretreatment  hematologic factors that could identify patients who derive significant benefit  from this vaccine. CONCLUSION: MVA-5T4 in combination with SOC was well  tolerated, but no difference in survival was observed in the overall study  population. Exploratory analyses indicate that there may be subsets of patients  who could gain significant benefit from MVA-5T4, but such results would need to  be confirmed in future randomized clinical studies.CI  - (c)2010 AACR.
CANIT0000096	20922784	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); FAK2 (Q14289); 	CTLA-4; FAK2	Tremelimumab plus sunitinib	N/A	Immune checkpoint therapy plus Target therapy	Tremelimumab (DB11771); sunitinib (DB01268); 	28	N/A	A phase I clinical trial 	In this study of tremelimumab plus sunitinib,  rapid-onset acute renal failure was observed unexpectedly, and further  investigation of tremelimumab doses > 6 mg/kg plus sunitinib 37.5 mg daily is not  recommended. Preclinical investigation may be warranted to understand the  mechanism of renal toxicity.	Overall, rapid-onset renal failure was the most common dose-limiting toxicities.	N/A	N/A	N/A	N/A	N/A	 2011 Feb 15	 Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with  metastatic renal cell carcinoma.	 Cancer	 BACKGROUND: On the basis of potential additive or synergistic immunostimulatory  antitumor effects, in this phase 1 study, the authors evaluated the combination  of sunitinib and tremelimumab (CP-675206; an antibody against cytotoxic  T-lymphocyte-associated antigen 4 [CTLA4]) in patients with metastatic renal cell  carcinoma (mRCC) was evaluated. METHODS: Adult patients with mRCC who had  received </= 1 previous systemic treatment received tremelimumab (6 mg/kg, 10  mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg  daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The  primary objective was to determine the maximum tolerated dose (MTD). Secondary  objectives were to assess antitumor activity, safety, and pharmacokinetics.  RESULTS: Twenty-eight patients were enrolled. Two of 5 patients who received 50  mg sunitinib plus tremelimumab 6 mg/kg experienced dose-limiting toxicities  (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing   was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of  7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden  death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib  experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10  mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs.  Overall, rapid-onset renal failure was the most common DLT. Nine of 21 patients  who were evaluable for response achieved partial responses (43%; 95% confidence  interval, 22%-66%), and 4 of those responses were ongoing at the time of the  current report. CONCLUSIONS: In this study of tremelimumab plus sunitinib,  rapid-onset acute renal failure was observed unexpectedly, and further  investigation of tremelimumab doses > 6 mg/kg plus sunitinib 37.5 mg daily is not  recommended. Preclinical investigation may be warranted to understand the  mechanism of renal toxicity.CI  - Copyright (c) 2010 American Cancer Society.
CANIT0000097	21056008	Clinical research	Metastatic gastric and esophageal adenocarcinomas	Esophageal adenocarcinoma	EFO:0000478	Esophagus	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	18	N/A	N/A	Tremelimumab induces immune responses mainly by direct activation of Teff rather than by affecting Tregs	N/A	N/A	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2011 Jan	 Tremelimumab (anti-CTLA4) mediates immune responses mainly by direct activation  of T effector cells rather than by affecting T regulatory cells.	 Clin Immunol	 Cytotoxic T Lymphocyte Antigen 4 (CTLA4) blockade has shown antitumor activity  against common cancers. However, the exact mechanism of immune mediation by  anti-CTLA4 remains to be elucidated. Further understanding of how CTLA4 blockade   with tremelimumab mediates immune responses may allow a more effective selection   of responsive patients. Our results show that tremelimumab enhanced the  proliferative response of T effector cells (Teff) upon TCR stimulation, and  abrogated Treg suppressive ability. In the presence of tremelimumab, frequencies   of IL-2-secreting CD4(+) T cells and IFN-gamma-secreting CD4(+) and CD8(+) T  cells were increased in response to polyclonal activation and tumor antigens.  Importantly, Treg frequency was not reduced in the presence of tremelimumab, and   expanded Tregs in cancer patients treated with tremelimumab expressed FoxP3 with   no IL-2 release, confirming them as bona fide Tregs. Taken together, this data  indicates that tremelimumab induces immune responses mainly by direct activation   of Teff rather than by affecting Tregs.CI  - Copyright (c) 2010 Elsevier Inc. All rights reserved.
CANIT0000098	21056008	Clinical research	Metastatic gastric and esophageal adenocarcinomas	Gastric adenocarcinoma	EFO:0000503	Stomach	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	18	N/A	N/A	Tremelimumab induces immune responses mainly by direct activation of Teff rather than by affecting Tregs	N/A	N/A	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2011 Jan	 Tremelimumab (anti-CTLA4) mediates immune responses mainly by direct activation  of T effector cells rather than by affecting T regulatory cells.	 Clin Immunol	 Cytotoxic T Lymphocyte Antigen 4 (CTLA4) blockade has shown antitumor activity  against common cancers. However, the exact mechanism of immune mediation by  anti-CTLA4 remains to be elucidated. Further understanding of how CTLA4 blockade   with tremelimumab mediates immune responses may allow a more effective selection   of responsive patients. Our results show that tremelimumab enhanced the  proliferative response of T effector cells (Teff) upon TCR stimulation, and  abrogated Treg suppressive ability. In the presence of tremelimumab, frequencies   of IL-2-secreting CD4(+) T cells and IFN-gamma-secreting CD4(+) and CD8(+) T  cells were increased in response to polyclonal activation and tumor antigens.  Importantly, Treg frequency was not reduced in the presence of tremelimumab, and   expanded Tregs in cancer patients treated with tremelimumab expressed FoxP3 with   no IL-2 release, confirming them as bona fide Tregs. Taken together, this data  indicates that tremelimumab induces immune responses mainly by direct activation   of Teff rather than by affecting Tregs.CI  - Copyright (c) 2010 Elsevier Inc. All rights reserved.
CANIT0000099	21088057	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	Case	All patients on ipilimumab and/or bevacizumab therapy should be monitored for signs or symptoms of thyroiditis.	Thyroid autoimmunity and ophthalmopathy	N/A	N/A	N/A	N/A	N/A	 2011 Feb	 Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy.	 Eur J Endocrinol	 OBJECTIVE: Ipilimumab is a fully human MAB against cytotoxic T-lymphocyte antigen  4 (CTLA4). CTLA4 negatively regulates immune cell activation. In patients with  metastatic melanoma, ipilimumab increases survival time and induces complete  remission in some patients. However, immune-related adverse events including  endocrinopathies have been reported. Bevacizumab, an angiogenesis inhibitor, has   been used in combination with ipilimumab in patients with advanced melanoma.  PATIENTS AND METHODS: In this study, we report three patients who received  ipilimumab alone or combined with bevacizumab therapy and developed thyroiditis,   and the first report of euthyroid Graves' ophthalmopathy. RESULTS: Case 1 is a  51-year-old female who presented with severe eye pain, proptosis, and periorbital  edema. Laboratory results revealed normal TSH, elevated thyroid antibodies but  low titer of anti-TSH receptor antibody. Imaging was consistent with Graves'  ophthalmopathy. Cases 2 and 3 were referred for hyperthyroidism, and workup  revealed thyroiditis. These three cases suggest that patients with advanced  melanoma treated with ipilimumab +/- bevacizumab may be susceptible to a variety   of thyroid disorders. CONCLUSIONS: Anti-CTLA4 therapy has shown promising results  in treating advanced malignancy such as melanoma and renal carcinoma. A number of  endocrinopathies, including thyroid disorders, may develop during ipilimumab  therapy. The association of bevacizumab with endocrinopathies is not clear,  although a few reports suggest a link to hypothyroidism. All patients on  ipilimumab and/or bevacizumab therapy should be monitored for signs or symptoms  of thyroiditis.
CANIT0000100	21090563	Clinical research	Unresectable stage III/IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus budesonide	Ipilimumab plus placebo	Immune checkpoint therapy plus Chemotherapy	 budesonide (DB01222); ipilimumab (DB06186); 	58	57	N/A	Prophylactic budesonide did not prevent ipilimumab-induced bowel inflammation.	Outcome measures included histologic assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease (IBD), fecal calprotectin levels, and polymorphisms in immune-related genes. Ipilimumab resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by altered antibody levels to enteric flora, inflammatory cell infiltration into gastrointestinal mucosa, and increased fecal calprotectin associated with diarrhea and clinical evidence of colitis. The pattern of ipilimumab-induced antibody titers to microbial flora and the histologic features and location of the inflammation were distinct from classic IBD. Prophylactic budesonide did not prevent ipilimumab-induced bowel inflammation. Despite an observed association between colonic inflammation and grade 2 or higher diarrhea, no baseline biomarkers could reliably predict development of gastrointestinal toxicity.	N/A	N/A	N/A	N/A	N/A	 2010 Nov 24	 Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in  dysregulation of gastrointestinal immunity in patients with advanced melanoma.	 Cancer Immun	 Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) by ipilimumab leads to  immune-mediated tumor regression and immune-related adverse events (irAEs),  including diarrhea and colitis. The current analyses were undertaken to promote  an understanding of the underlying mechanism of action and to identify potential   biomarkers that could help in the prediction and management of ipilimumab-induced  gastrointestinal irAEs. Treatment-naive or previously treated patients with  unresectable stage III/IV melanoma (n = 115) received open-label ipilimumab (10  mg/kg every 3 weeks for four doses) and were randomized to receive concomitant  blinded prophylactic oral budesonide (9 mg/d with gradual taper through week 16)   or placebo. Outcome measures included histologic assessment of bowel biopsies and  assessment of serologic markers of inflammatory bowel disease (IBD), fecal  calprotectin levels, and polymorphisms in immune-related genes. Ipilimumab  resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by  altered antibody levels to enteric flora, inflammatory cell infiltration into  gastrointestinal mucosa, and increased fecal calprotectin associated with  diarrhea and clinical evidence of colitis. The pattern of ipilimumab-induced  antibody titers to microbial flora and the histologic features and location of  the inflammation were distinct from classic IBD. Prophylactic budesonide did not   prevent ipilimumab-induced bowel inflammation. Despite an observed association  between colonic inflammation and grade 2 or higher diarrhea, no baseline  biomarkers could reliably predict development of gastrointestinal toxicity.  Although classic IBD and ipilimumab-related gastrointestinal toxicity are both  immune mediated, the observed pattern of biomarkers suggests ipilimumab-related  gastrointestinal toxicity may be a distinct clinicopathologic entity.
CANIT0000101	21106722	Clinical research	Resected high-risk stage IIIc/IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus GM-CSF	Ipilimumab	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386)	75	N/A	A phase II clinical trial	Adjuvant ipilimumab following resection of  melanoma at high risk for relapse appeared to be associated with improved outcome  compared to historical reports. Significant immune-related adverse events were  generally reversible and appeared to be associated with improved relapse-free  survival. Although vaccination failed to induce a consistent in vitro measurable   response, a higher change in Th-17 inducible cells and higher baseline C-reactive peptide levels  were positively associated with freedom from relapse.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2011 Feb 15	 Extended dose ipilimumab with a peptide vaccine: immune correlates associated  with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma.	 Clin Cancer Res	 PURPOSE: To determine safety and feasibility of adjuvant ipilimumab following  resection of high-risk melanoma and to identify surrogate markers for benefit.  EXPERIMENTAL DESIGN: In this phase II trial, 75 patients with resected stage  IIIc/IV melanoma received the CTLA-4 antibody ipilimumab every 6 to 8 weeks for 1  year. Eligible patients received further maintenance treatments. The first 25  patients received 3 mg/kg of ipilimumab, and an additional 50 patients received  10 mg/kg. HLA-A*0201+ patients received multipeptide immunizations in combination  with ipilimumab. Leukapheresis was performed prior to and 6 months after  initiation of treatment. RESULTS: Median overall and relapse-free survivals were   not reached after a median follow-up of 29.5 months. Significant immune-related  adverse events were observed in 28 of 75 patients and were positively associated   with longer relapse-free survival. Antigen-specific T cell responses to vaccine  were variable, and vaccine combination was not associated with additional  benefit. No effects on T regulatory cells were observed. Higher changes in Th-17   inducible frequency were a surrogate marker of freedom from relapse (P = 0.047),   and higher baseline C-reactive protein (CRP) levels were associated with freedom   from relapse (P = 0.035). CONCLUSIONS: Adjuvant ipilimumab following resection of  melanoma at high risk for relapse appeared to be associated with improved outcome  compared to historical reports. Significant immune-related adverse events were  generally reversible and appeared to be associated with improved relapse-free  survival. Although vaccination failed to induce a consistent in vitro measurable   response, a higher change in Th-17 inducible cells and higher baseline CRP levels  were positively associated with freedom from relapse.CI  - (c)2010 AACR.
CANIT0000102	21135147	Clinical research	Glioblastoma (WHO grade IV)	Glioblastoma multiforme	EFO:0000519	Brain	DENDRITIC CELL (N/A); 	DENDRITIC CELL; 	Autologous tumor lysate-pulsed dendritic cell vaccination	N/A	Tumor vaccine	Dendritic cell vaccine (NCIT:C28310); 	23	N/A	N/A	Autologous tumor lysate-pulsed DC vaccination in conjunction with TLR agonists is safe as adjuvant therapy in newly  diagnosed and recurrent glioblastoma patients. Our results suggest that the  mesenchymal gene expression profile may identify an immunogenic subgroup of  glioblastoma that may be more responsive to immune-based therapies.	DC vaccinations are safe and not associated with any dose-limiting toxicity.	N/A	ECO:0007120 - animal model system study evidence used in manual assertion	Mesenchymal gene (); 	Mesenchymal gene expression signatures	Gene expression signature on/in tumor cell	 2011 Mar 15	 Gene expression profile correlates with T-cell infiltration and relative survival  in glioblastoma patients vaccinated with dendritic cell immunotherapy.	 Clin Cancer Res	 PURPOSE: To assess the feasibility, safety, and toxicity of autologous tumor  lysate-pulsed dendritic cell (DC) vaccination and toll-like receptor (TLR)  agonists in patients with newly diagnosed and recurrent glioblastoma. Clinical  and immune responses were monitored and correlated with tumor gene expression  profiles. EXPERIMENTAL DESIGN: Twenty-three patients with glioblastoma (WHO grade  IV) were enrolled in this dose-escalation study and received three biweekly  injections of glioma lysate-pulsed DCs followed by booster vaccinations with  either imiquimod or poly-ICLC adjuvant every 3 months until tumor progression.  Gene expression profiling, immunohistochemistry, FACS, and cytokine bead arrays  were performed on patient tumors and peripheral blood mononuclear cells. RESULTS:  DC vaccinations are safe and not associated with any dose-limiting toxicity. The   median overall survival from the time of initial surgical diagnosis of  glioblastoma was 31.4 months, with a 1-, 2-, and 3-year survival rate of 91%,  55%, and 47%, respectively. Patients whose tumors had mesenchymal gene expression  signatures exhibited increased survival following DC vaccination compared with  historic controls of the same genetic subtype. Tumor samples with a mesenchymal  gene expression signature had a higher number of CD3(+) and CD8(+)  tumor-infiltrating lymphocytes compared with glioblastomas of other gene  expression signatures (P = 0.006). CONCLUSION: Autologous tumor lysate-pulsed DC   vaccination in conjunction with TLR agonists is safe as adjuvant therapy in newly  diagnosed and recurrent glioblastoma patients. Our results suggest that the  mesenchymal gene expression profile may identify an immunogenic subgroup of  glioblastoma that may be more responsive to immune-based therapies.CI  - (c)2010 AACR.
CANIT0000103	21170646	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	27	N/A	N/A	Ipilimumab was a feasible  treatment for malignant melanoma in heavily pretreated, progressing patients. A  sizeable proportion of patients experienced durable DC, including benefits to  long-term survival.Changes in lymphocyte count slope and absolute number  during ipilimumab treatment appear to correlate with clinical response and  survival, respectively. 	Adverse events were predominantly immune related, manageable, and generally reversible. One patient died from pancytopenia, considered possibly treatment related.	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2011 Apr	 Ipilimumab experience in heavily pretreated patients with melanoma in an expanded  access program at the University Hospital of Siena (Italy).	 Cancer Immunol Immunother	 AIM OF STUDY: To evaluate the feasibility of ipilimumab treatment for metastatic   melanoma outside the boundaries of clinical trials, in a setting similar to that   of daily practice. METHODS: Ipilimumab was available upon physician request in  the Expanded Access Programme for patients with life-threatening, unresectable  stage III/IV melanoma who failed or did not tolerate previous treatments and for   whom no therapeutic option was available. Induction treatment with ipilimumab 10   mg/kg was administered intravenously every 3 weeks, for a total of 4 doses, with   maintenance doses every 12 weeks based on physicians' discretion and clinical  judgment. Tumors were assessed at baseline, Week 12, and every 12 weeks  thereafter per mWHO response criteria, and clinical response was scored as  complete response (CR), partial response (PR), stable disease (SD), or  progressive disease. Durable disease control (DC) was defined as SD at least 24  weeks from the first dose, CR, or PR. RESULTS: Disease control rate at 24 and 60   weeks was 29.6% and 15%, respectively. Median overall survival at a median  follow-up of 8.5 months was 9 months. The 1- and 2-year survival rates were 34.8%  and 23.5%, respectively. Changes in lymphocyte count slope and absolute number  during ipilimumab treatment appear to correlate with clinical response and  survival, respectively. Adverse events were predominantly immune related,  manageable, and generally reversible. One patient died from pancytopenia,  considered possibly treatment related. CONCLUSION: Ipilimumab was a feasible  treatment for malignant melanoma in heavily pretreated, progressing patients. A  sizeable proportion of patients experienced durable DC, including benefits to  long-term survival.
CANIT0000104	21264545	Case report	Stage IV metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Hyponatremia associated with Ipilimumab-induced hypophysitis	N/A	N/A	N/A	N/A	N/A	 2012 Mar	 Hyponatremia associated with Ipilimumab-induced hypophysitis.	 Med Oncol	 A 75-year-old woman with a history of stage IV metastatic melanoma underwent  treatment with the CTLA-4 blocking agent Ipilimumab. She presented 2 months after  initiating treatment with a severe headache. Laboratories were consistent with  severe hyponatremia. MRI of the brain revealed enlargement of the pituitary  gland, enhancement of the infundibulum, and an enhancing, centrally necrotic foci  in the anterior pituitary. Based on the clinical and radiographic findings, she  was diagnosed with treatment-related syndrome of inappropriate antidiuretic  hormone secretion (SIADH). Effective treatment consisted of fluid restriction,  hyperosmolar therapy, and steroids.
CANIT0000105	21387109	Clinical research	Renal cancer	Renal carcinoma	EFO:0002890	Kidney	5T4 (Q13641); IL2R (A2N4P8); 	5T4; IL2R	MVA-5T4 vaccine plus IL2	IL2 plus placebo	Tumor vaccine plus Immune cytokine	 IFNA (DB00018); IL2 (NCIT:C24498); sunitinib (DB01268); MVA-5T4 vaccine (NCIT:C49087); 	288	302	A multicentre phase III clinical trial	MVA-5T4-induced immune responses are an early marker of efficacy in renal cancer patients.	N/A	N/A	N/A	MVA-5T4 response (NCIT:C49087); 	MVA-5T4 specific immune responses	Immune response	 2011 Jun	 MVA-5T4-induced immune responses are an early marker of efficacy in renal cancer   patients.	 Cancer Immunol Immunother	 Few immunotherapy compounds have demonstrated a direct link between the predicted  mode of action of the product and benefit to the patient. Since cancer vaccines  are thought to have a delayed therapeutic effect, identification of the active  moiety may enable the development of an early marker of efficacy. Patients with  renal cancer and requiring first-line treatment for metastatic disease were  randomized 1:1 to receive MVA-5T4 (TroVax((R))) or placebo alongside Sunitinib,  IL-2 or IFN-alpha in a multicentre phase III trial. Antibody responses were  quantified following the 3rd and 4th vaccinations. A surrogate for 5T4 antibody  response (the immune response surrogate; IRS) was constructed and then used in a   survival analysis to evaluate treatment benefit. Seven hundred and thirty-three  patients were randomized, and immune responses were assessed in 590 patients. A  high 5T4 antibody response was associated with longer survival within the  MVA-5T4-treated group. The IRS was constructed as a linear combination of  pre-treatment 5T4 antibody levels, hemoglobin and hematocrit and was shown to be   a significant predictor of treatment benefit in the phase III study. Importantly,  the IRS was also associated with antibody response and survival in an independent  dataset comprising renal, colorectal and prostate cancer patients treated with  MVA-5T4 in phase I-II studies. The derivation of the IRS formed part of an  exploratory, retrospective analysis; however, if confirmed in future studies, the  results have important implications for the development and use of the MVA-5T4  vaccine and potentially for other similar vaccines.
CANIT0000106	21387109	Clinical research	Renal cancer	Renal carcinoma	EFO:0002890	Kidney	5T4 (Q13641); INAR1 (P17181); 	5T4; INAR1	MVA-5T4 vaccine plus IFNA	IFNA plus placebo	Tumor vaccine plus Immune cytokine	 IFNA (DB00018); IL2 (NCIT:C24498); sunitinib (DB01268); MVA-5T4 vaccine (NCIT:C49087); 	288	302	A multicentre phase III clinical trial	MVA-5T4-induced immune responses are an early marker of efficacy in renal cancer patients.	N/A	N/A	N/A	MVA-5T4 response (NCIT:C49087); 	MVA-5T4 specific immune responses	Immune response	 2011 Jun	 MVA-5T4-induced immune responses are an early marker of efficacy in renal cancer   patients.	 Cancer Immunol Immunother	 Few immunotherapy compounds have demonstrated a direct link between the predicted  mode of action of the product and benefit to the patient. Since cancer vaccines  are thought to have a delayed therapeutic effect, identification of the active  moiety may enable the development of an early marker of efficacy. Patients with  renal cancer and requiring first-line treatment for metastatic disease were  randomized 1:1 to receive MVA-5T4 (TroVax((R))) or placebo alongside Sunitinib,  IL-2 or IFN-alpha in a multicentre phase III trial. Antibody responses were  quantified following the 3rd and 4th vaccinations. A surrogate for 5T4 antibody  response (the immune response surrogate; IRS) was constructed and then used in a   survival analysis to evaluate treatment benefit. Seven hundred and thirty-three  patients were randomized, and immune responses were assessed in 590 patients. A  high 5T4 antibody response was associated with longer survival within the  MVA-5T4-treated group. The IRS was constructed as a linear combination of  pre-treatment 5T4 antibody levels, hemoglobin and hematocrit and was shown to be   a significant predictor of treatment benefit in the phase III study. Importantly,  the IRS was also associated with antibody response and survival in an independent  dataset comprising renal, colorectal and prostate cancer patients treated with  MVA-5T4 in phase I-II studies. The derivation of the IRS formed part of an  exploratory, retrospective analysis; however, if confirmed in future studies, the  results have important implications for the development and use of the MVA-5T4  vaccine and potentially for other similar vaccines.
CANIT0000107	21387109	Clinical research	Renal cancer	Renal carcinoma	EFO:0002890	Kidney	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine plus sunitinib	Sunitinib plus placebo	Tumor vaccine plus Target therapy	 IFNA (DB00018); IL2 (NCIT:C24498); sunitinib (DB01268); MVA-5T4 vaccine (NCIT:C49087); 	288	302	A multicentre phase III clinical trial	MVA-5T4-induced immune responses are an early marker of efficacy in renal cancer patients.	N/A	N/A	N/A	MVA-5T4 response (NCIT:C49087); 	MVA-5T4 specific immune responses	Immune response	 2011 Jun	 MVA-5T4-induced immune responses are an early marker of efficacy in renal cancer   patients.	 Cancer Immunol Immunother	 Few immunotherapy compounds have demonstrated a direct link between the predicted  mode of action of the product and benefit to the patient. Since cancer vaccines  are thought to have a delayed therapeutic effect, identification of the active  moiety may enable the development of an early marker of efficacy. Patients with  renal cancer and requiring first-line treatment for metastatic disease were  randomized 1:1 to receive MVA-5T4 (TroVax((R))) or placebo alongside Sunitinib,  IL-2 or IFN-alpha in a multicentre phase III trial. Antibody responses were  quantified following the 3rd and 4th vaccinations. A surrogate for 5T4 antibody  response (the immune response surrogate; IRS) was constructed and then used in a   survival analysis to evaluate treatment benefit. Seven hundred and thirty-three  patients were randomized, and immune responses were assessed in 590 patients. A  high 5T4 antibody response was associated with longer survival within the  MVA-5T4-treated group. The IRS was constructed as a linear combination of  pre-treatment 5T4 antibody levels, hemoglobin and hematocrit and was shown to be   a significant predictor of treatment benefit in the phase III study. Importantly,  the IRS was also associated with antibody response and survival in an independent  dataset comprising renal, colorectal and prostate cancer patients treated with  MVA-5T4 in phase I-II studies. The derivation of the IRS formed part of an  exploratory, retrospective analysis; however, if confirmed in future studies, the  results have important implications for the development and use of the MVA-5T4  vaccine and potentially for other similar vaccines.
CANIT0000108	21558401	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	19	N/A	N/A	CTLA4 blockade induces frequent increases in ITI by T cells despite which only a   minority of patients have objective tumor responses.	N/A	N/A	N/A	N/A	N/A	N/A	 2011 Jun 15	 CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes  regardless of clinical responses in humans.	 Clin Cancer Res	 BACKGROUND: CTLA4 blocking monoclonal antibodies provide durable clinical benefit  in a subset of patients with advanced melanoma mediated by intratumoral  lymphocytic infiltrates. A key question is defining whether the intratumoral  infiltration (ITI) is a differentiating factor between patients with and without   tumor responses. METHODS: Paired baseline and postdosing tumor biopsy specimens  were prospectively collected from 19 patients with metastatic melanoma, including  3 patients with an objective tumor response, receiving the anti-CTLA4 antibody  tremelimumab within a clinical trial with primary endpoint of quantitating CD8(+)  cytotoxic T-lymphocyte (CTL) infiltration in tumors. Samples were analyzed for  cell density by automated imaging capture and further characterized for  functional lymphocyte properties by assessing the cell activation markers HLA-DR   and CD45RO, the cell proliferation marker Ki67, and the regulatory T-cell marker   FOXP3. RESULTS: There was a highly significant increase in ITI by CD8(+) cells in  biopsy samples taken after tremelimumab treatment. This included increases  between 1-fold and 100-fold changes in 14 of 18 evaluable cases regardless of  clinical tumor response or progression. There was no difference between the  absolute number, location, or cell density of infiltrating cells between clinical  responders and patients with nonresponding lesions that showed acquired  intratumoral infiltrates. There were similar levels of expression of T-cell  activation markers (CD45RO, HLA-DR) in both groups and no difference in markers  for cell replication (Ki67) or the suppressor cell marker FOXP3. CONCLUSION:  CTLA4 blockade induces frequent increases in ITI by T cells despite which only a   minority of patients have objective tumor responses.CI  - (c)2011 AACR.
CANIT0000109	21632857	Clinical research	Advanced epithelial malignancies	Bladder cancer	EFO:0000292	Bladder	GM-CSF (P04141); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	GM-CSF ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus GM-CSF	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); GM-CSF (DB05386); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000110	21632857	Clinical research	Advanced epithelial malignancies	Bladder cancer	EFO:0000292	Bladder	MRC1 (P22897); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	MRC1 ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus CDX-1307	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); poly-ICLC (NCIT:C1198); GM-CSF (DB05386); CDX-1307 (NCIT:C77858); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000111	21632857	Clinical research	Advanced epithelial malignancies	Bladder cancer	EFO:0000292	Bladder	TLR3 (O15455); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	TLR3 ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus poly-ICLC	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); poly-ICLC (NCIT:C1198); GM-CSF (DB05386); CDX-1307 (NCIT:C77858); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000112	21632857	Clinical research	Advanced epithelial malignancies	Colorectal cancer	EFO:0005842	Intestines	GM-CSF (P04141); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	GM-CSF ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus GM-CSF	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); GM-CSF (DB05386); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000113	21632857	Clinical research	Advanced epithelial malignancies	Colorectal cancer	EFO:0005842	Intestines	MRC1 (P22897); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	MRC1 ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus CDX-1307	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); poly-ICLC (NCIT:C1198); GM-CSF (DB05386); CDX-1307 (NCIT:C77858); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000114	21632857	Clinical research	Advanced epithelial malignancies	Colorectal cancer	EFO:0005842	Intestines	TLR3 (O15455); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	TLR3 ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus poly-ICLC	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); poly-ICLC (NCIT:C1198); GM-CSF (DB05386); CDX-1307 (NCIT:C77858); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000115	21632857	Clinical research	Advanced epithelial malignancies	Ovarian carcinoma	EFO:0001075	Ovary	GM-CSF (P04141); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	GM-CSF ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus GM-CSF	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); GM-CSF (DB05386); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000116	21632857	Clinical research	Advanced epithelial malignancies	Ovarian carcinoma	EFO:0001075	Ovary	MRC1 (P22897); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	MRC1 ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus CDX-1307	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); poly-ICLC (NCIT:C1198); GM-CSF (DB05386); CDX-1307 (NCIT:C77858); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000117	21632857	Clinical research	Advanced epithelial malignancies	Ovarian carcinoma	EFO:0001075	Ovary	TLR3 (O15455); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	TLR3 ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus poly-ICLC	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); poly-ICLC (NCIT:C1198); GM-CSF (DB05386); CDX-1307 (NCIT:C77858); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000118	21632857	Clinical research	Advanced epithelial malignancies	Pancreatic carcinoma	EFO:0002618	Pancreas	GM-CSF (P04141); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	GM-CSF ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus GM-CSF	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); GM-CSF (DB05386); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000119	21632857	Clinical research	Advanced epithelial malignancies	Pancreatic carcinoma	EFO:0002618	Pancreas	MRC1 (P22897); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	MRC1 ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus CDX-1307	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); poly-ICLC (NCIT:C1198); GM-CSF (DB05386); CDX-1307 (NCIT:C77858); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000120	21632857	Clinical research	Advanced epithelial malignancies	Pancreatic carcinoma	EFO:0002618	Pancreas	TLR3 (O15455); TLR8 (Q9NR97); TLR7 (Q9NYK1); 	TLR3 ;  TLR8 ;  TLR7 	TLR7 or 8 agonist plus poly-ICLC	N/A	Immune checkpoint therapy plus Tumor vaccine 	TLR-8 agonist (NCIT:C156395); TLR-7 agonist (NCIT:C95699); poly-ICLC (NCIT:C1198); GM-CSF (DB05386); CDX-1307 (NCIT:C77858); 	87	N/A	A phase I clinical trial 	APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.	Toxicity consisted chiefly of mild injection site reactions.	N/A	N/A	N/A	N/A	N/A	 2011 Jul 15	 Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with  Toll-like receptor stimulation to induce immunity to self-antigens in cancer  patients.	 Clin Cancer Res	 PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by  tolerance to these self-antigens. Tolerance may be broken by immunization with  activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting  cells (APC); however, targeting tumor antigen directly to APC in vivo would be a   less complicated strategy. We wished to test whether targeted delivery of an  otherwise poorly immunogenic, soluble antigen to APC through their mannose  receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN:  Two phase I studies were conducted with CDX-1307, a vaccine composed of human  chorionic gonadotropin beta-chain (hCG-beta) fused to an MR-specific monoclonal  antibody, administered either locally (intradermally) or systemically  (intravenously) in patients with advanced epithelial malignancies. An initial  dose escalation of single-agent CDX-1307 was followed by additional cohorts of  CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)   and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid  (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307   induced consistent humoral and T-cell responses to hCG-beta when coadministered  with TLR agonists. Greater immune responses and clinical benefit, including the  longest duration of stable disease, were observed with immunization combined with  local TLR agonists. Immune responses were induced equally efficiently in patients  with elevated and nonelevated levels of serum hCG-beta. Antibodies within the  serum of vaccinated participants had tumor suppressive function in vitro.  Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC  targeting and activation induce adaptive immunity against poorly immunogenic  self-antigens which has implications for enhancing the efficacy of cancer  immunotherapy.
CANIT0000121	21810572	Case report	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	4	N/A	Case	Patients receiving ipilimumab may respond very differently compared to how they might react to chemotherapy. Responses can take weeks or months to develop; therefore, clinicians should not terminate treatment prematurely, providing the patient's condition allows for continuation. 	Patients had various typical immune-related adverse events (irAEs), which were managed successfully.	N/A	N/A	N/A	N/A	N/A	 2011 Aug	 Atypical clinical response patterns to ipilimumab.	 Clin J Oncol Nurs	 Patients with advanced melanoma have few treatment options, and survival is poor.  However, improved understanding of how the immune system interacts with cancer  has led to the development of novel therapies. Ipilimumab is a monoclonal  antibody that inhibits cytotoxic T-lymphocyte antigen-4 (CTLA-4), a key negative   regulator of host T-cell responses. This article presents cases of patients  receiving ipilimumab in clinical trials along with a discussion of their  significance and relevance to nursing practice. The patients showed different  response patterns to ipilimumab and also had various typical immune-related  adverse events (irAEs), which were managed successfully. The atypical response  patterns produced by ipilimumab likely reflect its mechanism of action, which  requires time for the immune system to mount an effective antitumor response.  Meanwhile, lesions may appear to enlarge as a consequence of enhanced T-cell  infiltration, although this may not necessarily be true disease progression.  Patients receiving ipilimumab may respond very differently compared to how they  might react to chemotherapy. Responses can take weeks or months to develop;  therefore, clinicians should not terminate treatment prematurely, providing the  patient's condition allows for continuation. Early recognition of irAEs combined   with prompt management will ensure that events are more likely to resolve without  serious consequences.
CANIT0000122	21822917	Basic research	Murine colon adenocarcinoma	Colon adenocarcinoma	EFO:1001949	Intestines	HER2 (P04626); 	HER2; 	MVA-BN-HER2 vaccine	N/A	Tumor vaccine	MVA-BN-HER2 vaccine (NCIT:C71758); 	Cell lines	N/A	Basic research	Taken together, our data demonstrate that treatment with  MVA-BN(R)-HER2 controls tumor growth through mechanisms including the induction  of Th1-biased HER-2-specific immune responses and the control of tumor-mediated  immunosuppression.MVA-BN(R)-HER2-induced anti-tumor activity was characterized by an increased  infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cells  accompanied by a decrease in the frequency of T(reg) cells in the lung, resulting  in a significantly increased ratio of effector T cells to T(reg) cells. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD11c (P20702); CD8 (P01732); HER2 (P04626); T-Lymphocyte (NCIT:C12476); 	Tumor-infiltrating activated, HER2-specific, CD8(+)CD11c(+) T-cell 	Tumor-infiltrating immune cell	 2012 Jan	 Immunotherapy with MVA-BN(R)-HER2 induces HER-2-specific Th1 immunity and alters   the intratumoral balance of effector and regulatory T cells.	 Cancer Immunol Immunother	 MVA-BN(R)-HER2 is a new candidate immunotherapy designed for the treatment of  HER-2-positive breast cancer. Here, we demonstrate that a single treatment with  MVA-BN(R)-HER2 exerts potent anti-tumor efficacy in a murine model of  experimental pulmonary metastasis. This anti-tumor efficacy occurred despite a  strong tumor-mediated immunosuppressive environment characterized by a high  frequency of regulatory T cells (T(reg)) in the lungs of tumor-bearing mice.  Immunogenicity studies showed that treatment with MVA-BN(R)-HER2 induced strongly  Th1-dominated HER-2-specific antibody and T-cell responses.  MVA-BN(R)-HER2-induced anti-tumor activity was characterized by an increased  infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cells  accompanied by a decrease in the frequency of T(reg) cells in the lung, resulting  in a significantly increased ratio of effector T cells to T(reg) cells. In  contrast, administration of HER2 protein formulated in Complete Freund's Adjuvant  (CFA) induced a strongly Th2-biased immune response to HER-2. However, this did  not lead to significant infiltration of the tumor-bearing lungs by CD8+ T cells  or the decrease in the frequency of T(reg) cells nor did it result in anti-tumor   efficacy. In vivo depletion of CD8+ cells confirmed that CD8 T cells were  required for the anti-tumor activity of MVA-BN(R)-HER2. Furthermore, depletion of  CD4+ or CD25+ cells demonstrated that tumor-induced T(reg) cells promoted tumor  growth and that CD4 effector cells also contribute to MVA-BN(R)-HER2-mediated  anti-tumor efficacy. Taken together, our data demonstrate that treatment with  MVA-BN(R)-HER2 controls tumor growth through mechanisms including the induction  of Th1-biased HER-2-specific immune responses and the control of tumor-mediated  immunosuppression.
CANIT0000123	21933959	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	144	N/A	N/A	NY-ESO-1-seropositive patients with associated CD8(+) T cells experienced more frequent clinical benefit than those with undetectable CD8(+) T-cell response, as well as a significant survival advantage.	N/A	N/A	N/A	NY-ESO-1 (P78358); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	NY-ESO-1-seropositive with associated CD8(+) T-cell 	Gene expression signature on/in immune cell	 2011 Oct 4	 Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical  benefit in advanced melanoma patients treated with ipilimumab.	 Proc Natl Acad Sci U S A	 Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4  (CTLA-4), has been shown to improve survival in patients with advanced metastatic  melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen  expressed in a subset of patients with melanoma. To characterize the association   between immune response and clinical outcome, we first analyzed NY-ESO-1 serum  antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22  of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following   treatment. These NY-ESO-1-seropositive patients had a greater likelihood of  experiencing clinical benefit 24 wk after ipilimumab treatment than  NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher   test). To understand why some patients with NY-ESO-1 antibody failed to  experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+)  T-cell responses by intracellular multicytokine staining in 20  NY-ESO-1-seropositive patients and found a surprising dissociation between  NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive  patients with associated CD8(+) T cells experienced more frequent clinical  benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one   of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as  a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent  Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses   may have predictive value for ipilimumab treatment and argue for prospective  studies in patients with established NY-ESO-1 immunity. The current findings  provide a strong rationale for the clinical use of modulators of  immunosuppression with concurrent approaches to favor tumor antigen-specific  immune responses, such as vaccines or adoptive transfer, in patients with cancer.
CANIT0000124	21933959	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	144	N/A	N/A	These NY-ESO-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative patients.	N/A	N/A	N/A	NY-ESO-1 (P78358); 	NY-ESO-1-seropositive	Gene expression signature on/in tumor cell	 2011 Oct 4	 Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical  benefit in advanced melanoma patients treated with ipilimumab.	 Proc Natl Acad Sci U S A	 Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4  (CTLA-4), has been shown to improve survival in patients with advanced metastatic  melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen  expressed in a subset of patients with melanoma. To characterize the association   between immune response and clinical outcome, we first analyzed NY-ESO-1 serum  antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22  of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following   treatment. These NY-ESO-1-seropositive patients had a greater likelihood of  experiencing clinical benefit 24 wk after ipilimumab treatment than  NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher   test). To understand why some patients with NY-ESO-1 antibody failed to  experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+)  T-cell responses by intracellular multicytokine staining in 20  NY-ESO-1-seropositive patients and found a surprising dissociation between  NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive  patients with associated CD8(+) T cells experienced more frequent clinical  benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one   of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as  a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent  Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses   may have predictive value for ipilimumab treatment and argue for prospective  studies in patients with established NY-ESO-1 immunity. The current findings  provide a strong rationale for the clinical use of modulators of  immunosuppression with concurrent approaches to favor tumor antigen-specific  immune responses, such as vaccines or adoptive transfer, in patients with cancer.
CANIT0000125	22033581	Clinical research	Malignant melanoma	Melanoma	EFO:0000756	Skin	MLIAP (Q96CA5); 	MLIAP; 	Recombinant ML-IAP protein	N/A	Tumor vaccine	Recombinant ML-IAP protein (NCIT:C20951); 	100	N/A	N/A	Several melanoma patients who received CTLA-4   blockade with ipilimumab developed augmented humoral immune responses to ML-IAP  as a function of treatment which was associated with beneficial clinical  outcomes.High frequency immune responses in melanoma patients, associations with  favorable treatment outcomes, and its essential role in melanoma pathogenesis  support the development of ML-IAP as a disease marker and therapeutic target.	N/A	N/A	N/A	ML-IAP (Q96CA5); 	ML-IAP expression levels on tumor cells	Gene expression signature on/in tumor cell	 2012 May	 Immunity to the melanoma inhibitor of apoptosis protein (ML-IAP; livin) in  patients with malignant melanoma.	 Cancer Immunol Immunother	 Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte  differentiation or cancer-testis families. Antigen-loss variants can often  result, as these antigens are not critical for tumor cell survival. Exploration  of functionally relevant targets has been limited. The melanoma inhibitor of  apoptosis protein (ML-IAP; livin) is overexpressed in melanoma, contributing to  disease progression and treatment resistance. Improved understanding of the  significance of ML-IAP immune responses in patients has possible therapeutic  applications. We found ML-IAP frequently expressed in melanoma metastases by  immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping  peptide library representing full-length protein was utilized to screen cellular   responses in stage I-IV patients and healthy controls by ELISPOT. A broad array  of CD4(+) and CD8(+) cellular responses against ML-IAP was observed with novel  class I and class II epitopes identified. Specific HLA-A*0201 epitopes were  analyzed further for frequency of reactivity. The generation of specific CD4(+)  and cytotoxic T cells revealed potent functional capability including cytokine  responsiveness to melanoma cell lines and tumor cell killing. In addition,  recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody  responses in a subset of patients. Several melanoma patients who received CTLA-4   blockade with ipilimumab developed augmented humoral immune responses to ML-IAP  as a function of treatment which was associated with beneficial clinical  outcomes. High frequency immune responses in melanoma patients, associations with  favorable treatment outcomes, and its essential role in melanoma pathogenesis  support the development of ML-IAP as a disease marker and therapeutic target.
CANIT0000126	22051508	Clinical research	Melanoma patients with brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	12	N/A	A retrospective cohort study	Although the present study is limited by the fact that it is a retrospective analysis of a small number of patients, the results provide further evidence for the safety and efficacy of ipilimumab in melanoma patients with stable brain metastases.	Central nervous system-related adverse events of grade 3-4, specifically cerebral edema and convulsion/seizure, occurred in two of 16 patients.	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2011 Dec	 Safety and clinical activity of ipilimumab in melanoma patients with brain  metastases: retrospective analysis of data from a phase 2 trial.	 Melanoma Res	 Melanoma has a high propensity to metastasize to the brain, and this is often  responsible for treatment failure in patients with advanced disease. Melanoma  patients with brain metastases are usually excluded from clinical trials because   of their expected survival of approximately 5 months. A growing body of evidence   suggests that ipilimumab, a human monoclonal antibody that blocks cytotoxic  T-lymphocyte antigen-4, has activity against melanoma brain metastases. We  conducted a retrospective analysis of data from a phase II study of ipilimumab in  advanced melanoma patients. Twelve of 115 patients randomized in the parent trial  had stable brain metastases at baseline, as identified by an Independent Review  Committee, and were evaluated for efficacy. Two of the 12 patients achieved a  partial response and three had stable disease. Both patients with a partial  response and one with stable disease were alive at the last follow-up, with  survival time of more than 4 years. The median overall survival of the 12  patients was 14 months (range: 2.7-56.4+). An additional four patients with  stable brain metastases at baseline were identified by a secondary Independent  Review Committee reviewer, and were evaluated for safety. Central nervous  system-related adverse events of grade 3-4, specifically cerebral edema and  convulsion/seizure, occurred in two of 16 patients. Although the present study is  limited by the fact that it is a retrospective analysis of a small number of  patients, the results provide further evidence for the safety and efficacy of  ipilimumab in melanoma patients with stable brain metastases.
CANIT0000127	22130164	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	115	N/A	A phase II clinical trial	These retrospective analyses are the first to provide survival data for ipilimumab in treatment-naive and previously treated patients within the same clinical trial.	N/A	N/A	N/A	N/A	N/A	N/A	 2012 Jan	 Ipilimumab in treatment-naive and previously treated patients with metastatic  melanoma: retrospective analysis of efficacy and safety data from a phase II  trial.	 J Immunother	 Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic  T-lymphocyte antigen-4 to potentiate antitumor T-cell responses. In a phase III  trial, ipilimumab monotherapy at 3 mg/kg demonstrated an improvement in overall  survival (OS) in patients with previously treated, metastatic melanoma. Here, we   conducted a retrospective analysis of efficacy and safety data from a phase II  clinical trial in which treatment-naive and previously treated patients with  metastatic melanoma received ipilimumab at an investigational dose of 10 mg/kg.  Patients were randomized 1:1 to receive oral budesonide or placebo, and  ipilimumab at 10 mg/kg every 3 weeks for 4 doses, to determine whether  prophylactic budesonide affected the rate of grade >/=2 diarrhea. One hundred  fifteen patients were randomized and treated: 62 had received prior systemic  therapy for metastatic disease and 53 had not. No efficacy endpoint was affected   by budesonide therapy, and the efficacy data were therefore pooled for budesonide  and placebo subgroups. Median OS was 30.5 months for treatment-naive patients who  received ipilimumab, with survival rates of 69.4%, 62.9%, and 56.9% at 12, 18,  and 24 months. In previously treated patients who received ipilimumab, median OS   was 13.6 months, with survival rates of 50.0%, 37.7%, and 28.5% at 12, 18, and 24  months. There were no meaningful differences in the number of objective responses  or rate of grade >/=2 diarrhea between groups. These retrospective analyses are  the first to provide survival data for ipilimumab in treatment-naive and  previously treated patients within the same clinical trial.
CANIT0000128	22210552	Clinical research	PSA-recurrent prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab plus short-term androgen deprivation	Short-term androgen deprivation	Immune checkpoint therapy plus Hormone therapy	Short-term androgen deprivation (NCIT:C15676); tremelimumab (DB11771); 	11	N/A	An open-label, dose-escalation, single-institution phase I trial	The identification of  delayed, prolonged favorable changes in serum PSA suggests that future studies  could explore this combination in studies evaluating time to disease progression.	Dose-limiting toxicities included grade 3 diarrhea and skin rash.	N/A	N/A	N/A	N/A	N/A	 2012 Jul	 Phase I trial of tremelimumab in combination with short-term androgen deprivation  in patients with PSA-recurrent prostate cancer.	 Cancer Immunol Immunother	 CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The  antitumor mechanism is presumably mediated in part by the expansion of  tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for  patients with metastatic prostate cancer, has been shown to elicit prostate  tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment  with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a  tumor-specific immune response elicited by androgen deprivation. We report here  the results of a phase I trial evaluating a humanized monoclonal antibody  targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen  deprivation using an antiandrogen. Eligible patients were those with  PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not  previously treated with androgen deprivation, and without radiographic evidence  of metastatic disease. Subjects were treated in two cycles, 3 months apart, in  which they received bicalutamide 150 mg daily days 1-28 and tremelimumab on day  29. The primary endpoint of the trial was safety. Secondary endpoints included  measures of PSA kinetics and identification of a maximum tolerated dose. Eleven  patients were enrolled and completed at least 1 year of follow-up. Dose-limiting   toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA  doubling time were observed in a period shortly after completing treatment;  however, three patients experienced a prolongation in PSA doubling time  detectable several months after completing treatment. The identification of  delayed, prolonged favorable changes in serum PSA suggests that future studies  could explore this combination in studies evaluating time to disease progression.
CANIT0000129	22231551	Case report	Advanced melanoma patients	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	We report a case of severe neurologic disease after ipilimumab treatment. Veinoglobulins were then infused and the patient began to improve and recovered almost normal activity two years later.	N/A	N/A	N/A	N/A	N/A	 2012 Dec	 Severe meningo-radiculo-neuritis associated with ipilimumab.	 Invest New Drugs	 PURPOSE: Ipilimumab is a T-cell-potentiating monoclonal antibody directed against  cytotoxic T-lymphocyte antigen-4 (CTLA-4) to promote antitumoural immunity. In  phase III trials, ipilimumab was shown to be the first agent to improve survival   in advanced melanoma patients, regardless of previous treatment. We report a case  of severe neurologic disease after ipilimumab treatment. PATIENT AND METHODS:  Neurologic symptoms including facial diplegia, tetraplegia, areflexia progressed   with time a few days after the fourth monthly ipilimumab infusion. Analysis of  the cerebro-spinal fluid showed elevated proteinorachy and lymphocytic  meningitis. Despite high doses of steroids and symptomatic treatment, the  symptoms worsened. RESULTS: Veinoglobulins were then infused and the patient  began to improve and recovered almost normal activity two years later.  CONCLUSION: The adverse event profile associated with ipilimumab was primarily  immune-related. This is the first case in which such a severe event has been  reported.
CANIT0000130	22271879	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	177	N/A	N/A	This report provides the longest follow-up of patients with melanoma treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma. The combination of ipilimumab and interleukin-2 seems to have an increased CR rate, but this needs to be tested in a randomized trial.	N/A	N/A	N/A	N/A	N/A	N/A	 2012 Apr 1	 CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with  metastatic melanoma.	 Clin Cancer Res	 PURPOSE: Treatment with ipilimumab can cause objective tumor responses in  patients with metastatic melanoma. We have treated 177 evaluable patients in  three clinical trials and have long-term follow-up to evaluate the durability of   responses. EXPERIMENTAL DESIGN: Patients with metastatic melanoma were treated in  three trials from 2002 to 2005. In protocol 1, 56 patients received ipilimumab  with gp100 peptides. In protocol 2, 36 patients received ipilimumab with  interleukin-2. In protocol 3, 85 patients received ipilimumab with intrapatient  dose-escalation and were randomized to receive gp100 peptides. We have analyzed  their long-term follow-up and survival data. RESULTS: With median follow-up for  protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16,  and 13 months with 5-year survival rates being 13%, 25%, and 23%, respectively.  Patients in protocol 2 had a 17% complete response (CR) rate, compared with 7% in  protocol 1 and 6% in protocol 3. These CR rates are higher than previously  reported for the same trials because some patients who eventually became complete  responders had continual tumor regression months to years after therapy. All but   one of the 15 complete responders are ongoing at 54+ to 99+ months. CONCLUSIONS:   This report provides the longest follow-up of patients with melanoma treated with  ipilimumab and shows that ipilimumab can induce durable, potentially curative  tumor regression in a small percentage of patients with metastatic melanoma. The   combination of ipilimumab and interleukin-2 seems to have an increased CR rate,  but this needs to be tested in a randomized trial.CI  - (c)2012 AACR.
CANIT0000131	22326922	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); GM-CSF (P04141); 	CTLA-4; GM-CSF	Ipilimumab plus GM-CSF	N/A	Immune checkpoint therapy plus Tumor vaccine 	GVAX (DB04901); ipilimumab (DB06186); 	28	N/A	A phase I clinical trial 	GVAX combined  with 3.0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and  ipilimumab is warranted.	We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 30 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 50 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 30 mg/kg dose level, rather than enrol a further three patients at the 50 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 30 mg/kg or 50 mg/kg ipilimumab.	N/A	N/A	N/A	N/A	N/A	 2012 May	 Combined immunotherapy with granulocyte-macrophage colony-stimulating  factor-transduced allogeneic prostate cancer cells and ipilimumab in patients  with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation  trial.	 Lancet Oncol	 BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced  allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against  prostate cancer; preclinical studies have shown potent synergy when combined with  ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to  assess the safety of combined treatment with GVAX and ipilimumab in patients with  metastatic castration-resistant prostate cancer (mCRPC). METHODS: We did an  open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with  a fixed dose of GVAX, with a subsequent expansion phase, both at the VU  University Medical Centre (Amsterdam, Netherlands). Eligible patients had  documented mCRPC and had not been previously treated with chemotherapy. All  patients received a 5x10(8) cell priming dose of GVAX intradermally on day 1 with  subsequent intradermal injections of 3x10(8) cells every 2 weeks for 24 weeks.  The vaccinations were combined with intravenous ipilimumab every 4 weeks. We  enrolled patients in cohorts of three; each cohort received an escalating dose of  ipilimumab at 0.3, 1.0, 3.0, or 5.0 mg/kg. Our primary endpoint was safety. This   study is registered with ClinicalTrials.gov, number NCT01510288. FINDINGS: We  enrolled 12 patients into our dose-escalation cohort. We did not record any  severe immune-related adverse events at the first two dose levels. At the 3.0  mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis;   at the 5.0 mg/kg dose level, two patients had grade 3 hypophysitis and one  patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due   to observed clinical activity and toxic events, we decided to expand the 3.0  mg/kg dose level, rather than enrol a further three patients at the 5.0 mg/kg  level. 16 patients were enrolled in the expansion cohort, two of whom developed  grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade   3 hepatitis--all immune-related adverse events. The most common adverse events  noted in all 28 patients were injection-site reactions (grade 1-2 events seen in   all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia  (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in  prostate-specific antigen from baseline was recorded in seven patients (25%); all  had received 3.0 mg/kg or 5.0 mg/kg ipilimumab. INTERPRETATION: GVAX combined  with 3.0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further   research on the combined treatment of patients with mCRPC with vaccination and  ipilimumab is warranted. FUNDING: Cell Genesys Inc, Prostate Cancer Foundation,  Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer  Center Amsterdam.CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
CANIT0000132	22326924	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus the PSA-Tricom vaccine.	N/A	Immune checkpoint therapy plus Tumor vaccine 	PSA-Tricom vaccine (NCIT:C38708); ipilimumab (DB06186); 	30	N/A	A phase I dose-escalation trial	The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC.	We did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient).	N/A	N/A	N/A	N/A	N/A	 2012 May	 Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in  metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.	 Lancet Oncol	 BACKGROUND: Therapeutic cancer vaccines have shown activity in metastatic  castration-resistant prostate cancer (mCRPC), and methods are being assessed to  enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that  binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule  expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed  to assess the safety and tolerability of ipilimumab in combination with a  poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing  transgenes for T-cell co-stimulatory molecule expression, including CD80.  METHODS: We did a phase 1 dose-escalation trial, with a subsequent expansion  phase, to assess the safety and tolerability of escalating doses of ipilimumab in  combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC  received 2x10(8) plaque-forming units of recombinant vaccinia PSA-Tricom  subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1x10(9)  plaque-forming units, starting on day 15. Intravenous ipilimumab was given  monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal  was to assess the safety of the combination. This study is registered with  ClinicalTrials.gov, number NCT00113984. FINDINGS: We completed enrolment with 30   patients (24 of whom had not been previously treated with chemotherapy) and we  did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site   reactions were the most common toxic effects: three of 30 patients had grade 1  reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater  immune-related adverse events. Grade 3 or 4 immune-related adverse events  included diarrhoea or colitis in four patients and grade 3 rash (two patients),  grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related  adverse events (two patients), and grade 4 neutropenia (one patient). Only one of  the six patients previously treated with chemotherapy had a PSA decline from  baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA  declines from baseline, of which six were greater than 50%. INTERPRETATION: The  use of a vaccine targeting PSA that also enhances co-stimulation of the immune  system did not seem to exacerbate the immune-related adverse events associated  with ipilimumab. Randomised trials are needed to further assess clinical outcomes  of the combination of ipilimumab and vaccine in mCRPC. FUNDING: US National  Institutes of Health.CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
CANIT0000133	22382362	Clinical research	Unresectable stage III/IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	82	N/A	A randomized, double-blind, multicenter	No association between BRAF-V600E mutation status of melanoma tumors and DDC after treatment with ipilimumab was detected.	N/A	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2012 May	 Assessment of association between BRAF-V600E mutation status in melanomas and  clinical response to ipilimumab.	 Cancer Immunol Immunother	 Ipilimumab, a fully human monoclonal antibody against cytotoxic T lymphocyte  antigen-4, has demonstrated significant improvement in overall survival in  previously treated advanced melanoma patients. The BRAF inhibitor, vemurafenib,  has shown up to 78% objective response rates in melanoma patients harboring the  BRAF-V600E mutation but not in patients lacking the mutation. As an immune  potentiator, the mechanism of action of ipilimumab may not be dependent of the  activity of the BRAF pathway. To test this, we investigated whether the clinical   activity of ipilimumab would be affected by the BRAF-V600E mutation status of the  tumors. Thus, this retrospective analysis was carried using a set of tumor  biopsies from a completed phase II clinical trial. CA184004 was a randomized,  double-blind, multicenter trial of 82 previously treated or untreated patients  with unresectable stage III/IV melanoma. Patients received ipilimumab 3 or 10  mg/kg every 3 weeks for four doses followed by maintenance dosing in eligible  patients. The BRAF-V600E mutation status for 80 patients was determined in tumor   biopsies by PCR-based assays. Data on disease control were available for 69  patients with evaluated BRAF-V600E mutation status. Rates of objective responses   and stable disease in patients with BRAF-V600E mutation positive tumors (30%)  were comparable to those in patients with the wild-type gene (~33%). Eleven  patients displayed Durable Disease Control (DDC) of which 55% had BRAF-V600E  mutation positive tumors and 45% did not. In the 48 patients showing no DDC, the   mutation frequency was 50%. In this study, no association between BRAF-V600E  mutation status of melanoma tumors and DDC after treatment with ipilimumab was  detected.
CANIT0000134	22456429	Clinical research	Melanoma and brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	72	N/A	An open-label, phase II trial	Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are  small and asymptomatic. The drug has no unexpected toxic effects in this  population.	The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis.	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2012 May	 Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2  trial.	 Lancet Oncol	 BACKGROUND: Brain metastases commonly develop in patients with melanoma and are a  frequent cause of death of patients with this disease. Ipilimumab improves  survival in patients with advanced melanoma. We aimed to investigate the safety  and activity of this drug specifically in patients with brain metastases.  METHODS: Between July 31, 2008, and June 3, 2009, we enrolled patients with  melanoma and brain metastases from ten US centres who were older than 16 years  into two parallel cohorts. Patients in cohort A were neurologically asymptomatic   and were not receiving corticosteroid treatment at study entry; those in cohort B  were symptomatic and on a stable dose of corticosteroids. Patients were to  receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks.  Individuals who were clinically stable at week 24 were eligible to receive 10  mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the  proportion of patients with disease control, defined as complete response,  partial response, or stable disease after 12 weeks, assessed with modified WHO  criteria. Analyses of safety and efficacy included all treated patients. This  trial is registered with ClinicalTrials.gov, number NCT00623766. FINDINGS: We  enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine  patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one  patient in cohort B (5%, 0.1-24). When the brain alone was assessed, 12 patients   in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease  control. We noted disease control outside of the brain in 14 patients (27%,  16-42) in cohort A and in one individual (5%, 0.1-24) in cohort B. The most  common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and  fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]),   hyperglycaemia (two [10%]), and increased concentrations of serum aspartate  aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion.  The most common grade 3 immune-related adverse events were diarrhoea (six  patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%])  and increased concentrations of serum aspartate aminotransferase (two [10%]) in  cohort B. One patient in cohort A died of drug-related complications of  immune-related colitis. INTERPRETATION: Ipilimumab has activity in some patients   with advanced melanoma and brain metastases, particularly when metastases are  small and asymptomatic. The drug has no unexpected toxic effects in this  population. FUNDING: Bristol-Myers Squibb.CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
CANIT0000135	22493370	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); BRAF (P15056); 	CTLA-4; BRAF	Ipilimumab followed by vemurafenib	N/A	Immune checkpoint therapy followed by Target therapy	Vemurafenib (DB08881); ipilimumab (DB06186); 	1	N/A	Case	Exacerbation of sarcoidosis	N/A	N/A	N/A	N/A	N/A	N/A	 2012 Apr	 Sarcoidosis in a patient with metastatic melanoma sequentially treated with  anti-CTLA-4 monoclonal antibody and selective BRAF inhibitor.	 Anticancer Res	 A female patient with stage IV-M1c (distant lymph node and breast metastases),  chemotherapy-refractory melanoma was treated with the cytotoxic T-lymphocyte  antigen 4 (CTLA-4)-inhibitory monoclonal antibody ipilimumab. At first evaluation  following induction treatment, there was marked increase in the volume of the  lymphadenopathies (including new adenopathies) and strong uptake of  (18)Fluorodeoxy-D-glucose ((18)FDG); marked enlargement of the spleen and  interstitial lung infiltrates were also observed. Non-necrotising granulomas were  discovered on transbronchial mucosal biopsy and cytology on bronchoalveolar  lavage established the diagnosis of sarcoidosis. There was a marked clinical and   (18)FDG-positron emission tomography/computed tomography ((18)FDG-PET/CT)  documented response following six weeks of corticotherapy. At follow-up,  progression of subdiaphragmatic melanoma lymph node metastases was documented.  Regression of these metastatic sites was observed during treatment with the  selective v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor  vemurafenib. The patient died due to progressive disease after three months of  vemurafenib treatment. Our case report illustrates the need to take into  consideration exacerbation of sarcoidosis as a potential confounder in the  assessment of tumor response in a melanoma patient treated with the anti-CTLA-4  mononclonal antibody ipilimumab.
CANIT0000136	22547592	Clinical research	Stage IIIB/IV non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel and carboplatin followed by placebo plus paclitaxel and carboplatin	Placebo in combination with paclitaxel and carboplatin	Immune checkpoint therapy followed by Chemotherapy	Carboplatin (DB00958); paclitaxel (DB01229); ipilimumab (DB06186); 	68	68	A randomized, double-blind, multicenter phase II study	Not improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC.	Overall rates of grade 3 and 4 immune-related AEs were  20% and 6% for  concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity.	N/A	N/A	N/A	N/A	N/A	 2012 Jun 10	 Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment  in stage IIIB/IV non-small-cell lung cancer: results from a randomized,  double-blind, multicenter phase II study.	 J Clin Oncol	 PURPOSE: Ipilimumab, which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal  antibody, showed a survival benefit in melanoma with adverse events (AEs) managed  by protocol-defined guidelines. A phase II study in lung cancer assessed the  activity of ipilimumab plus paclitaxel and carboplatin. PATIENTS AND METHODS:  Patients (N = 204) with chemotherapy-naive non-small-cell lung cancer (NSCLC)  were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m(2)) and carboplatin   (area under the curve, 6) with either placebo (control) or ipilimumab in one of  the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus   paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and  carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and  carboplatin followed by four doses of ipilimumab plus paclitaxel and  carboplatin).Treatment was administered intravenously every 3 weeks for </= 18  weeks (induction). Eligible patients continued ipilimumab or placebo every 12  weeks as maintenance therapy. Response was assessed by using immune-related  response criteria and modified WHO criteria. The primary end point was  immune-related progression-free survival (irPFS). Other end points were  progression-free survival (PFS), best overall response rate (BORR),  immune-related BORR (irBORR), overall survival (OS), and safety. RESULTS: The  study met its primary end point of improved irPFS for phased ipilimumab versus  the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab  (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified  WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and  control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6  months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an   irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%,  respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of  grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab,  concurrent ipilimumab, and the control, respectively. Two patients (concurrent,  one patient; control, one patient) died from treatment-related toxicity.  CONCLUSION: Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and   PFS, which supports additional investigation of ipilimumab in NSCLC.
CANIT0000137	22547592	Clinical research	Stage IIIB/IV non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Placebo plus paclitaxel and carboplatin followed by ipilimumab plus paclitaxel and carboplatin	Placebo in combination with paclitaxel and carboplatin	Chemotherapy followed by Immune checkpoint therapy	Carboplatin (DB00958); paclitaxel (DB01229); ipilimumab (DB06186); 	68	68	A randomized, double-blind, multicenter phase II study	Improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC.	Overall rates of grade 3 and 4 immune-related AEs were 15%, and 6% for phased ipilimumab and the control, respectively. One patients ( control) died from treatment-related toxicity.	N/A	N/A	N/A	N/A	N/A	 2012 Jun 10	 Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment  in stage IIIB/IV non-small-cell lung cancer: results from a randomized,  double-blind, multicenter phase II study.	 J Clin Oncol	 PURPOSE: Ipilimumab, which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal  antibody, showed a survival benefit in melanoma with adverse events (AEs) managed  by protocol-defined guidelines. A phase II study in lung cancer assessed the  activity of ipilimumab plus paclitaxel and carboplatin. PATIENTS AND METHODS:  Patients (N = 204) with chemotherapy-naive non-small-cell lung cancer (NSCLC)  were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m(2)) and carboplatin   (area under the curve, 6) with either placebo (control) or ipilimumab in one of  the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus   paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and  carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and  carboplatin followed by four doses of ipilimumab plus paclitaxel and  carboplatin).Treatment was administered intravenously every 3 weeks for </= 18  weeks (induction). Eligible patients continued ipilimumab or placebo every 12  weeks as maintenance therapy. Response was assessed by using immune-related  response criteria and modified WHO criteria. The primary end point was  immune-related progression-free survival (irPFS). Other end points were  progression-free survival (PFS), best overall response rate (BORR),  immune-related BORR (irBORR), overall survival (OS), and safety. RESULTS: The  study met its primary end point of improved irPFS for phased ipilimumab versus  the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab  (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified  WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and  control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6  months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an   irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%,  respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of  grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab,  concurrent ipilimumab, and the control, respectively. Two patients (concurrent,  one patient; control, one patient) died from treatment-related toxicity.  CONCLUSION: Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and   PFS, which supports additional investigation of ipilimumab in NSCLC.
CANIT0000138	22614208	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Ipilimumab may cause several immune-mediated toxicities, the most common of which is enterocolitis. Physicians interpreting FDG PET/CT examinations of patients treated with ipilimumab should be aware of these FDG-avid immune-mediated toxicities.	An FDG PET/CT study demonstrated new FDG-avid (maximum standardized uptake value 15.6) diffuse colonic wall thickening, suggestive of ipilimumab-induced colitis. The patient was treated with systemic steroids, with subsequent resolution of her symptoms. Based on the response to steroids, the diagnosis of ipilimumab-induced enterocolitis was made.	N/A	N/A	N/A	N/A	N/A	 2012 Jun	 Ipilimumab-induced colitis on FDG PET/CT.	 Clin Nucl Med	 A 52-year-old woman with metastatic melanoma was treated with ipilimumab. After 2  cycles of treatment, she developed watery diarrhea, sweats, and chills. An FDG  PET/CT study demonstrated new FDG-avid (maximum standardized uptake value 15.6)  diffuse colonic wall thickening, suggestive of ipilimumab-induced colitis. The  patient was treated with systemic steroids, with subsequent resolution of her  symptoms. Based on the response to steroids, the diagnosis of ipilimumab-induced   enterocolitis was made. Ipilimumab may cause several immune-mediated toxicities,   the most common of which is enterocolitis. Physicians interpreting FDG PET/CT  examinations of patients treated with ipilimumab should be aware of these  FDG-avid immune-mediated toxicities.
CANIT0000139	22694829	Clinical research	Unresectable stage III or IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus gp100 vaccine	Gp100 vaccine	Immune checkpoint therapy plus Tumor vaccine 	Gp100 vaccine (NCIT:C29068); ipilimumab (DB06186); 	403	137	A phase III, randomized, double-blind study	Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients.	N/A	N/A	N/A	N/A	N/A	N/A	 2012 Jun 13	 Health related quality of life outcomes for unresectable stage III or IV melanoma  patients receiving ipilimumab treatment.	 Health Qual Life Outcomes	 BACKGROUND: In an international, randomized Phase III trial ipilimumab  demonstrated a significant overall survival benefit in previously treated  advanced melanoma patients. This report summarizes health-related quality of life  (HRQL) outcomes for ipilimumab with/without gp100 vaccine compared to gp100 alone  during the clinical trial's 12 week treatment induction period. METHODS: The  Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676   previously treated advanced unresectable stage III or IV melanoma patients.  Patients were randomized 3:1:1 to receive either ipilimumab (3 mg/kg q3w x 4  doses) + gp100 (peptide vaccine; 1 mg q3w x 4 doses; ipilimumab plus gp100, n =  403); gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimumab + placebo  (ipilimumab alone, n = 137). The European Organization for Research and Treatment  of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline  to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom  scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100   alone. Mean change in scores were categorized no change (0-5), a little (5-10  points), moderate (10-20 points), and very much (>20). RESULTS: In the  ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to   Week 12 generally indicated no change or a little impairment across EORTC  QLQ-C30 global health status, function, and symptom subscales. Significant  differences in constipation, favoring ipilimumab, were observed (p < 0.05). For  ipilimumab alone arm, subscales with no or a little impairment were physical,  emotional, cognitive, social function, global health, nausea, pain, dyspnea,  constipation, and diarrhea subscales. For the gp100 alone group, the observed  changes were moderate to large for global health, role function, fatigue, and for  pain. CONCLUSIONS: Ipilimumab with/without gp100 vaccine does not have a  significant negative HRQL impact during the treatment induction phase relative to  gp100 alone in stage III or IV melanoma patients. TRIAL REGISTRATION:  Clinicaltrials.gov identification number NCT00094653.
CANIT0000140	22694829	Clinical research	Unresectable stage III or IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus gp100 vaccine	Ipilimumab	Immune checkpoint therapy plus Tumor vaccine 	Gp100 vaccine (NCIT:C29068); ipilimumab (DB06186); 	403	137	A phase III, randomized, double-blind study	Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients.	N/A	N/A	N/A	N/A	N/A	N/A	 2012 Jun 13	 Health related quality of life outcomes for unresectable stage III or IV melanoma  patients receiving ipilimumab treatment.	 Health Qual Life Outcomes	 BACKGROUND: In an international, randomized Phase III trial ipilimumab  demonstrated a significant overall survival benefit in previously treated  advanced melanoma patients. This report summarizes health-related quality of life  (HRQL) outcomes for ipilimumab with/without gp100 vaccine compared to gp100 alone  during the clinical trial's 12 week treatment induction period. METHODS: The  Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676   previously treated advanced unresectable stage III or IV melanoma patients.  Patients were randomized 3:1:1 to receive either ipilimumab (3 mg/kg q3w x 4  doses) + gp100 (peptide vaccine; 1 mg q3w x 4 doses; ipilimumab plus gp100, n =  403); gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimumab + placebo  (ipilimumab alone, n = 137). The European Organization for Research and Treatment  of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline  to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom  scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100   alone. Mean change in scores were categorized no change (0-5), a little (5-10  points), moderate (10-20 points), and very much (>20). RESULTS: In the  ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to   Week 12 generally indicated no change or a little impairment across EORTC  QLQ-C30 global health status, function, and symptom subscales. Significant  differences in constipation, favoring ipilimumab, were observed (p < 0.05). For  ipilimumab alone arm, subscales with no or a little impairment were physical,  emotional, cognitive, social function, global health, nausea, pain, dyspnea,  constipation, and diarrhea subscales. For the gp100 alone group, the observed  changes were moderate to large for global health, role function, fatigue, and for  pain. CONCLUSIONS: Ipilimumab with/without gp100 vaccine does not have a  significant negative HRQL impact during the treatment induction phase relative to  gp100 alone in stage III or IV melanoma patients. TRIAL REGISTRATION:  Clinicaltrials.gov identification number NCT00094653.
CANIT0000141	22713795	Case report	Primary rhabdoid melanoma of the urinary bladder	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Partial response	N/A	N/A	N/A	N/A	N/A	N/A	 2012 Aug	 A rare case of primary rhabdoid melanoma of the urinary bladder treated with  ipilimumab, an anti-CTLA 4 monoclonal antibody.	 Melanoma Res	 Primary melanoma of the urinary bladder is a rare subentity of melanoma. The same  applies for melanoma of the rhabdoid histopathologic phenotype. A female patient   was initially diagnosed with melanoma of unknown origin caused by macroscopic  lymph node metastasis in the left inguinal and parailiacal regions. Because of  the extent of the disease, radical surgery could not be performed. The patient  underwent systemic chemotherapy with dacarbazine, followed by the experimental  compound tasisulam. Upon sudden macrohematuria, cystoscopy showed a large  infiltrating tumorous structure located on the left side of the urinary bladder.   Clinically, the amelanotic tumor showed endophytic growth into the lumen; on the   histopathological specimen, the growth pattern was partially undermining the  urothelium, which is commonly observed in primary melanoma of the urinary  bladder. Cytologically, the tumor cells were classified as rhabdoid melanoma, a  very rare variant of melanoma, which is commonly amelanotic and expresses S100,  vimentin and Ncam. Mutational analysis showed positive results for BRAF V600E.  After detecting the primary melanoma, the patient received anti-CTLA4 antibody  treatment with 3 mg/kg ipilimumab, through which a partial response was achieved.  Past computed tomography scans should be re-evaluated for suspicious lesions, and  cystoscopy should be included in the clinical workup if the pattern of metastasis  is congruent with the drainage sites of the urinary bladder.
CANIT0000142	22727601	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	Case	N/A	Radiation necrosis of the brain	N/A	N/A	N/A	N/A	N/A	 2012 Nov	 Radiation necrosis of the brain in melanoma patients successfully treated with  ipilimumab, three case studies.	 Eur J Cancer	 Metastasis to the brain is a frequent event in patients with advanced melanoma.  Despite treatment with neurosurgery, pancranial irradiation and high-precision  conformal radiotherapy, the prognosis of patients suffering from melanoma brain  metastasis has remained very poor. Ipilimumab is a new effective immunotherapy  for the treatment of advanced melanoma and has demonstrated activity against  brain metastases. We report three patients successfully treated with ipilimumab  who subsequently developed focal necrosis of the brain following prior  radiotherapy of their melanoma brain metastases. As new active systemic treatment  options become available that improve the survival of patients with melanoma  brain metastases, adequate diagnosis and management of the late sequela from  radiation to the brain is likely to gain importance in the management of these  patients.CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
CANIT0000143	22858559	Clinical research	Extensive-disease-small-cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel or carboplatin followed by placebo plus paclitaxel or carboplatin	Placebo plus paclitaxel or carboplatin	Immune checkpoint therapy followed by Chemotherapy	Carboplatin (DB00958); paclitaxel (DB01229); ipilimumab (DB06186); 	42	44	A randomized, double-blind, multicenter phase II trial	Improved progression-free survival	Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively.	N/A	N/A	N/A	N/A	N/A	 2013 Jan	 Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy  in extensive-disease-small-cell lung cancer: results from a randomized,  double-blind, multicenter phase 2 trial.	 Ann Oncol	 BACKGROUND: Ipilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival   benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by  the protocol-defined guidelines. This phase 2 study evaluated  ipilimumab+paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung  cancer (ED-SCLC). DESIGN: Patients (n=130) with chemotherapy-naive ED-SCLC were  randomized 1: 1: 1 to receive paclitaxel (175 mg/m2)/carboplatin (area under the   curve=6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative   regimens, concurrent ipilimumab (ipilimumab+paclitaxel/carboplatin followed by  placebo+paclitaxel/carboplatin) or phased ipilimumab  (placebo+paclitaxel/carboplatin followed by ipilimumab+paclitaxel/carboplatin).  Treatment was administered every 3 weeks for a maximum of 18 weeks (induction),  followed by maintenance ipilimumab or placebo every 12 weeks. End points included  progression-free survival (PFS), irPFS, best overall response rate (BORR);  irBORR, overall survival (OS), and safety. RESULTS: Phased ipilimumab, but not  concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio)=0.64;  P=0.03]. No improvement in PFS (HR=0.93; P=0.37) or OS (HR=0.75; P=0.13)  occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively,  were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2,   3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade  3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and  control, respectively. CONCLUSION: These results suggest further investigation of  ipilimumab in ED-SCLC.
CANIT0000144	22858559	Clinical research	Extensive-disease-small-cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); 	CTLA-4; 	Placebo plus paclitaxel or carboplatin followed by ipilimumab plus paclitaxel or carboplatin	Placebo plus paclitaxel or carboplatin	Chemotherapy followed by Immune checkpoint therapy	Carboplatin (DB00958); paclitaxel (DB01229); ipilimumab (DB06186); 	44	44	A randomized, double-blind, multicenter phase III trial	Not improved progression-free survival	Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively.	N/A	N/A	N/A	N/A	N/A	 2013 Jan	 Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy  in extensive-disease-small-cell lung cancer: results from a randomized,  double-blind, multicenter phase 2 trial.	 Ann Oncol	 BACKGROUND: Ipilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival   benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by  the protocol-defined guidelines. This phase 2 study evaluated  ipilimumab+paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung  cancer (ED-SCLC). DESIGN: Patients (n=130) with chemotherapy-naive ED-SCLC were  randomized 1: 1: 1 to receive paclitaxel (175 mg/m2)/carboplatin (area under the   curve=6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative   regimens, concurrent ipilimumab (ipilimumab+paclitaxel/carboplatin followed by  placebo+paclitaxel/carboplatin) or phased ipilimumab  (placebo+paclitaxel/carboplatin followed by ipilimumab+paclitaxel/carboplatin).  Treatment was administered every 3 weeks for a maximum of 18 weeks (induction),  followed by maintenance ipilimumab or placebo every 12 weeks. End points included  progression-free survival (PFS), irPFS, best overall response rate (BORR);  irBORR, overall survival (OS), and safety. RESULTS: Phased ipilimumab, but not  concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio)=0.64;  P=0.03]. No improvement in PFS (HR=0.93; P=0.37) or OS (HR=0.75; P=0.13)  occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively,  were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2,   3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade  3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and  control, respectively. CONCLUSION: These results suggest further investigation of  ipilimumab in ED-SCLC.
CANIT0000145	22878899	Clinical research	Castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); GVAX (DB04901); 	28	N/A	A phase I/II dose escalation/expansion trial	Better outcome in patients with increased absolute lymphocyte counts	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2013 Feb	 T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor  for survival after prostate GVAX/ipilimumab treatment.	 Cancer Immunol Immunother	 Immune checkpoint blockade enhances antitumor responses, but can also lead to  severe immune-related adverse events (IRAE). To avoid unnecessary exposure to  these potentially hazardous agents, it is important to identify biomarkers that  correlate with clinical activity and can be used to select patients that will  benefit from immune checkpoint blockade. To understand the consequences of CTLA-4  blockade and identify biomarkers for clinical efficacy and/or survival, an  exploratory T cell monitoring study was performed in a phase I/II dose  escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab  immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after   Prostate GVAX/ipilimumab treatment revealed striking differences between patients  who benefited from therapy and patients that did not. Treatment-induced rises in   absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+)   T cell activation were all associated with clinical benefit. Moreover,  significantly prolonged overall survival (OS) was observed for patients with high  pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated  (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of  differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these  immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T  cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab  therapy and to thus provide a putative and much-needed biomarker for patient  selection prior to therapeutic CTLA4 blockade.
CANIT0000146	22878899	Clinical research	Castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	GM-CSF (P04141); 	GM-CSF; 	GM-CSF	N/A	Tumor vaccine	Ipilimumab (DB06186); GM-CSF (DB05386)	28	N/A	A phase I/II dose escalation/expansion trial	Better outcome in patients with increased absolute lymphocyte counts	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2013 Feb	 T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor  for survival after prostate GVAX/ipilimumab treatment.	 Cancer Immunol Immunother	 Immune checkpoint blockade enhances antitumor responses, but can also lead to  severe immune-related adverse events (IRAE). To avoid unnecessary exposure to  these potentially hazardous agents, it is important to identify biomarkers that  correlate with clinical activity and can be used to select patients that will  benefit from immune checkpoint blockade. To understand the consequences of CTLA-4  blockade and identify biomarkers for clinical efficacy and/or survival, an  exploratory T cell monitoring study was performed in a phase I/II dose  escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab  immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after   Prostate GVAX/ipilimumab treatment revealed striking differences between patients  who benefited from therapy and patients that did not. Treatment-induced rises in   absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+)   T cell activation were all associated with clinical benefit. Moreover,  significantly prolonged overall survival (OS) was observed for patients with high  pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated  (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of  differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these  immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T  cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab  therapy and to thus provide a putative and much-needed biomarker for patient  selection prior to therapeutic CTLA4 blockade.
CANIT0000147	22878899	Clinical research	Castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); GVAX (DB04901); 	28	N/A	A phase I/II dose escalation/expansion trial	Better outcome in patients with increased CD4(+) T cell activation	N/A	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD4(+) T-cell activation	Gene expression signature on/in immune cell	 2013 Feb	 T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor  for survival after prostate GVAX/ipilimumab treatment.	 Cancer Immunol Immunother	 Immune checkpoint blockade enhances antitumor responses, but can also lead to  severe immune-related adverse events (IRAE). To avoid unnecessary exposure to  these potentially hazardous agents, it is important to identify biomarkers that  correlate with clinical activity and can be used to select patients that will  benefit from immune checkpoint blockade. To understand the consequences of CTLA-4  blockade and identify biomarkers for clinical efficacy and/or survival, an  exploratory T cell monitoring study was performed in a phase I/II dose  escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab  immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after   Prostate GVAX/ipilimumab treatment revealed striking differences between patients  who benefited from therapy and patients that did not. Treatment-induced rises in   absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+)   T cell activation were all associated with clinical benefit. Moreover,  significantly prolonged overall survival (OS) was observed for patients with high  pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated  (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of  differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these  immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T  cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab  therapy and to thus provide a putative and much-needed biomarker for patient  selection prior to therapeutic CTLA4 blockade.
CANIT0000148	22878899	Clinical research	Castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	GM-CSF (P04141); 	GM-CSF; 	GM-CSF	N/A	Tumor vaccine	Ipilimumab (DB06186); GM-CSF (DB05386)	28	N/A	A phase I/II dose escalation/expansion trial	Better outcome in patients with increased CD4(+) T cell activation	N/A	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD4(+) T-cell activation	Gene expression signature on/in immune cell	 2013 Feb	 T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor  for survival after prostate GVAX/ipilimumab treatment.	 Cancer Immunol Immunother	 Immune checkpoint blockade enhances antitumor responses, but can also lead to  severe immune-related adverse events (IRAE). To avoid unnecessary exposure to  these potentially hazardous agents, it is important to identify biomarkers that  correlate with clinical activity and can be used to select patients that will  benefit from immune checkpoint blockade. To understand the consequences of CTLA-4  blockade and identify biomarkers for clinical efficacy and/or survival, an  exploratory T cell monitoring study was performed in a phase I/II dose  escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab  immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after   Prostate GVAX/ipilimumab treatment revealed striking differences between patients  who benefited from therapy and patients that did not. Treatment-induced rises in   absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+)   T cell activation were all associated with clinical benefit. Moreover,  significantly prolonged overall survival (OS) was observed for patients with high  pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated  (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of  differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these  immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T  cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab  therapy and to thus provide a putative and much-needed biomarker for patient  selection prior to therapeutic CTLA4 blockade.
CANIT0000149	22878899	Clinical research	Castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); GVAX (DB04901); 	28	N/A	A phase I/II dose escalation/expansion trial	Better outcome in patients with increased CD4(+) T cell differentiation	N/A	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD4(+) T-cell differentiation	Gene expression signature on/in immune cell	 2013 Feb	 T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor  for survival after prostate GVAX/ipilimumab treatment.	 Cancer Immunol Immunother	 Immune checkpoint blockade enhances antitumor responses, but can also lead to  severe immune-related adverse events (IRAE). To avoid unnecessary exposure to  these potentially hazardous agents, it is important to identify biomarkers that  correlate with clinical activity and can be used to select patients that will  benefit from immune checkpoint blockade. To understand the consequences of CTLA-4  blockade and identify biomarkers for clinical efficacy and/or survival, an  exploratory T cell monitoring study was performed in a phase I/II dose  escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab  immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after   Prostate GVAX/ipilimumab treatment revealed striking differences between patients  who benefited from therapy and patients that did not. Treatment-induced rises in   absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+)   T cell activation were all associated with clinical benefit. Moreover,  significantly prolonged overall survival (OS) was observed for patients with high  pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated  (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of  differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these  immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T  cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab  therapy and to thus provide a putative and much-needed biomarker for patient  selection prior to therapeutic CTLA4 blockade.
CANIT0000150	22878899	Clinical research	Castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	GM-CSF (P04141); 	GM-CSF; 	GM-CSF	N/A	Tumor vaccine	Ipilimumab (DB06186); GM-CSF (DB05386)	28	N/A	A phase I/II dose escalation/expansion trial	Better outcome in patients with increased CD4(+) T cell differentiation	N/A	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD4(+) T-cell differentiation	Gene expression signature on/in immune cell	 2013 Feb	 T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor  for survival after prostate GVAX/ipilimumab treatment.	 Cancer Immunol Immunother	 Immune checkpoint blockade enhances antitumor responses, but can also lead to  severe immune-related adverse events (IRAE). To avoid unnecessary exposure to  these potentially hazardous agents, it is important to identify biomarkers that  correlate with clinical activity and can be used to select patients that will  benefit from immune checkpoint blockade. To understand the consequences of CTLA-4  blockade and identify biomarkers for clinical efficacy and/or survival, an  exploratory T cell monitoring study was performed in a phase I/II dose  escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab  immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after   Prostate GVAX/ipilimumab treatment revealed striking differences between patients  who benefited from therapy and patients that did not. Treatment-induced rises in   absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+)   T cell activation were all associated with clinical benefit. Moreover,  significantly prolonged overall survival (OS) was observed for patients with high  pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated  (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of  differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these  immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T  cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab  therapy and to thus provide a putative and much-needed biomarker for patient  selection prior to therapeutic CTLA4 blockade.
CANIT0000151	22878899	Clinical research	Castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); GVAX (DB04901); 	28	N/A	A phase I/II dose escalation/expansion trial	Better outcome in patients with increased CD8(+) T cell activation	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Percentage of CD8(+) effector-memory type 1 T-cell 	Gene expression signature on/in immune cell	 2013 Feb	 T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor  for survival after prostate GVAX/ipilimumab treatment.	 Cancer Immunol Immunother	 Immune checkpoint blockade enhances antitumor responses, but can also lead to  severe immune-related adverse events (IRAE). To avoid unnecessary exposure to  these potentially hazardous agents, it is important to identify biomarkers that  correlate with clinical activity and can be used to select patients that will  benefit from immune checkpoint blockade. To understand the consequences of CTLA-4  blockade and identify biomarkers for clinical efficacy and/or survival, an  exploratory T cell monitoring study was performed in a phase I/II dose  escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab  immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after   Prostate GVAX/ipilimumab treatment revealed striking differences between patients  who benefited from therapy and patients that did not. Treatment-induced rises in   absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+)   T cell activation were all associated with clinical benefit. Moreover,  significantly prolonged overall survival (OS) was observed for patients with high  pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated  (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of  differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these  immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T  cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab  therapy and to thus provide a putative and much-needed biomarker for patient  selection prior to therapeutic CTLA4 blockade.
CANIT0000152	22878899	Clinical research	Castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	GM-CSF (P04141); 	GM-CSF; 	GM-CSF	N/A	Tumor vaccine	Ipilimumab (DB06186); GM-CSF (DB05386)	28	N/A	A phase I/II dose escalation/expansion trial	Better outcome in patients with increased CD8(+) T cell activation	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Percentage of CD8(+) effector-memory type 1 T-cell 	Gene expression signature on/in immune cell	 2013 Feb	 T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor  for survival after prostate GVAX/ipilimumab treatment.	 Cancer Immunol Immunother	 Immune checkpoint blockade enhances antitumor responses, but can also lead to  severe immune-related adverse events (IRAE). To avoid unnecessary exposure to  these potentially hazardous agents, it is important to identify biomarkers that  correlate with clinical activity and can be used to select patients that will  benefit from immune checkpoint blockade. To understand the consequences of CTLA-4  blockade and identify biomarkers for clinical efficacy and/or survival, an  exploratory T cell monitoring study was performed in a phase I/II dose  escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab  immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after   Prostate GVAX/ipilimumab treatment revealed striking differences between patients  who benefited from therapy and patients that did not. Treatment-induced rises in   absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+)   T cell activation were all associated with clinical benefit. Moreover,  significantly prolonged overall survival (OS) was observed for patients with high  pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated  (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of  differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these  immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T  cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab  therapy and to thus provide a putative and much-needed biomarker for patient  selection prior to therapeutic CTLA4 blockade.
CANIT0000153	22894884	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus fotemustine	N/A	Immune checkpoint therapy plus Chemotherapy	Fotemustine (DB04106); ipilimumab (DB06186); 	86	N/A	An open-label, single-arm phase II	The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases.	47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase.	N/A	N/A	N/A	N/A	N/A	 2012 Sep	 Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an  open-label, single-arm phase 2 trial.	 Lancet Oncol	 BACKGROUND: Ipilimumab improves survival of patients with metastatic melanoma,  many of whom develop brain metastases. Chemotherapy-induced release of tumour  antigens might amplify ipilimumab's antitumour activity. We aimed to investigate   the efficacy and safety of ipilimumab plus fotemustine in patients with  metastatic melanoma with or without asymptomatic brain metastases. METHODS: In  our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older   with measurable, locally advanced, unresectable stage III or stage IV melanoma  between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy  of 16 weeks or more and an Eastern Cooperative Oncology Group performance status   of 1 or less, and could have received a maximum of one previous line of  chemotherapy. Participants received induction treatment of 10 mg/kg intravenous  ipilimumab every 3 weeks to a total of four doses, and 100 mg/m(2) intravenous  fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24.  Patients with a confirmed clinical response were eligible for maintenance  treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3  weeks. The primary endpoint was the proportion of patients with immune-related  disease control as established with immune-related response criteria. Analyses  were done per protocol. This trial is registered with EudraCT, number  2010-019356-50, and with ClinicalTrials.gov, number NCT01654692. FINDINGS: 86  patients were eligible for treatment, of whom 20 had asymptomatic brain  metastases at baseline. 40 patients in the study population achieved disease  control (46.5%, 95% CI 35.7-57.6), as did ten with brain metastases (50.0%,  27.2-72.8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events,   of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients  and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse  events were hepatic: 21 patients (24%) had grade 3 or 4 increases in  concentrations of alanine aminotransferase or aspartate aminotransferase.  INTERPRETATION: The combination of ipilimumab plus fotemustine has clinical  activity in patients with metastatic melanoma, including those with brain  metastases. FUNDING: Bristol-Myers Squibb.CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
CANIT0000154	23032745	Clinical research	Advanced ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	TLR3 (O15455); 	TLR3; 	Overlapping long peptides plus montanide-ISA-51	N/A	Tumor vaccine	MVA-5T4 vaccine (NCIT:C49087); IL2 (NCIT:C24498); 	25	N/A	A phase II clinical trial	TroVax in combination with IL-2 was safe  and well tolerated in all patients. The high frequency of 5T4-specific immune  responses and good clinical response rate are encouraging and warrant further  investigation.	MVA-5T4 (TroVax) was well tolerated with no serious adverse event attributed to vaccination. 	N/A	N/A	MVA-5T4 response (NCIT:C49087); 	MVA-5T4 specific immune responses	Immune response	 2008 Nov 15	 Vaccination of renal cell cancer patients with modified vaccinia ankara  delivering tumor antigen 5T4 (TroVax) administered with interleukin 2: a phase II  trial.	 Clin Cancer Res	 PURPOSE: The attenuated vaccinia virus modified vaccinia ankara (MVA) has been  engineered to deliver the tumor antigen 5T4 (TroVax). TroVax has been evaluated  in an open-label phase II trial in metastatic renal cell cancer patients in which  the vaccine was administered in combination with interleukin-2 (IL-2). The  safety, immunologic, and clinical efficacy of TroVax in combination with IL-2 was  determined. EXPERIMENTAL DESIGN: Twenty-five patients with metastatic renal cell   cancer were treated with TroVax plus IL-2. 5T4-specific cellular and humoral  responses were monitored throughout the study. Clinical responses were assessed  by measuring changes in tumor burden by computed tomography or magnetic resonance  imaging scan. RESULTS: TroVax was well tolerated with no serious adverse event  attributed to vaccination. Of 25 intention-to-treat patients, 21 mounted  5T4-specific antibody responses. Two patients showed a complete response for > 24  months and one a partial response for > 12 months. Six patients had disease  stabilization from 6 to > 21 months. Median progression-free survival (PFS) and  overall survival (OS) were > 3.37 months (range, 1.50- > 24.76) and > 12.87  months (range, 1.90- > 24.76), respectively. A statistically significant  relationship was detected between the magnitude of 5T4-specific antibody  responses and PFS and OS. CONCLUSION: TroVax in combination with IL-2 was safe  and well tolerated in all patients. The high frequency of 5T4-specific immune  responses and good clinical response rate are encouraging and warrant further  investigation.
CANIT0000155	23032745	Clinical research	Advanced ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	TLR3 (O15455); 	TLR3; 	Overlapping long peptides plus montanide-ISA-51 plus poly-ICLC	N/A	Tumor vaccine	Poly-ICLC (NCIT:C1198); Montanide ISA 51 VG (NCIT:C84843); OLP (NCIT:C90918); 	28	N/A	A phase I clinical trial 	NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.	The vaccine was generally well tolerated with injection site reactions and fatigue that resolved.	N/A	N/A	N/A	N/A	N/A	 2012 Dec 1	 Phase I trial of overlapping long peptides from a tumor self-antigen and  poly-ICLC shows rapid induction of integrated immune response in ovarian cancer  patients.	 Clin Cancer Res	 PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T  cells after intracellular processing by antigen-presenting cells. To investigate   the safety and in vivo immunogenicity of synthetic overlapping long peptides  (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with  OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.  EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second  or third remission were enrolled sequentially in three cohorts and received at  least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2  (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP +  1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and  cellular responses were evaluated by standardized immunomonitoring techniques  (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).  RESULTS: The vaccine was generally well tolerated with injection site reactions  and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were  undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%)  and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide,  and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after  vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were  detected in all patients with greater frequency and polyclonality when  Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant   further accelerated the induction of NY-ESO-1-specific immune responses.  CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.CI  - (c)2012 AACR.
CANIT0000156	23037483	Case report	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); BRAF (P15056); 	CTLA-4; BRAF	Ipilimumab followed by vemurafenib	N/A	Immune checkpoint therapy followed by Target therapy	Vemurafenib (DB08881); ipilimumab (DB06186); 	1	N/A	Case	Long-term survival	N/A	N/A	N/A	N/A	N/A	N/A	2012	 Long-term survival in metastatic malignant melanoma: ipilimumab followed by  vemurafenib in a patient with brain metastasis.	 Intern Med	 A 46-year-old man was diagnosed with brain metastasis after a two-year history of  melanoma. Paliative radiotherapy was administered followed by dacarbazine,  temozolamide, ipilimumab, stereotactic radiosurgery, ipilimumab reinduction and  finally vemurafenib, to which the patient showed objective responses. The patient  received vemurafenib for four months and died after progresive disease. Long-term  follow-ups after surgery have been reported in the literature. However, in  patients with unresectable metastases, outcomes are mostly detrimental. The  present patient survived for 40 months after brain metastasis. The unusually long  survival observed in the present case indicates the sequential effectiveness of  radiotherapy, chemotherapy, ipilimumab, stereotactic radiosurgery and  vemurafenib.
CANIT0000157	23060594	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Immune-related renal failure	N/A	N/A	N/A	N/A	N/A	 2012 Oct	 Ipilimumab-induced immune-related renal failure--a case report.	 Anticancer Res	 Ipilimumab is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte   antigen-4 and has become the first immune checkpoint inhibitor to enter clinical   practice, being recently approved for the treatment of metastatic melanoma.  Immune toxicity due to ipilimumab causing colitis, hepatitis, dermatitis and  hypophysitis is well-described. We report on a case of acute renal failure  resolving rapidly with high-dose corticosteroid treatment highlighting the  importance of vigilance for rarer immune-related toxicities as clinical  experience with ipilimumab grows.
CANIT0000158	23090079	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); INAR2 (P48551); 	CTLA-4; INAR2	Tremelimumab plus IFN2B	GM-CSF with Peptide Vaccination	Immune checkpoint therapy plus Immune cytokine	GM-CSF with Peptide Vaccination (DB05386); IFN2B (DB00018); tremelimumab (DB11771); 	37	20	N/A	Collectively, our findings suggest significant modulation of the host suppressor immune response using the IFN-/treme regimen.In addition, we see parallel downregulation in several populations of MDSC after IFN/treme but not the TLR-9/GM combination, which may serve to reduce immune suppression in patients treated with IFN/treme. Taken together with the clinical observations, these findings suggest a differential ability of the two regimens to overcome self-tolerance of melanoma.	N/A	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); Immune response (NCIT:C17930); 	Percentage of monocytic myeloid-derived suppressor cells	Cell percentage/counts in blood	 2012 Nov-Dec	 Differing patterns of circulating regulatory T cells and myeloid-derived  suppressor cells in metastatic melanoma patients receiving anti-CTLA4 antibody  and interferon-alpha or TLR-9 agonist and GM-CSF with peptide vaccination.	 J Immunother	 Changes in the biomarkers of host suppressor immune response were evaluated in  patients with melanoma enrolled in 2 trials. Two similar cohorts of patients  participating in the 2 studies were evaluated. The first (IFN/treme) tested  interferon (IFN)-alpha2b and tremelimumab in metastatic melanoma and reported a  response rate of 24%, 6.4 months median progression-free survival, and 21 months   median overall survival. The second [toll-like receptor 9 (TLR)/GM] tested  vaccination with MART-1, gp100, tyrosinase given with TLR-9 agonist and  granulocyte-macrophage colony-stimulating factor and reported 9% response rate,  median progression-free survival of 1.9 months, and median overall survival of  13.4 months. We monitored circulating T regulatory cells (T-reg) and  myeloid-derived suppressor cells (MDSC) utilizing multicolor flow cytometry. In  IFN/treme, changes in circulating T-reg and MDSC were compared between  baseline, day 29 (end of IFN-alpha induction) and day 85 (1 course). The  CD4(+)CD25hi(+)CD39(+) T-reg percentage was increased most at day 85 (P = 0.018)   and less significantly at day 29 (P = 0.09). There was a decrease in the  percentage of MDSC populations taken in aggregate, which was most significant for  monocytic MDSC (HLA-DR(+) low/CD14(+)) at day 29 (P < 0.0001) and day 85 (P =  0.001). In TLR-9/GM, changes in T-reg and MDSC were compared between baseline  and day 50 (4 vaccinations) and day 90 (8 vaccinations). There were no  significant changes in T-reg or MDSC, except for a trend towards decreased  (HLA-DR(+) low/CD14(+)) MDSC at day 50 (P = 0.07). Therefore, IFN/treme  significantly downregulated MDSC suggesting a role on the significant clinical  activity observed in this trial. T-reg findings suggest that IFN/treme induced  clinically significant antitumor responses by inhibiting CTLA4 suppressive  effects on T effectors, and less so by affecting T-reg.
CANIT0000159	23090080	Clinical research	Metastatic melanoma who progressed on high-dose IL-2	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Systemic therapy	Immune checkpoint therapy	Systemic therapy (NCIT:C15698); ipilimumab (DB06186); 	130	48	N/A	Prospective trials of high-dose interleukin-2 (HD IL-2) followed by ipilimumab could potentially identify patients most likely to benefit from a sequential approach of HD IL-2 followed by ipilimumab.	N/A	N/A	N/A	N/A	N/A	N/A	 2012 Nov-Dec	 Characterizing the clinical benefit of ipilimumab in patients who progressed on  high-dose IL-2.	 J Immunother	 Ipilimumab improves overall survival (OS) in patients with metastatic melanoma  including those previously treated with high-dose interleukin-2 (HD IL-2). The  primary objective of this study was to determine if clinical response or  progression-free survival (PFS) to HD IL-2 could predict benefit to subsequent  ipilimumab. The secondary objective was to further characterize the clinical  benefit of ipilimumab in patients who have progressed on HD IL-2. We reviewed the  records of all patients with metastatic melanoma who received HD IL-2 at MD  Anderson Cancer Center or Beth Israel Deaconess Medical Center from 2003 to 2009   and further identified patients who also received ipilimumab after progressing on  HD IL-2. OS to ipilimumab was calculated from the first dose of ipilimumab,  determined by Kaplan-Meier analysis, and was compared in patients based on their   prior clinical response and PFS to HD IL-2 using the log-rank test. Patients were  grouped based on their prior response to HD IL-2 as follows: complete response  and partial response, stable disease, and progressive disease. Patients were also  grouped and compared by prior PFS to HD IL-2 in >60 days versus </=60 days. A  total of 208 patients with melanoma were treated with HD IL-2, 130 (63%) received  additional systemic therapy after confirmed disease progression, and 48 (23%)  received ipilimumab. The clinical benefit of ipilimumab was similar to previously  published results (OS, 12.0 mo; PFS, 2.5 mo; response rate, 16.7%). Prior  clinical response or PFS to HD IL-2 did not predict benefit to subsequent  ipilimumab. Prospective trials of HD IL-2 followed by ipilimumab could  potentially identify patients most likely to benefit from a sequential approach  of HD IL-2 followed by ipilimumab.
CANIT0000160	23171508	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	44	N/A	A phase I multi-center study	This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion.	No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies.	N/A	N/A	N/A	N/A	N/A	 2012 Nov 21	 Safety profile and pharmacokinetic analyses of the anti-CTLA4 antibody  tremelimumab administered as a one hour infusion.	 J Transl Med	 BACKGROUND: CTLA4 blocking monoclonal antibodies provide a low frequency but  durable tumor responses in patients with metastatic melanoma, which led to the  regulatory approval of ipilimumab based on two randomized clinical trials with  overall survival advantage. The similarly fully human anti-CTLA4 antibody  tremelimumab had been developed in the clinic at a fixed rate infusion, resulting  in very prolonged infusion times. A new formulation of tremelimumab allowed  testing a shorter infusion time. METHODS: A phase 1 multi-center study to  establish the safety and tolerability of administering tremelimumab as a 1-hour  infusion to patients with metastatic melanoma. Secondary endpoints included  pharmacokinetic and clinical effects of tremelimumab. RESULTS: No grade 3 or  greater infusion-related adverse events or other adverse events preventing the  administration of the full tremelimumab dose were noted in 44 treated patients.  The overall side effect profile was consistent with prior experiences with  anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable  patients with metastatic melanoma, which is also consistent with the prior  experience with CTLA4 antagonistic antibodies. CONCLUSIONS: This study did not  identify any safety concerns when tremelimumab was administered as a 1-hour  infusion. These data support further clinical testing of the 1-hour infusion of  tremelimumab. (Clinical trial registration number NCT00585000).
CANIT0000161	23211620	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Polyradiculoneuritis is a rare but very severe immune-mediated complication of ipilimumab. Occlusive enteric neuropathy may mimic the digestive symptoms of colitis, which is so frequent under ipilimumab.	Colitis	N/A	N/A	N/A	N/A	N/A	 2013 Jan	 A severe case of ipilimumab-induced guillain-barre syndrome revealed by an  occlusive enteric neuropathy: a differential diagnosis for ipilimumab-induced  colitis.	 J Immunother	 Ipilimumab is a fully human monoclonal antibody directed against cytotoxic  T-lymphocyte antigen-4 recently approved for the treatment of metastatic melanoma  and currently under investigation in the adjuvant setting of high-risk stage III   melanoma. The blockade of CTLA-4 induces activation of T cells, with an expected   increase in the immunological reaction directed to cancer. We report a case of  ipilimumab-induced Guillain-Barre syndrome revealed by an occlusive enteric  neuropathy. Two weeks after the second dose of ipilimumab, our patient started to  complain of abdominal meteorism and nausea. Within a few days, an occlusive  syndrome developed. Wall biopsies during colonoscopy revealed a slight edema of  the mucosa and a high number of lymphocytic follicles, leading to the diagnosis  of ipilimumab-induced immune colitis. A respiratory failure occurred and a  neurological deficiency developed rapidly. The diagnosis of polyradiculoneuritis   was retained. Despite IV steroids, tacrolimus than plasmatic exchanges, the  patient died within a few days because of multivisceral failure.  Polyradiculoneuritis is a rare but very severe immune-mediated complication of  ipilimumab. Occlusive enteric neuropathy may mimic the digestive symptoms of  colitis, which is so frequent under ipilimumab.
CANIT0000162	23242086	Case report	Coexistent metastatic spindle cell-type melanoma of the kidney and renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Despite aggressive treatment with ipilimumab, the patient's disease progressed quickly.	N/A	N/A	N/A	N/A	N/A	N/A	 2012 Dec 14	 Coexistent metastatic melanoma of the kidney with unknown primary and renal cell   carcinoma.	 BMJ Case Rep	 In this report, we present an African-American female patient who presented with   haematuria to her primary care physician. The symptoms persisted and coexistent  metastatic spindle cell-type melanoma of the kidney and renal cell carcinoma were  discovered on further evaluation. No primary site for melanoma was identified.  Despite aggressive treatment with ipilimumab, the patient's disease progressed  quickly. The patient opted for palliative care and was referred to a hospice.  Coexistent melanoma and renal cell carcinoma is exceedingly rare. Melanoma itself  is rare in the African-American population. However, when it does present, it  usually is at an advanced stage, as was the case in our patient. Since no primary  tumour site for melanoma was found and the diagnosis was made after the tumour  had metastasised, we think this case highlights the importance of cutaneous  cancer surveillance in the non-Caucasian population. Earlier identification of  melanoma in this population will help to improve outcomes.
CANIT0000163	23270484	Clinical research	Recurrent high-grade glioma	Glioma	EFO:0005543	Brain	DENDRITIC CELL (N/A); 	DENDRITIC CELL; 	Type-1 polarized dendritic cell-based vaccination	N/A	Tumor vaccine	Dendritic cell vaccine (NCIT:C28310); 	9	N/A	A phase I clinical trial 	These results indicate peptide cocktail-treated activated  A-type-1 DC-based immunotherapy to be a potential therapeutic tool against  recurrent high-grade glioma with mainly HLA-A*2402	All 76 DC injections were well tolerated except for transient liver dysfunction with grade II.	N/A	N/A	HLA (P04439); 	HLA-A*2402	Mutational status	 2012 Dec 27	 alpha-type-1 polarized dendritic cell-based vaccination in recurrent high-grade  glioma: a phase I clinical trial.	 BMC Cancer	 BACKGROUND: High-grade gliomas including glioblastoma multiforme (GBM) are among   the most malignant and aggressive of tumors, and have a very poor prognosis  despite a temozolomide-based intensive treatment. Therefore, a novel therapeutic   approach to controlling recurrence is needed. In the present study, we  investigated the effect of activated dendritic cell (DC) (alpha-type-1 polarized   DC)-based immunotherapy on high-grade glioma patients with the HLA-A2 or A24  genotype. METHODS: Nine patients with recurrent high-grade gliomas including 7  with GBMs who fulfilled eligibility criteria were enrolled into a phase I study  of monocyte-derived DC-based immunotherapy. HLA-genotyping revealed 1 case of  HLA-A*0201 and 8 cases of A*2402. Enriched monocytes obtained using OptiPrep(TM)   from leukapheresis products on day1, were incubated with GM-CSF and IL-4 in a  closed serum-free system, and activated on day6 with TNF-alpha, IL-1beta,  IFN-alpha, IFN-gamma, and poly I/C. After pulsing with a cocktail of 5 synthetic   peptides (WT-1, HER2, MAGE-A3, and MAGE-A1 or gp100) restricted to HLA-A2 or A24   and KLH, cells were cryopreserved until used. Thawed DCs were injected  intradermally in the posterior neck at a dose per cohort of 1.0, 2.0 and 5.0x  10(7)/body. RESULTS: The frequency of CD14(+) monocytes increased to 44.6% from  11.9% after gradient centrifugation. After a 7-day-incubation with cytokines, the  mean percentage of DCs rated as lin(-)HLA-DR(+) in patients was 56.2 +/- 19.1%.  Most DCs expressed high levels of maturation markers, co-stimulatory molecules  and type-1 phenotype (CD11c+HLA-DR+) with a DC1/2 ratio of 35.6. The amount of  IL-12 produced from activated DCs was 1025 +/- 443 pg/ml per 10(5) cells. All 76   DC injections were well tolerated except for transient liver dysfunction with  grade II. Six patients showed positive immunological responses to peptides in an   ELISPOT assay, and positive skin tests to peptide-pulsed DC and KLH were  recognized in 4 cases. The clinical response to DC injections was as follows :1  SD and 8 PD. Interestingly, the SD patient, given 24 DC injections, showed a  long-term recurrence-free and immunological positive response period.  CONCLUSIONS: These results indicate peptide cocktail-treated activated  alpha-type-1 DC-based immunotherapy to be a potential therapeutic tool against  recurrent high-grade glioma with mainly HLA-A*2402. TRIAL REGISTRATION: Current  non-randomized investigational trial UMIN-CTR UMIN ID: 000000914.
CANIT0000164	23295794	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	Chemotherapy	Immune checkpoint therapy	Chemotherapy (NCIT:C15632); tremelimumab (DB11771); 	328	327	A phase III open-label randomized comparative study	This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of  patients with metastatic melanoma.	Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor.	N/A	N/A	N/A	N/A	N/A	 2013 Feb 10	 Phase III randomized clinical trial comparing tremelimumab with standard-of-care   chemotherapy in patients with advanced melanoma.	 J Clin Oncol	 PURPOSE: In phase I/II trials, the cytotoxic T lymphocyte-associated  antigen-4-blocking monoclonal antibody tremelimumab induced durable responses in   a subset of patients with advanced melanoma. This phase III study evaluated  overall survival (OS) and other safety and efficacy end points in patients with  advanced melanoma treated with tremelimumab or standard-of-care chemotherapy.  PATIENTS AND METHODS: Patients with treatment-naive, unresectable stage IIIc or  IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15  mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy   (temozolomide or dacarbazine). RESULTS: In all, 655 patients were enrolled and  randomly assigned. The test statistic crossed the prespecified futility boundary   at second interim analysis after 340 deaths, but survival follow-up continued. At  final analysis with 534 events, median OS by intent to treat was 12.6 months (95%  CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for  chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were  similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the  chemotherapy arm. However, response duration (measured from date of random  assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P =   .0011). Diarrhea, pruritus, and rash were the most common treatment-related  adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven  deaths in the tremelimumab arm and one in the chemotherapy arm were considered  treatment related by either investigators or sponsor. CONCLUSION: This study  failed to demonstrate a statistically significant survival advantage of treatment  with tremelimumab over standard-of-care chemotherapy in first-line treatment of  patients with metastatic melanoma.
CANIT0000165	23348421	Clinical research	Nasopharyngeal carcinoma	Nasopharyngeal squamous cell carcinoma	EFO:1000058	Head and neck	EBNA1 (P03211); LMP2 (P13285); 	EBNA1; LMP2	MVA-EL vaccine	N/A	Tumor vaccine	MVA-EBNA1/LMP2 Vaccine (NCIT:C91076); 	18	N/A	A phase I clinical trial 	We concluded that MVA-EL is both safe and immunogenic, allowing the highest dose to be forwarded to phase II studies examining clinical benefit.	N/A	N/A	N/A	N/A	N/A	N/A	 2013 Mar 15	 Phase I trial of recombinant modified vaccinia ankara encoding Epstein-Barr viral  tumor antigens in nasopharyngeal carcinoma patients.	 Cancer Res	 Epstein-Barr virus (EBV) is associated with several malignancies including  nasopharyngeal carcinoma, a high incidence tumor in Chinese populations, in which  tumor cells express the two EBV antigens EB nuclear antigen 1 (EBNA1) and latent   membrane protein 2 (LMP2). Here, we report the phase I trial of a recombinant  vaccinia virus, MVA-EL, which encodes an EBNA1/LMP2 fusion protein designed to  boost T-cell immunity to these antigens. The vaccine was delivered to Hong Kong  patients with nasopharyngeal carcinoma to determine a safe and immunogenic dose.   The patients, all in remission more than 12 weeks after primary therapy, received  three intradermal MVA-EL vaccinations at three weekly intervals, using five  escalating dose levels between 5 x 10(7) and 5 x 10(8) plaque-forming unit (pfu).  Blood samples were taken during prescreening, immediately before vaccination, one  week afterward and at intervals up to one year later. Immunogenicity was tested  by IFNG ELIspot assays using complete EBNA1 and LMP2 15-mer peptide mixes  and known epitope peptides relevant to patient MHC type. Eighteen patients were  treated, three per dose level one to four and six at the highest dose, without  dose-limiting toxicity. T-cell responses to one or both vaccine antigens were  increased in 15 of 18 patients and, in many cases, were mapped to known CD4 and  CD8 epitopes in EBNA1 and/or LMP2. The range of these responses suggested a  direct relationship with vaccine dose, with all six patients at the highest dose   level giving strong EBNA1/LMP2 responses. We concluded that MVA-EL is both safe  and immunogenic, allowing the highest dose to be forwarded to phase II studies  examining clinical benefit.
CANIT0000166	23400564	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	676	N/A	A phase III clinical trial	Most ipilimumab-associated irAEs, including grade 3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12 weeks of onset. immune-related adverse events were well characterized in their evolution and could be managed using published algorithms.	Grade 2 through 5 irAEs generally developed during the induction phase of treatment (0-12 weeks). Most, including grade 3/4 irAEs, were reversible when managed with treatment guidelines using vigilant monitoring and corticosteroids. The median time to resolution (to grade 1 or 0 or to the grade at baseline) of irAEs that had an onset during the induction phase was approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4 irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved within 12 weeks.	N/A	N/A	N/A	N/A	N/A	 2013 May 1	 Patterns of onset and resolution of immune-related adverse events of special  interest with ipilimumab: detailed safety analysis from a phase 3 trial in  patients with advanced melanoma.	 Cancer	 BACKGROUND: Ipilimumab 3 mg/kg was the first agent to demonstrate improved  survival in previously treated patients with metastatic melanoma in a phase 3  trial (MDX010-20). Ipilimumab produced a characteristic spectrum of  immune-related adverse events (irAEs) of special interest, consistent with its  immune-based mechanism of action. METHODS: In MDX010-20, 676 previously treated  patients were randomized 3:1:1 to receive ipilimumab 3 mg/kg plus the  glycoprotein 100 melanoma antigen vaccine (gp100), ipilimumab 3 mg/kg + placebo,   or gp100 vaccine + placebo. For the current report, the authors conducted a  detailed analysis of the time to onset and resolution of irAEs associated with  ipilimumab therapy. RESULTS: Grade 2 through 5 irAEs generally developed during  the induction phase of treatment (0-12 weeks). Most, including grade 3/4 irAEs,  were reversible when managed with treatment guidelines using vigilant monitoring   and corticosteroids. The median time to resolution (to grade 1 or 0 or to the  grade at baseline) of irAEs that had an onset during the induction phase was  approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4  irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved  within 12 weeks. CONCLUSIONS: Most ipilimumab-associated irAEs, including grade  3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12   weeks of onset. IrAEs were well characterized in their evolution and could be  managed using published algorithms.CI  - Copyright (c) 2013 American Cancer Society.
CANIT0000167	23408334	Case report	Unresectable or metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6	N/A	Case	In summary, ipilimumab associated hepatitis may demonstrate variable imaging findings according to its clinical severity, and histologically may manifest either as a predominant injury to hepatocytes (acute hepatitis pattern) or as a predominant injury to bile ducts (biliary pattern).	Ipilimumab associated hepatitis	N/A	N/A	N/A	N/A	N/A	 2013 Aug	 Ipilimumab associated hepatitis: imaging and clinicopathologic findings.	 Invest New Drugs	 Ipilimumab is a novel immunomodulator demonstrating promising efficacy in  treatment of melanoma and other cancers. The clinical benefit from ipilimumab can  be hampered by the immure-related adverse events (irAEs) caused by dysregulation   of host immune system. Ipilimumab associated hepatitis is also an important irAE,  however, there have been limited descriptions of its clinicopathologic and  imaging characteristics. We aim to describe the clinicopathologic and imaging  characteristics of 6 patients who were diagnosed as ipilimumab associated  hepatitis during the ipilimumab treatment for melanoma. The clinical features of   these patients were as follows: (1) severe cases with systemic symptoms and  highly increased level of liver function tests (LFTs), and (2) mild asymptomatic   cases with mildly increased level of LFTs. In severe cases with ALT >1,000 IU/L,   imaging findings were characterized by mild hepatomegaly, periportal edema, and  periportal lymphadenopathy, while mild cases showed normal imaging findings. This  spectrum of imaging findings in our series was similar to that of common causes  of acute hepatitis. Among 3 cases with pathologic specimen, two cases showed  severe panlobular hepatitis with prominent perivenular infiltrate with  endothelialitis, suggestive of predominant injury to hepatocytes, while the other  case showed mild portal mononuclear infiltrate around proliferated bile ductules,  suggestive of predominant injury to bile ducts. In summary, ipilimumab associated  hepatitis may demonstrate variable imaging findings according to its clinical  severity, and histologically may manifest either as a predominant injury to  hepatocytes (acute hepatitis pattern) or as a predominant injury to bile ducts  (biliary pattern).
CANIT0000168	23439861	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	73	N/A	N/A	 Ipilimumab toxic effect is manageable in real life. Biological data such as  lymphocyte and eosinophil counts at the time of the second ipilimumab infusion  appear to be early markers associated with better OS. A lymphocyte count >1000/mm(3) at the start of the second course was correlated with an improved OS.	Immune-related adverse events were observed in 45 patients (62%), including 19 grade 3-4 events (26%). No drug-related death occurred.	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2013 Jun	 Experience in daily practice with ipilimumab for the treatment of patients with  metastatic melanoma: an early increase in lymphocyte and eosinophil counts is  associated with improved survival.	 Ann Oncol	 BACKGROUND: Ipilimumab is a recently approved immunotherapy that has demonstrated  an improvement in the overall survival (OS) of patients with metastatic melanoma.  We report a single-institution experience in patients treated in a  compassionate-use program. PATIENTS AND METHODS: In this prospective study,  patients were treated between June 2010 and September 2011. Inclusion criteria  were a diagnosis of unresectable stage III or IV melanoma, at least one previous   line of chemotherapy, and survival 12 weeks after the first perfusion. Four  courses of ipilimumab were administered at a dose of 3 mg/kg every 3 weeks.  RESULTS: Seventy-three patients were included. Median OS was 9.1 months (95% CI  6.4-11.3) from the start of ipilimumab. Immune-related adverse events were  observed in 45 patients (62%), including 19 grade 3-4 events (26%). No  drug-related death occurred. A lymphocyte count >1000/mm(3) at the start of the  second course and an increase in the eosinophil count >100/mm(3) between the  first and second infusions were correlated with an improved OS. CONCLUSION:  Ipilimumab toxic effect is manageable in real life. Biological data such as  lymphocyte and eosinophil counts at the time of the second ipilimumab infusion  appear to be early markers associated with better OS.
CANIT0000169	23439861	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	73	N/A	N/A	Ipilimumab toxic effect is manageable in real life. Biological data such as  lymphocyte and eosinophil counts at the time of the second ipilimumab infusion  appear to be early markers associated with better OS. An increase in the eosinophil count >100/mm(3) between the first and second infusions was correlated with an improved OS.	Immune-related adverse events were observed in 45 patients (62%), including 19 grade 3-4 events (26%). No drug-related death occurred.	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Eosinophil counts	Cell percentage/counts in blood	 2013 Jun	 Experience in daily practice with ipilimumab for the treatment of patients with  metastatic melanoma: an early increase in lymphocyte and eosinophil counts is  associated with improved survival.	 Ann Oncol	 BACKGROUND: Ipilimumab is a recently approved immunotherapy that has demonstrated  an improvement in the overall survival (OS) of patients with metastatic melanoma.  We report a single-institution experience in patients treated in a  compassionate-use program. PATIENTS AND METHODS: In this prospective study,  patients were treated between June 2010 and September 2011. Inclusion criteria  were a diagnosis of unresectable stage III or IV melanoma, at least one previous   line of chemotherapy, and survival 12 weeks after the first perfusion. Four  courses of ipilimumab were administered at a dose of 3 mg/kg every 3 weeks.  RESULTS: Seventy-three patients were included. Median OS was 9.1 months (95% CI  6.4-11.3) from the start of ipilimumab. Immune-related adverse events were  observed in 45 patients (62%), including 19 grade 3-4 events (26%). No  drug-related death occurred. A lymphocyte count >1000/mm(3) at the start of the  second course and an increase in the eosinophil count >100/mm(3) between the  first and second infusions were correlated with an improved OS. CONCLUSION:  Ipilimumab toxic effect is manageable in real life. Biological data such as  lymphocyte and eosinophil counts at the time of the second ipilimumab infusion  appear to be early markers associated with better OS.
CANIT0000170	23444228	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus gp100 vaccine	Ipilimumab	Immune checkpoint therapy plus Tumor vaccine 	Gp100 vaccine (NCIT:C29068); ipilimumab (DB06186); 	23	8	A phase III clinical trial	Ipilimumab provided durable objective responses and/or stable disease in qualifying patients who received retreatment upon disease progression with a similar toxicity profile to that seen during their original treatment regimen.	No new types of toxicities occurred during retreatment and most events were mild-to-moderate.	N/A	N/A	N/A	N/A	N/A	 2013 Apr 15	 Efficacy and safety of retreatment with ipilimumab in patients with pretreated  advanced melanoma who progressed after initially achieving disease control.	 Clin Cancer Res	 PURPOSE: Ipilimumab is a fully human monoclonal antibody against cytotoxic  T-lymphocyte-associated antigen-4 (CTLA-4) that has been shown to improve  survival in patients with pretreated, advanced melanoma in a phase III trial.  Some patients in this study who initially responded to ipilimumab treatment but  later progressed were eligible for retreatment with their original randomized  regimen. Here, outcomes for these patients concerning baseline characteristics,  best overall response, and disease control rate are assessed and considered with   respect to the overall study population. EXPERIMENTAL DESIGN: In the phase III  study, 676 pretreated patients were randomly allocated to treatment with  ipilimumab 3 mg/kg plus gp100 vaccine, ipilimumab 3 mg/kg plus placebo, or gp100   vaccine alone. Of these patients, 32 had a partial or complete objective response  or stable disease after treatment and met the eligibility criteria for  retreatment, although a total of 40 patients were retreated. RESULTS: Best  overall response rates (complete responses plus partial responses) for 31  retreatment-eligible patients in the ipilimumab plus gp100 and ipilimumab plus  placebo groups were 3 of 23 (13.0%) and 3 of 8 (37.5%), respectively, and disease  control rates were 65.2% and 75.0%. No new types of toxicities occurred during  retreatment and most events were mild-to-moderate. CONCLUSION: Ipilimumab  provided durable objective responses and/or stable disease in qualifying patients  who received retreatment upon disease progression with a similar toxicity profile  to that seen during their original treatment regimen.
CANIT0000171	23458760	Case report	Stage IVM1C melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Ipilimumab-induced acute severe colitis treated by infliximab	N/A	N/A	N/A	N/A	N/A	N/A	 2013 Jun	 Ipilimumab-induced acute severe colitis treated by infliximab.	 Melanoma Res	 Ipilimumab (anti-CTLA-4 antibody) is a new tool for the treatment of metastatic  melanoma patients that has led to an improvement in survival rates worldwide. New  types of toxicities have been described with ipilimumab called 'immune-related  adverse events' or irAEs. Here, we report an acute and steroid resistant case of   ipilimumab-induced colitis treated with infliximab in a melanoma stage IV AJCC  patient. The patient presented with acute grade 3 diarrhea after the second  perfusion of ipilimumab. After the administration of intravenous steroids, the  patient continued to have grade 2 diarrhea with erythematous mucous with several   ulceration sites on rectosigmoidoscopy. Infliximab perfusion (5 mg/kg) was  performed and resulted in resolution of symptoms within 2 days with complete  healing was observed by rectal sigmoidoscopy on day 7. After failure of two  further lines of chemotherapy, the patient died 10 months after the diagnosis of   stage IVM1C melanoma. Treatment algorithms exist for the management of these  digestive adverse events; however, some points remain unclear. No predictive  marker for the occurrence of this digestive toxicity has been validated to date.   Modes of administration of steroids and dosage are not clearly defined, except in  cases of acute abdomen; surgery is difficult to propose for patients with a poor   prognosis. Infliximab is another option for the treatment of steroid-resistant  ipilimumab-induced colitis but its use in metastatic melanoma raises questions of  its possible impact on the evolution of cancer. We reviewed at least 19 cases  published of infliximab administration for ipilimumab-mediated colitis.  Unfortunately, tolerance and cancer evolution have scarcely been reported. Thus,   because more patients are being treated with CTLA-4 blockade, management of  ipilimumab-induced colitis requires further studies.
CANIT0000172	23466307	Clinical research	Hepatocellular carcinoma and chronic hepatitis C	Hepatocellular carcinoma	EFO:0000182	Liver	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	20	N/A	N/A	Tremelimumab safety profile and antitumor and antiviral activity support further investigation, in patients with advanced HCC developed on HCV-induced liver cirrhosis.	A good safety profile was recorded and no patient needed steroids because of severe immune-mediated adverse events. Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles.	N/A	N/A	N/A	N/A	N/A	 2013 Jul	 A clinical trial of CTLA-4 blockade with tremelimumab in patients with  hepatocellular carcinoma and chronic hepatitis C.	 J Hepatol	 BACKGROUND & AIMS: Tremelimumab is a monoclonal antibody that blocks cytotoxic  T-lymphocyte-associated antigen 4 (CTLA-4), an inhibitory co-receptor that  interferes with T cell activation and proliferation. The purpose of this pilot  clinical trial was to test the antitumor and antiviral effect of tremelimumab in   patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV)   infection; and to study the safety of its administration to cirrhotic patients.  METHODS: Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered  until tumor progression or severe toxicity. Twenty patients were assessable for  toxicity and viral response and 17 were assessable for tumor response. Most  patients were in the advanced stage and 43% had an altered liver function  (Child-Pugh class B). RESULTS: A good safety profile was recorded and no patient   needed steroids because of severe immune-mediated adverse events. Some patients  had a transient albeit intense elevation of transaminases after the first dose,  but not following subsequent cycles. Partial response rate was 17.6% and disease   control rate was 76.4%. Time to progression was 6.48 months (95% CI 3.95-9.14). A  significant drop in viral load was observed while new emerging variants of the  hypervariable region 1 of HCV replaced the predominant variants present before  therapy, particularly in those patients with a more prominent drop in viral load.  This antiviral effect was associated with an enhanced specific anti-HCV immune  response. CONCLUSIONS: Tremelimumab safety profile and antitumor and antiviral  activity, in patients with advanced HCC developed on HCV-induced liver cirrhosis,  support further investigation.CI  - Copyright (c) 2013 European Association for the Study of the Liver. Published by   Elsevier B.V. All rights reserved.
CANIT0000173	23487828	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Case	N/A	We present three patients with neurological irAEs from ipilimumab treatment: hypophysitis, meningitis and Guillain-Barr syndrome. Once an irAE occurs, ipilimumab should be stopped and corticosteroids started. Usually, ipilimumab-induced irAE symptoms improve within days to weeks, but can be life-threatening if unrecognised.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2013 Aug	 Neurological immune-related adverse events of ipilimumab.	 Pract Neurol	 Ipilimumab enhances the T lymphocyte mediated immune response to both tumour  cells and healthy tissue, improving survival in patients with metastatic melanoma  but also leads to more immune-related adverse events (irAEs) than previously used  treatments, such as dacarbazine. We present three patients with neurological  irAEs from ipilimumab treatment: hypophysitis, meningitis and Guillain-Barre  syndrome. Once an irAE occurs, ipilimumab should be stopped and corticosteroids  started. Usually, ipilimumab-induced irAE symptoms improve within days to weeks,   but can be life-threatening if unrecognised.
CANIT0000174	23502769	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	50	N/A	N/A	Baseline serum absolute lymphocyte count (ALC) measured on week 6 significantly correlated with OS.	Most immune-related adverse events were mild and reversible.	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2013 Apr	 Single-center experience with ipilimumab in an expanded access program for  patients with pretreated advanced melanoma.	 J Immunother	 Ipilimumab, a CTLA-4-blocking monoclonal antibody, improved the overall survival   (OS) of advanced melanoma patients treated in prospective clinical trials. We  here report a study on the outcome of patients with pretreated advanced melanoma   offered ipilimumab (at its licensed dose of 3 mg/kg, every 3 wk for a total of 4   doses) in an expanded access program at a single-center university hospital. Of  the 50 patients initiating ipilimumab, 31 patients completed induction therapy  and 9 patients were offered reinduction therapy. Most immune-related adverse  events were mild and reversible. The best objective response rate by  mWHO-criteria included 1 complete response and 4 partial responses (best  objective response rate of 10%). Two additional patients obtained a partial  response by immune-related response criteria. Median OS was 7 months, with a 1-  and 2-year survival rate of 45.2% and 28.8%, respectively. Long-term disease  control with ipilimumab was observed in 7 patients of which 4 received  reinduction. Baseline serum C-reactive protein (CRP) and the absolute lymphocyte   count (ALC) measured on week 6 significantly correlated with OS. In conclusion,  in this single-center experience with ipilimumab for advanced pretreated melanoma  patients, clinical outcome was comparable with the results of published  prospective studies. Reinduction therapy was of importance for maintaining  long-term disease control in the majority of responding patients. Baseline CRP  and ALC at week 6 deserve further prospective evaluation as prognostic and/or  predictive (surrogate) markers.
CANIT0000175	23502769	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	50	N/A	N/A	Baseline serum C-reactive protein (CRP) measured on week 6 significantly correlated with OS.	Most immune-related adverse events were mild and reversible.	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2013 Apr	 Single-center experience with ipilimumab in an expanded access program for  patients with pretreated advanced melanoma.	 J Immunother	 Ipilimumab, a CTLA-4-blocking monoclonal antibody, improved the overall survival   (OS) of advanced melanoma patients treated in prospective clinical trials. We  here report a study on the outcome of patients with pretreated advanced melanoma   offered ipilimumab (at its licensed dose of 3 mg/kg, every 3 wk for a total of 4   doses) in an expanded access program at a single-center university hospital. Of  the 50 patients initiating ipilimumab, 31 patients completed induction therapy  and 9 patients were offered reinduction therapy. Most immune-related adverse  events were mild and reversible. The best objective response rate by  mWHO-criteria included 1 complete response and 4 partial responses (best  objective response rate of 10%). Two additional patients obtained a partial  response by immune-related response criteria. Median OS was 7 months, with a 1-  and 2-year survival rate of 45.2% and 28.8%, respectively. Long-term disease  control with ipilimumab was observed in 7 patients of which 4 received  reinduction. Baseline serum C-reactive protein (CRP) and the absolute lymphocyte   count (ALC) measured on week 6 significantly correlated with OS. In conclusion,  in this single-center experience with ipilimumab for advanced pretreated melanoma  patients, clinical outcome was comparable with the results of published  prospective studies. Reinduction therapy was of importance for maintaining  long-term disease control in the majority of responding patients. Baseline CRP  and ALC at week 6 deserve further prospective evaluation as prognostic and/or  predictive (surrogate) markers.
CANIT0000176	23521917	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	162	N/A	Two phase II clinical trials	Gene expression profiling of peripheral blood, sampled before or early in the course of treatment with ipilimumab, resulted in the identification of a set of potential biomarkers that were associated with occurrence of GI immune-related adverse events. However, because of the low  sensitivity of these biomarkers, they cannot be used alone to predict which  patients will develop GI immune-related adverse events.	In particular, on-treatment expression increases of CD177 and CEACAM1, two neutrophil-activation markers, were closely associated with gastrointestinal immune-related adverse events(GI irAEs), suggesting a possible role of neutrophils in ipilimumab-associated GI irAEs.	N/A	N/A	CEACAM1 (P13688); CD177 (Q8N6Q3); 	On-treatment expression increases of CD177	Gene expression signature on/in tumor cell	 2013 Mar 22	 Gene expression profiling of whole blood in ipilimumab-treated patients for  identification of potential biomarkers of immune-related gastrointestinal adverse  events.	 J Transl Med	 BACKGROUND: Treatment with ipilimumab, a fully human anti-CTLA-4 antibody  approved for the treatment of advanced melanoma, is associated with some  immune-related adverse events (irAEs) such as colitis (gastrointestinal irAE, or   GI irAE) and skin rash, which are managed by treatment guidelines. Nevertheless,   predictive biomarkers that can help identify patients more likely to develop  these irAEs could enhance the management of these toxicities. METHODS: To  identify candidate predictive biomarkers associated with GI irAEs, gene  expression profiling was performed on whole blood samples from 162 advanced  melanoma patients at baseline, 3 and 11 weeks after the start of ipilimumab  treatment in two phase II clinical trials (CA184004 and CA184007). Overall, 49  patients developed Grade 2 or higher (grade 2+) GI irAEs during the course of  treatment. A repeated measures analysis of variance (ANOVA) was used to evaluate   the differences in mean expression levels between the GI irAE and No-GI irAE  groups of patients at the three time points. RESULTS: In baseline samples, 27  probe sets showed differential mean expression (>/= 1.5 fold, P </= 0.05) between  the GI irAE and No-GI irAE groups. Most of these probe sets belonged to three  functional categories: immune system, cell cycle, and intracellular trafficking.   Changes in gene expression over time were also characterized. In the GI irAE  group, 58 and 247 probe sets had a >/= 1.5 fold change in expression from  baseline to 3 and 11 weeks after first ipilimumab dose, respectively. In  particular, on-treatment expression increases of CD177 and CEACAM1, two  neutrophil-activation markers, were closely associated with GI irAEs, suggesting   a possible role of neutrophils in ipilimumab-associated GI irAEs. In addition,  the expression of several immunoglobulin genes increased over time, with greater   increases in patients with grade 2+ GI irAEs. CONCLUSIONS: Gene expression  profiling of peripheral blood, sampled before or early in the course of treatment  with ipilimumab, resulted in the identification of a set of potential biomarkers   that were associated with occurrence of GI irAEs. However, because of the low  sensitivity of these biomarkers, they cannot be used alone to predict which  patients will develop GI irAEs. Further investigation of these biomarkers in a  larger patient cohort is warranted.
CANIT0000177	23521917	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	162	N/A	Two phase II clinical trials	Gene expression profiling of peripheral blood, sampled before or early in the course of treatment with ipilimumab, resulted in the identification of a set of potential biomarkers that were associated with occurrence of GI immune-related adverse events. However, because of the low  sensitivity of these biomarkers, they cannot be used alone to predict which  patients will develop GI immune-related adverse events.	In particular, on-treatment expression increases of CD177 and CEACAM1, two neutrophil-activation markers, were closely associated with gastrointestinal immune-related adverse events(GI irAEs), suggesting a possible role of neutrophils in ipilimumab-associated GI irAEs.	N/A	N/A	CEACAM1 (P13688); CD177 (Q8N6Q3); 	On-treatment expression increases of CEACAM1	Gene expression signature on/in tumor cell	 2013 Mar 22	 Gene expression profiling of whole blood in ipilimumab-treated patients for  identification of potential biomarkers of immune-related gastrointestinal adverse  events.	 J Transl Med	 BACKGROUND: Treatment with ipilimumab, a fully human anti-CTLA-4 antibody  approved for the treatment of advanced melanoma, is associated with some  immune-related adverse events (irAEs) such as colitis (gastrointestinal irAE, or   GI irAE) and skin rash, which are managed by treatment guidelines. Nevertheless,   predictive biomarkers that can help identify patients more likely to develop  these irAEs could enhance the management of these toxicities. METHODS: To  identify candidate predictive biomarkers associated with GI irAEs, gene  expression profiling was performed on whole blood samples from 162 advanced  melanoma patients at baseline, 3 and 11 weeks after the start of ipilimumab  treatment in two phase II clinical trials (CA184004 and CA184007). Overall, 49  patients developed Grade 2 or higher (grade 2+) GI irAEs during the course of  treatment. A repeated measures analysis of variance (ANOVA) was used to evaluate   the differences in mean expression levels between the GI irAE and No-GI irAE  groups of patients at the three time points. RESULTS: In baseline samples, 27  probe sets showed differential mean expression (>/= 1.5 fold, P </= 0.05) between  the GI irAE and No-GI irAE groups. Most of these probe sets belonged to three  functional categories: immune system, cell cycle, and intracellular trafficking.   Changes in gene expression over time were also characterized. In the GI irAE  group, 58 and 247 probe sets had a >/= 1.5 fold change in expression from  baseline to 3 and 11 weeks after first ipilimumab dose, respectively. In  particular, on-treatment expression increases of CD177 and CEACAM1, two  neutrophil-activation markers, were closely associated with GI irAEs, suggesting   a possible role of neutrophils in ipilimumab-associated GI irAEs. In addition,  the expression of several immunoglobulin genes increased over time, with greater   increases in patients with grade 2+ GI irAEs. CONCLUSIONS: Gene expression  profiling of peripheral blood, sampled before or early in the course of treatment  with ipilimumab, resulted in the identification of a set of potential biomarkers   that were associated with occurrence of GI irAEs. However, because of the low  sensitivity of these biomarkers, they cannot be used alone to predict which  patients will develop GI irAEs. Further investigation of these biomarkers in a  larger patient cohort is warranted.
CANIT0000178	23535954	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus radiotherapy	Ipilimumab	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); radiotherapy (NCIT:C15313); ipilimumab (DB06186); 	34	16	An open-label, multicenter phase I/II study.	In mCRPC patients, ipilimumab 10 mg/kg  radiotherapy suggested clinical antitumor activity with disease control and manageable AEs.	N/A	N/A	N/A	N/A	N/A	N/A	 2013 Jul	 Ipilimumab alone or in combination with radiotherapy in metastatic  castration-resistant prostate cancer: results from an open-label, multicenter  phase I/II study.	 Ann Oncol	 BACKGROUND: This phase I/II study in patients with metastatic  castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy  and in combination with radiotherapy, based on the preclinical evidence of  synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy.  PATIENTS AND METHODS: In dose escalation, 33 patients (>/=6/cohort) received  ipilimumab every 3 weeks x 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg +  radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients  (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included  adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor  response. RESULTS: Common immune-related AEs (irAEs) among the 50 patients  receiving 10 mg/kg +/- radiotherapy were diarrhea (54%), colitis (22%), rash  (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis  (10%). One treatment-related death (5 mg/kg group) occurred. Among patients  receiving 10 mg/kg +/- radiotherapy, eight had PSA declines of >/=50% (duration:   3-13+ months), one had complete response (duration: 11.3+ months), and six had  stable disease (duration: 2.8-6.1 months). CONCLUSIONS: In mCRPC patients,  ipilimumab 10 mg/kg +/- radiotherapy suggested clinical antitumor activity with  disease control and manageable AEs. Two phase III trials in mCRPC patients  evaluating ipilimumab 10 mg/kg +/- radiotherapy are ongoing. ClinicalTrials.gov  identifier: NCT00323882.
CANIT0000179	23541015	Case report	Chemotherapy-naive, castration-resistant metastatic prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	With ipilimumab being used more commonly in the treatment of melanoma and prostate cancer, we believe that physicians should be aware of this potential adverse outcome when evaluating a patient who experiences persistent diarrhea during or after ipilimumab treatment.	Celiac disease	N/A	N/A	N/A	N/A	N/A	 2013 Apr	 Association between ipilimumab and celiac disease.	 Mayo Clin Proc	 A 62-year-old man with chemotherapy-naive, castration-resistant metastatic  prostate cancer presented with refractory diarrhea despite prolonged high-dose  corticosteroid treatment after receiving 3 doses of ipilimumab as part of a phase  3 clinical trial. The investigative work-up and response to a gluten-free diet  essentially confirm celiac disease. Although ipilimumab-induced enterocolitis is   a well-reported complication, there have been no reported cases of celiac disease  with ipilimumab therapy, to our knowledge. We suspect that ipilimumab may have  amplified the symptomatic presentation of previously unrecognized celiac disease   or perhaps even triggered the disease itself. With ipilimumab being used more  commonly in the treatment of melanoma and prostate cancer, we believe that  physicians should be aware of this potential adverse outcome when evaluating a  patient who experiences persistent diarrhea during or after ipilimumab treatment.CI  - Copyright (c) 2013 Mayo Foundation for Medical Education and Research. Published   by Elsevier Inc. All rights reserved.
CANIT0000180	23576166	Case report	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	An almost complete regression of distant metastases.	N/A	N/A	N/A	N/A	N/A	N/A	 2013 Apr	 [Metastatic malignant melanoma. Successfull treatment with ipilimumab].	 Hautarzt	 A 73-year-old man, in whom 26 years ago a malignant melanoma with cervical lymph   node metastases of the right retroauricular region was diagnosed, developed BRAF   V600E-negative distant metastases, which progressed during both monochemotherapy   and polychemotherapy. Therefore he was started on ipilimumab in a dose of 3 mg/kg  body weight four times in intervals of 3 weeks. Subsequently, there was an almost  complete regression of distant metastases. In several phase III trials a  significant survival benefit has been identified for patients treated with  ipilimumab. The human monoclonal antibody has been approved since July 2011 as a   second-line treatment in Germany and was incorporated in January 2013 into the  new guidelines for the treatment of malignant melanoma. The CTLA-4 antibody is  the first drug that can improve significantly survival in patients with  metastatic melanoma. In advanced (unresectable or metastatic) melanoma,  immunostimulatory treatment with ipilimumab represents a new therapeutic option.
CANIT0000181	23591982	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	27	N/A	N/A	Ipilimumab can induce long-term survival benefits in heavily pretreated patients with metastatic melanoma. An neutrophils/lymphocytes (N/L) ratio below the median at W7 and W10 was also associated with better survival compared with an N/L ratio above the median.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2013 Jun	 Long-term survival and immunological parameters in metastatic melanoma patients  who responded to ipilimumab 10 mg/kg within an expanded access programme.	 Cancer Immunol Immunother	 BACKGROUND: Ipilimumab can result in durable clinical responses among patients  with advanced melanoma. However, no predictive marker of clinical activity has  yet been identified. We provide preliminary data describing the correlation  between immunological parameters and response/survival among patients with  advanced melanoma who received ipilimumab 10 mg/kg in an expanded access  programme. METHODS: Patients received ipilimumab 10 mg/kg every 3 weeks (Q3W) for  four doses (induction) and Q12W from week 24 (W24) as maintenance therapy. Tumor   assessments were conducted Q12W. Expression of inducible T cell costimulator  (ICOS) on CD4(+) and CD8(+) T cells was assessed at baseline, W7, W12 and W24,  and the ratio between absolute neutrophils (N) and lymphocytes (L) determined at   baseline, W4, W7 and W10. RESULTS: Median overall survival among 27 patients was   9.6 months (95 % CI 3.2-16.1), with 3- and 4-year survival rates of 20.4 %. Five   patients survived >4 years. Patients with an increase in the number of  circulating ICOS(+) T cells at W7 were more likely to experience disease control   and have improved survival. An N/L ratio below the median at W7 and W10 was also   associated with better survival compared with an N/L ratio above the median.  CONCLUSIONS: Ipilimumab can induce long-term survival benefits in heavily  pretreated patients with metastatic melanoma. Changes in the number of  circulating ICOS(+) T cells or N/L ratio during ipilimumab treatment may  represent early markers of response. However, given the limited sample size,  further investigation is required.
CANIT0000182	23591982	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	27	N/A	N/A	Ipilimumab can induce long-term survival benefits in heavily pretreated patients with metastatic melanoma. Patients with an increase in the number of circulating inducible T cell costimulator (ICOS)(+) T cells at W7 were more likely to experience disease control and have improved survival.	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	Number of circulating inducible T-cell costimulator(+) T-cell at W7	Gene expression signature on/in immune cell	 2013 Jun	 Long-term survival and immunological parameters in metastatic melanoma patients  who responded to ipilimumab 10 mg/kg within an expanded access programme.	 Cancer Immunol Immunother	 BACKGROUND: Ipilimumab can result in durable clinical responses among patients  with advanced melanoma. However, no predictive marker of clinical activity has  yet been identified. We provide preliminary data describing the correlation  between immunological parameters and response/survival among patients with  advanced melanoma who received ipilimumab 10 mg/kg in an expanded access  programme. METHODS: Patients received ipilimumab 10 mg/kg every 3 weeks (Q3W) for  four doses (induction) and Q12W from week 24 (W24) as maintenance therapy. Tumor   assessments were conducted Q12W. Expression of inducible T cell costimulator  (ICOS) on CD4(+) and CD8(+) T cells was assessed at baseline, W7, W12 and W24,  and the ratio between absolute neutrophils (N) and lymphocytes (L) determined at   baseline, W4, W7 and W10. RESULTS: Median overall survival among 27 patients was   9.6 months (95 % CI 3.2-16.1), with 3- and 4-year survival rates of 20.4 %. Five   patients survived >4 years. Patients with an increase in the number of  circulating ICOS(+) T cells at W7 were more likely to experience disease control   and have improved survival. An N/L ratio below the median at W7 and W10 was also   associated with better survival compared with an N/L ratio above the median.  CONCLUSIONS: Ipilimumab can induce long-term survival benefits in heavily  pretreated patients with metastatic melanoma. Changes in the number of  circulating ICOS(+) T cells or N/L ratio during ipilimumab treatment may  represent early markers of response. However, given the limited sample size,  further investigation is required.
CANIT0000183	23632354	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Ipilimumab-induced perforating colitis. Although steroid therapy is the standard treatment for ipilimumab-induced colitis, surgery may be necessary. In the setting of progressive or worsening diarrhea after steroid therapy in patients with colitis, bowel perforation should be considered.	N/A	N/A	N/A	N/A	N/A	 2013 Oct	 Ipilimumab-induced perforating colitis.	 J Clin Gastroenterol	 Recently, a monoclonal antibody to cytotoxic T-lymphocyte-associated antigen 4,  ipilimumab, was approved for the treatment of metastatic melanoma. One of the  most common side effects associated with this therapy is diarrhea and colitis. We  report 3 cases of perforating colitis induced by ipilimumab requiring colectomy.   The histologic findings of mucosal biopsies have been previously described.  Herein, we describe novel associated histologic findings (pseudopolyp formation,   fissuring ulcers, dilated crypts, and lack of intraepithelial lymphocytosis and  epithelial apoptosis) of segmental resections in patients who required subtotal  colectomy after perforation due to the severity of their ipilimumab-induced  colitis. Although steroid therapy is the standard treatment for  ipilimumab-induced colitis, surgery may be necessary. In the setting of  progressive or worsening diarrhea after steroid therapy in patients with colitis,  bowel perforation should be considered.
CANIT0000184	23634660	Basic research	Melanoma cell lines	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines/ animal models	N/A	Basic research	Our studies demonstrate that Ipilimumab triggers effector lymphocytes to cytotoxicity and TNF- release. These findings suggest that Ipilimumab, besides blocking CTLA-4, can directly activate the elimination of CTLA-4+ melanomas.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2013 May 1	 The engagement of CTLA-4 on primary melanoma cell lines induces  antibody-dependent cellular cytotoxicity and TNF-alpha production.	 J Transl Med	 BACKGROUND: CTLA-4 (Cytotoxic T lymphocyte antigen-4) is traditionally known as a  negative regulator of T cell activation. The blocking of CTLA-4 using human  monoclonal antibodies, such as Ipilimumab, is currently used to relieve  CTLA-4-mediated inhibition of anti-tumor immune response in metastatic melanoma.   Herein, we have analyzed CTLA-4 expression and Ipilimumab reactivity on melanoma   cell lines and tumor tissues from cutaneous melanoma patients. Then, we  investigated whether Ipilimumab can trigger innate immunity in terms of antibody   dependent cellular cytotoxicity (ADCC) or Tumor Necrosis Factor (TNF)-alpha  release. Finally, a xenograft murine model was set up to determine in vivo the  effects of Ipilimumab and NK cells on melanoma. METHODS: CTLA-4 expression and  Ipilimumab reactivity were analyzed on 17 melanoma cell lines (14 primary and 3  long-term cell lines) by cytofluorimetry and on 33 melanoma tissues by  immunohistochemistry. CTLA-4 transcripts were analyzed by quantitative RT-PCR.  Soluble CTLA-4 and TNF-alpha were tested by ELISA. Peripheral blood mononuclear  cells (PBMC), NK and gammadeltaT cells were tested in ADCC assay with Ipilimumab   and melanoma cell lines. TNF-alpha release was analyzed in NK-melanoma cell  co-cultures in the presence of ipilimumab. In vivo experiments of  xenotransplantation were carried out in NOD/SCID mice. Results were analyzed  using unpaired Student's t-test. RESULTS: All melanoma cell lines expressed mRNA   and cytoplasmic CTLA-4 but surface reactivity with Ipilimumab was quite  heterogeneous. Accordingly, about 2/3 of melanoma specimens expressed CTLA-4 at  different level of intensity.Ipilimumab triggered, via FcgammaReceptorIIIA  (CD16), ex vivo NK cells as well as PBMC, IL-2 activated NK and gammadeltaT cells  to ADCC of CTLA-4+ melanoma cells. No ADCC was detected upon interaction with  CTLA-4- FO-1 melanoma cell line. TNF-alpha was released upon interaction of NK  cells with CTLA-4+ melanoma cell lines. Remarkably, Ipilimumab neither affected  proliferation and viability nor triggered ADCC of CTLA-4+ T lymphocytes. In a  chimeric murine xenograft model, the co-engraftment of Ipilimumab-treated  melanoma cells with human allogeneic NK cells delayed and significantly reduced  tumor growth, as compared to mice receiving control xenografts. CONCLUSIONS: Our   studies demonstrate that Ipilimumab triggers effector lymphocytes to cytotoxicity  and TNF-alpha release. These findings suggest that Ipilimumab, besides blocking  CTLA-4, can directly activate the elimination of CTLA-4+ melanomas.
CANIT0000185	23640225	Case report	A high-risk melanoma of the right thigh	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Ipilimumab can induce inflammatory immunomediated reactions that should be taken into account to avoid misinterpretation.	Biopsy at the abdominal wall revealed a chronic granulomatous inflammation. After oral steroid treatment, all the areas of abnormal tracer uptake disappeared.	N/A	N/A	N/A	N/A	N/A	 2014 May	 Ipilimumab-induced immunomediated adverse events: possible pitfalls in (18)F-FDG   PET/CT interpretation.	 Clin Nucl Med	 A 42-year-old woman underwent resection of a high-risk melanoma of the right  thigh. Adjuvant treatment with ipilimumab was then started within a phase III  randomised, double-blind clinical trial. F-FDG PET/CT scan showed intense uptake   in mediastinal hilar lymph nodes, bilaterally, and in rectus abdominis muscle.  Biopsy at the abdominal wall revealed a chronic granulomatous inflammation. After  oral steroid treatment, all the areas of abnormal tracer uptake disappeared.  Ipilimumab can induce inflammatory immunomediated reactions that should be taken   into account to avoid misinterpretation.
CANIT0000186	23652314	Clinical research	Melanoma or advanced solid tumours	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); TLR9 (Q9NR96); 	CTLA-4; TLR9	Tremelimumab plus PF-3512676	N/A	Immune checkpoint therapy plus Tumor vaccine 	PF-3512676 (NCIT:C28580); tremelimumab (DB11771); 	21	N/A	A phase I, open-label, non-randomised, dose-escalation study	Weekly PF-3512676 (0.15 mg kg(-1)) plus tremelimumab (10 mg kg(-1) every 12 weeks) was tolerable.	Twenty-one patients with stage IV melanoma (n=17) or advanced solid tumours (n=4) were enrolled. Injection-site reactions (n=21; 100%), influenza-like illness (n=18; 86%), and diarrhoea (n=13; 62%) were the most common treatment-related adverse events (TAEs). Grade 3 TAEs were reported (n=7; 33%). Dose-limiting toxicities (prespecified 6-week observation) occurred in one of the six patients in the 10 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 hypothalamopituitary disorder) and two of the six patients in the 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 diarrhoea). Consequently, 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 exceeded the MTD.	N/A	N/A	N/A	N/A	N/A	 2013 May 28	 Phase I study of tremelimumab (CP-675 206) plus PF-3512676 (CPG 7909) in patients  with melanoma or advanced solid tumours.	 Br J Cancer	 BACKGROUND: Tremelimumab, a fully human cytotoxic T-lymphocyte antigen 4  monoclonal antibody, and PF-3512676, a Toll-like receptor-9 agonist, are targeted  immune modulators that elicit durable single-agent antitumour activity in  advanced cancer. METHODS: To determine the maximum tolerated dose (MTD) of these   agents combined during this phase I study, patients received intravenous  tremelimumab (6.0, 10.0, or 15.0 mg kg(-1)) every 12 weeks plus subcutaneous  PF-3512676 (0.05, 0.10, or 0.15 mg kg(-1)) weekly. Primary end points were safety  and tolerability; secondary end points included pharmacokinetics and antitumour  activity. RESULTS: Twenty-one patients with stage IV melanoma (n=17) or advanced   solid tumours (n=4) were enrolled. Injection-site reactions (n=21; 100%),  influenza-like illness (n=18; 86%), and diarrhoea (n=13; 62%) were the most  common treatment-related adverse events (TAEs). Grade >/=3 TAEs were reported  (n=7; 33%). Dose-limiting toxicities (prespecified 6-week observation) occurred  in one of the six patients in the 10 mg kg(-1) tremelimumab plus 0.05 mg kg(-1)  PF-3512676 cohort (grade 3 hypothalamopituitary disorder) and two of the six  patients in the 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort  (grade 3 diarrhoea). Consequently, 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1)   PF-3512676 exceeded the MTD. Two melanoma patients achieved durable (>/=170 days)  partial response. No human antihuman antibody responses to tremelimumab were  observed. CONCLUSION: Weekly PF-3512676 (</=0.15 mg kg(-1)) plus tremelimumab  (</=10 mg kg(-1) every 12 weeks) was tolerable.
CANIT0000187	23666915	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	487	N/A	A phase II clinical trial	Durable survival in a significant proportion of patients with metastatic melanoma who received ipilimumab therapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2013 Aug	 Four-year survival rates for patients with metastatic melanoma who received  ipilimumab in phase II clinical trials.	 Ann Oncol	 BACKGROUND: This analysis was carried out to evaluate the long-term survival of  patients with metastatic melanoma who received ipilimumab, a fully human  monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4, in clinical  trials. PATIENTS AND METHODS: Patients received ipilimumab in one of three  completed phase II clinical trials (CA184-008, CA184-022, and CA184-007).  Previously treated patients were enrolled in all studies, and treatment-naive  patients were also included in study CA184-007. Patients received ipilimumab at a  dose of 10 mg/kg in studies CA184-008 and CA184-007, and at doses of 0.3, 3, or  10 mg/kg in study CA184-022. Ipilimumab was given every 3 weeks for four doses,  and eligible patients could receive ipilimumab maintenance therapy every 12  weeks. In study CA184-022, patients could cross over to be retreated with  ipilimumab at 10 mg/kg upon disease progression. Ongoing survival follow-up is  conducted in a companion study, CA184-025. RESULTS: Four-year survival rates [95%  confidence interval (95% CI)] for previously treated patients who received  ipilimumab at 0.3, 3, or 10 mg/kg were 13.8% [6.1-22.5], 18.2% [9.5-27.6], and  19.7% [13.4-26.5] to 28.4% [13.9-44.2], respectively. In treatment-naive patients  who received ipilimumab at 10 mg/kg, 4-year survival rates were 37.7% [18.6-57.4]  to 49.5% [23.8-75.4]. CONCLUSIONS: These results demonstrate durable survival in   a significant proportion of patients with metastatic melanoma who received  ipilimumab therapy.
CANIT0000188	23690483	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	Young tumor-infiltrating lymphocytes plus high-dose IL2	N/A	Cell immunotherapy plus Immune cytokine	IL2 (NCIT:C24498); 	80	N/A	N/A	Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed.	No additional toxicities to TIL therapy occurred following ipilimumab treatment.	N/A	N/A	N/A	N/A	N/A	 2013 Sep 1	 Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic  melanoma: intent-to-treat analysis and efficacy after failure to prior  immunotherapies.	 Clin Cancer Res	 PURPOSE: Adoptive cell transfer (ACT) using autologous tumor-infiltrating  lymphocytes (TIL) was reported to yield objective responses in about 50% of  metastatic patients with melanoma. Here, we present the intent-to-treat analysis   of TIL ACT and analyze parameters predictive to response as well as the impact of  other immunotherapies. EXPERIMENTAL DESIGN: Eighty patients with stage IV  melanoma were enrolled, of which 57 were treated with unselected/young TIL and  high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting  conditioning. RESULTS: TIL cultures were established from 72 of 80 enrolled  patients. Altogether 23 patients were withdrawn from the study mainly due to  clinical deterioration during TIL preparation. The overall response rate and  median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2  months for treated patients. Five patients achieved complete and 18 partial  remission. All complete responders are on unmaintained remission after a median  follow-up of 28 months and the 3-year survival of responding patients was 78%.  Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days  of TIL in culture, and the total number of infused CD8+ cells as independent  predictive markers for clinical outcome. Thirty-two patients received the  CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective  analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the   same overall response rate to ACT as other patients receiving TIL. No additional   toxicities to TIL therapy occurred following ipilimumab treatment. CONCLUSION:  Adoptive transfer of TIL can yield durable and complete responses in patients  with refractory melanoma, even when other immunotherapies have failed.CI  - (c)2013 AACR.
CANIT0000189	23724846	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Lambrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	135	N/A	N/A	In patients with  advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects.	Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade.	N/A	N/A	N/A	N/A	N/A	 2013 Jul 11	 Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.	 N Engl J Med	 BACKGROUND: The programmed death 1 (PD-1) receptor is a negative regulator of  T-cell effector mechanisms that limits immune responses against cancer. We tested  the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients  with advanced melanoma. METHODS: We administered lambrolizumab intravenously at a  dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram  every 3 weeks in patients with advanced melanoma, both those who had received  prior treatment with the immune checkpoint inhibitor ipilimumab and those who had  not. Tumor responses were assessed every 12 weeks. RESULTS: A total of 135  patients with advanced melanoma were treated. Common adverse events attributed to  treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events   were low grade. The confirmed response rate across all dose cohorts, evaluated by  central radiologic review according to the Response Evaluation Criteria in Solid   Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44),  with the highest confirmed response rate observed in the cohort that received 10   mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not   differ significantly between patients who had received prior ipilimumab treatment  and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37%  [95% CI, 26 to 49], respectively). Responses were durable in the majority of  patients (median follow-up, 11 months among patients who had a response); 81% of   the patients who had a response (42 of 52) were still receiving treatment at the   time of analysis in March 2013. The overall median progression-free survival  among the 135 patients was longer than 7 months. CONCLUSIONS: In patients with  advanced melanoma, including those who had had disease progression while they had  been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate  of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by  Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.).
CANIT0000190	23741070	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	498	N/A	A phase II/III clinical trial 	Higher doses of ipilimumab produce greater Cminss that may be associated with increased tumor responses, longer survival, and higher rates of immune-related adverse events.	Model-based estimates indicate that the probabilities of a grade 3 or more irAE at the median Cminss for the 0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively.	N/A	N/A	Treatment doses (NCIT:C25488); 	Doses of ipilimumab	Exposure factors/status	 2013 Jul 15	 Exposure-response relationships of the efficacy and safety of ipilimumab in  patients with advanced melanoma.	 Clin Cancer Res	 PURPOSE: This retrospective analysis was conducted to characterize ipilimumab  exposure-response relationships for measures of efficacy and safety in patients  with advanced melanoma. EXPERIMENTAL DESIGN: Data were pooled from 498 patients  who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed  phase II clinical trials. The relationships between steady-state ipilimumab  trough concentration (Cminss), complete or partial tumor response (CR or PR), and  safety [immune-related adverse events (irAEs)] were described by logistic  regression models. The relationship between exposure and overall survival was  characterized using a Cox proportional-hazards model. RESULTS: The steady-state  trough concentration of ipilimumab was found to be a significant predictor of a  CR or PR (P < 0.001). Model-based estimates indicate that the probabilities of a   CR or PR at median Cminss for the 0.3, 3, and 10 mg/kg groups were 0.6%, 4.9%,  and 11.6%, respectively. Overall survival at the median Cminss for ipilimumab at   0.3 mg/kg was estimated to be 0.85- and 0.58-fold lower relative to that at the  median Cminss for 3 and 10 mg/kg, respectively. Model-based estimates indicate  that the probabilities of a grade 3 or more irAE at the median Cminss for the  0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively. CONCLUSIONS:  Higher doses of ipilimumab produce greater Cminss that may be associated with  increased tumor responses, longer survival, and higher rates of irAEs. The  efficacy and safety of ipilimumab at 3 versus 10 mg/kg in patients with advanced   melanoma is being evaluated in an ongoing phase III trial.
CANIT0000191	23752227	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines/ animal models	N/A	Basic research	Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells.	Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells.	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2013 Jul 1	 Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T  cell immunotherapy targeting CTLA-4.	 J Exp Med	 The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab  results in durable responses in metastatic melanoma, though therapeutic benefit  has been limited to a fraction of patients. This calls for identification of  resistance mechanisms and development of combinatorial strategies. Here, we  examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the antitumor  efficacy of CTLA-4 blockade. In IDO knockout mice treated with anti-CTLA-4  antibody, we demonstrate a striking delay in B16 melanoma tumor growth and  increased overall survival when compared with wild-type mice. This was also  observed with antibodies targeting PD-1-PD-L1 and GITR. To highlight the  therapeutic relevance of these findings, we show that CTLA-4 blockade strongly  synergizes with IDO inhibitors to mediate rejection of both IDO-expressing and  nonexpressing poorly immunogenic tumors, emphasizing the importance of the  inhibitory role of both tumor- and host-derived IDO. This effect was T cell  dependent, leading to enhanced infiltration of tumor-specific effector T cells  and a marked increase in the effector-to-regulatory T cell ratios in the tumors.   Overall, these data demonstrate the immunosuppressive role of IDO in the context   of immunotherapies targeting immune checkpoints and provide a strong incentive to  clinically explore combination therapies using IDO inhibitors irrespective of IDO  expression by the tumor cells.
CANIT0000192	23773743	Case report	Heel melanoma with mediastinal metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	A woman on ipilimumab for a heel melanoma with mediastinal metastases was referred for evaluation of painful diplopia and proptosis that began three days after the fourth infusion of ipilimumab. The clinical examination disclosed a left abductiondeficit associated with conjunctival hyperaemia and palpebral oedema. Orbital MRI disclosed enlargement of the left lateral rectus, enhancing after contrast. An extensive work-up did not find any evidence for thyroid-related eye disease, as well as other orbital inflammatory processes, orbital cellulitis or orbital metastases. Treatment with high-dose oral steroids resulted in complete clinical recovery within a few days.	Orbital myositis associated with ipilimumab. Treatment with high-dose oral steroids resulted in complete clinical recovery within a few days.	N/A	N/A	N/A	N/A	N/A	 2013 Jun-Jul	 [Orbital myositis associated with ipilimumab].	 Ann Dermatol Venereol	 BACKGROUND: Ipilimumab is a monoclonal antibody targeting cytotoxic T-lymphocyte   antigen 4 (CTLA-4) that allows increased survival and, occasionally, complete  remission, in the treatment of metastatic melanoma. The most frequent adverse  effects are attributed to dysimmunity. We report the case of a female patient who  developed orbital myositis during treatment with ipilimumab. PATIENTS AND  METHODS: A woman on ipilimumab for a heel melanoma with mediastinal metastases  was referred for evaluation of painful diplopia and proptosis that began three  days after the fourth infusion of ipilimumab. The clinical examination disclosed   a left abductiondeficit associated with conjunctival hyperaemia and palpebral  oedema. Orbital MRI disclosed enlargement of the left lateral rectus, enhancing  after contrast. An extensive work-up did not find any evidence for  thyroid-related eye disease, as well as other orbital inflammatory processes,  orbital cellulitis or orbital metastases. Treatment with high-dose oral steroids   resulted in complete clinical recovery within a few days. DISCUSSION: To our  knowledge, this is the first clinical report of orbital myositis as an adverse  event related to anti-CTLA-4 antibody treatment. Both timing and usual profile of  adverse events support the hypothesis that orbital myositis has to be attributed   there to ipilimumab. Several dysimmune toxicities were observed with ipilimumab.   Ophtalmic toxicity has unusually been described. Most cases were uveitis. Whether  immune-related adverse events correlate with clinical response to ipilimumab  treatment remains to be determined.CI  - Copyright (c) 2013 Elsevier Masson SAS. All rights reserved.
CANIT0000193	23787916	Clinical research	Stage III/IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus dacarbazine	Dacarbazine plus placebo	Immune checkpoint therapy plus Chemotherapy	Dacarbazine (DB00851); dacarbazine (DB00851); ipilimumab (DB06186); 	250	252	A multinational, randomised, double-blind, phase III study	During the first year of study, there was little  difference between groups in quality-adjusted survival. However, after 2, 3 and 4  years follow-up for patients with extended survival, the benefits of IPI+DTIC vs PLA+DTIC for advanced melanoma continue to accrue.	N/A	N/A	N/A	N/A	N/A	N/A	 2013 Jul 9	 Q-TWiST analysis comparing ipilimumab/dacarbazine vs placebo/dacarbazine for  patients with stage III/IV melanoma.	 Br J Cancer	 BACKGROUND: Study CA184024 was a multinational, randomised, double-blind, phase 3  study comparing ipilimumab/dacarbazine (DTIC) vs placebo/DTIC in patients with  untreated stage III/IV melanoma, which showed that ipilimumab significantly  improves survival in patients with metastatic melanoma. The objective of this  analysis was to compare the quality-adjusted survival experience among patients  in this trial. METHODS: Survival time was partitioned into health states:  toxicity, time before progression without toxicity, and relapse until death or  end of follow-up. Q-TWiST (quality-adjusted time without symptoms of disease or  toxicity of treatment) was calculated as the utility-weighted sum of the mean  health state durations. Analyses were repeated over extended follow-up periods.  RESULTS: Based on a combination of trial-based and external utility scores, the  Q-TWiST difference in this trial was 0.50 months (P=0.0326) favoring ipilimumab  after 1 year. The Q-TWiST difference was 1.5 months with 2 years of follow-up  (P=0.0091), 2.36 months at 3 years (P=0.005) and 3.28 months at 4 years  (P=0.0074). CONCLUSION: During the first year of study, there was little  difference between groups in quality-adjusted survival. However, after 2, 3 and 4  years follow-up for patients with extended survival, the benefits of IPI+DTIC vs   PLA+DTIC for advanced melanoma continue to accrue.
CANIT0000194	23824275	Clinical research	Brain metastasis in melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	38	N/A	A multicentre, retrospective cohort study	Effective in a few patients with central nervous system metastasis. But poor outcome in patients with brain metastases.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2014 Jan	 Ipilimumab in melanoma patients with brain metastasis: a retro-spective  multicentre evaluation of thirty-eight patients.	 Acta Derm Venereol	 Treatment with ipilimumab, a monoclonal antibody that antagonizes cytotoxic  T-lymphocyte antigen-4 (CTLA-4), results in improved survival of patients with  stage IIIc-IV melanoma. However, there is a lack of data on the efficacy of  ipilimumab in patients with brain metastases. To evaluate the efficacy of  ipilimumab for the treatment of brain metastasis in melanoma, a multicentre,  retrospective analysis of 38 patients with brain metastases in melanoma, treated   with ipilimumab in the context of the French Expanded Access Program, was  performed. Three patients had a 3 partial response, 5 stable disease, 15 disease   progression and 15 patients died during the induction phase due to disease  progression. Median overall survival was 101 days (range 54-154). The brain  metastases control rate was 16% (6/38). Ipilimumab may be effective in a few  patients with central nervous system metastasis. However, patients with brain  metastases and a low life expectancy may not benefit sufficiently from treatment   with ipilimumab.
CANIT0000195	23833564	Clinical research	Untreated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Carboplatin or paclitaxel followed by ipilimumab	Immune checkpoint therapy	Paclitaxel (DB01229); carboplatin (DB00958); ipilimumab (DB06186); 	20	20	A three-arm phase I	Ipilimumab can be combined safely with two chemotherapy regimens commonly used in advanced melanoma.	N/A	N/A	N/A	N/A	N/A	N/A	2013	 Randomized phase I pharmacokinetic study of ipilimumab with or without one of two  different chemotherapy regimens in patients with untreated advanced melanoma.	 Cancer Immun	 We describe a randomized three-arm phase I study of ipilimumab administered alone  (I group) or in combination with dacarbazine (D group) or carboplatin/paclitaxel   (CP group) in patients with previously untreated advanced melanoma. The primary  objective was to estimate the effect of ipilimumab on the pharmacokinetics (PK)  of dacarbazine and paclitaxel and, conversely, to estimate the effects of  dacarbazine and carboplatin/paclitaxel on the PK of ipilimumab. Secondary  objectives included evaluation of the safety and anti-tumor activity of  ipilimumab when administered alone or with either dacarbazine or  carboplatin/paclitaxel, and assessment of pharmacodynamic (PD) effects of  ipilimumab on the immune system when administered alone or with either of the two  chemotherapies. Ipilimumab was administered at a dose of 10 mg/kg intravenously  (IV) every 3 weeks for up to 4 doses. Patients in the D group received  dacarbazine 850 mg/m(2) IV every 3 weeks. Patients in the CP group received  paclitaxel 175 mg/m(2) IV and carboplatin [AUC=6] IV every 3 weeks. Starting at  week 24, patients without dose-limiting toxicities were eligible to receive  maintenance ipilimumab at 10 mg/kg every 12 weeks until disease progressed or  toxicity required discontinuation. Of 59 randomized patients, 18 (30.5%)  discontinued treatment due to adverse events. Response rates by modified WHO  criteria were 29.4% (I group), 27.8% (D group), and 11.1% (CP group). No major PK  or PD interactions were observed when ipilimumab was administered with  dacarbazine or with the carboplatin/paclitaxel combination. This study  demonstrated that ipilimumab can be combined safely with two chemotherapy  regimens commonly used in advanced melanoma.
CANIT0000196	23833564	Clinical research	Untreated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Dacarbazine followed by ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); dacarbazine (DB00851); ipilimumab (DB06186); 	20	19	A three-arm phase I	Ipilimumab can be combined safely with two chemotherapy regimens commonly used in advanced melanoma.	N/A	N/A	N/A	N/A	N/A	N/A	2013	 Randomized phase I pharmacokinetic study of ipilimumab with or without one of two  different chemotherapy regimens in patients with untreated advanced melanoma.	 Cancer Immun	 We describe a randomized three-arm phase I study of ipilimumab administered alone  (I group) or in combination with dacarbazine (D group) or carboplatin/paclitaxel   (CP group) in patients with previously untreated advanced melanoma. The primary  objective was to estimate the effect of ipilimumab on the pharmacokinetics (PK)  of dacarbazine and paclitaxel and, conversely, to estimate the effects of  dacarbazine and carboplatin/paclitaxel on the PK of ipilimumab. Secondary  objectives included evaluation of the safety and anti-tumor activity of  ipilimumab when administered alone or with either dacarbazine or  carboplatin/paclitaxel, and assessment of pharmacodynamic (PD) effects of  ipilimumab on the immune system when administered alone or with either of the two  chemotherapies. Ipilimumab was administered at a dose of 10 mg/kg intravenously  (IV) every 3 weeks for up to 4 doses. Patients in the D group received  dacarbazine 850 mg/m(2) IV every 3 weeks. Patients in the CP group received  paclitaxel 175 mg/m(2) IV and carboplatin [AUC=6] IV every 3 weeks. Starting at  week 24, patients without dose-limiting toxicities were eligible to receive  maintenance ipilimumab at 10 mg/kg every 12 weeks until disease progressed or  toxicity required discontinuation. Of 59 randomized patients, 18 (30.5%)  discontinued treatment due to adverse events. Response rates by modified WHO  criteria were 29.4% (I group), 27.8% (D group), and 11.1% (CP group). No major PK  or PD interactions were observed when ipilimumab was administered with  dacarbazine or with the carboplatin/paclitaxel combination. This study  demonstrated that ipilimumab can be combined safely with two chemotherapy  regimens commonly used in advanced melanoma.
CANIT0000197	23877659	Clinical research	Castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine plus docetaxel	Docetaxel	Tumor vaccine plus Chemotherapy	Docetaxel (DB01248); MVA-5T4 vaccine (NCIT:C49087); 	12	13	A randomized phase II trial	Importantly, a pre-treatment biomarker  previously demonstrated to predict 5T4 immune response and treatment benefit showed a strong association with 5T4 antibody response and a statistically significant association with progression-free survival in patients treated with TroVax plus docetaxel, but not docetaxel alone.	TroVax was well tolerated in all patients.	N/A	N/A	Immune response (NCIT:C17930); 	Immune response surrogate	Immune response	 2013 Sep	 Vaccination of castration-resistant prostate cancer patients with TroVax  (MVA-5T4) in combination with docetaxel: a randomized phase II trial.	 Cancer Immunol Immunother	 The attenuated vaccinia virus, modified vaccinia Ankara, has been engineered to  deliver the tumor antigen 5T4 (TroVax(R)). Here, we report results from a  randomized open-label phase II trial in castration-resistant prostate cancer  patients in which TroVax was administered in combination with docetaxel and  compared against docetaxel alone. The aim was to recruit 80 patients (40 per  arm), but the study was terminated early due to recruitment challenges.  Therefore, this paper reports the comparative safety and immunological and  clinical efficacy in 25 patients, 12 of whom were treated with TroVax plus  docetaxel and 13 with docetaxel alone. 5T4-specific immune responses were  monitored throughout the study. Clinical responses were assessed by measuring  changes in tumor burden by CT and bone scan and by quantifying PSA  concentrations. TroVax was well tolerated in all patients. Of 10 immunologically   evaluable patients, 6 mounted 5T4-specific antibody responses. Patients treated  with TroVax plus docetaxel showed a greater median progression-free survival of  9.67 months compared with 5.10 months for patients on the docetaxel alone arm (P   = 0.097; HR = 0.31; 95% CI 0.08-1.24). Importantly, a pre-treatment biomarker  previously demonstrated to predict 5T4 immune response and treatment benefit  showed a strong association with 5T4 antibody response and a statistically  significant association with progression-free survival in patients treated with  TroVax plus docetaxel, but not docetaxel alone.
CANIT0000198	23913718	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	39	N/A	A multicentre, retrospective cohort study	An absolute lymphocyte count  1000 cells/L at week 7 was associated with improved survival.	Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab.	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2013 Oct 15	 Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective  review of the Dana-Farber Cancer Institute, Massachusetts General Hospital,  Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne  experience.	 Cancer	 BACKGROUND: Uveal melanoma exhibits a high incidence of metastases; and, to date,  there is no systemic therapy that clearly improves outcomes. The anticytotoxic  T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard  of care for metastatic melanoma; however, the clinical activity of CTLA-4  inhibition in patients with metastatic uveal melanoma is poorly defined. METHODS:  To assess ipilimumab in this setting, the authors performed a multicenter,  retrospective analysis of 4 hospitals in the United States and Europe. Clinical  characteristics, toxicities, and radiographic disease burden, as determined by  central, blinded radiology review, were evaluated. RESULTS: Thirty-nine patients   with uveal melanoma were identified, including 34 patients who received 3 mg/kg  ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response  criteria and modified World Health Organization criteria were used to assess the   response rate (RR) and the combined response plus stable disease (SD) rate after   12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6  months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at  week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1  complete response and 1 late partial response (at 100 weeks after initial SD) for  an immune-related RR of 5.1%. Immune-related adverse events were observed in 28  patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related  adverse events were more frequent in patients who received 10 mg/kg ipilimumab  than in those who received 3 mg/kg ipilimumab. The median overall survival from  the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4  months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level,  and an absolute lymphocyte count >/= 1000 cells/muL at week 7 were associated  significantly with survival. CONCLUSIONS: In this multicenter, retrospective  analysis of 4 hospitals in the United States and Europe of patients with uveal  melanoma, durable responses to ipilimumab and manageable toxicity were observed.CI  - Copyright (c) 2013 American Cancer Society.
CANIT0000199	23913718	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	39	N/A	A multicentre, retrospective cohort study	An LDH level within normal limits (vs elevated LDH; log-rank P 5 .005) was associated with improved survival.	Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab.	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2013 Oct 15	 Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective  review of the Dana-Farber Cancer Institute, Massachusetts General Hospital,  Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne  experience.	 Cancer	 BACKGROUND: Uveal melanoma exhibits a high incidence of metastases; and, to date,  there is no systemic therapy that clearly improves outcomes. The anticytotoxic  T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard  of care for metastatic melanoma; however, the clinical activity of CTLA-4  inhibition in patients with metastatic uveal melanoma is poorly defined. METHODS:  To assess ipilimumab in this setting, the authors performed a multicenter,  retrospective analysis of 4 hospitals in the United States and Europe. Clinical  characteristics, toxicities, and radiographic disease burden, as determined by  central, blinded radiology review, were evaluated. RESULTS: Thirty-nine patients   with uveal melanoma were identified, including 34 patients who received 3 mg/kg  ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response  criteria and modified World Health Organization criteria were used to assess the   response rate (RR) and the combined response plus stable disease (SD) rate after   12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6  months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at  week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1  complete response and 1 late partial response (at 100 weeks after initial SD) for  an immune-related RR of 5.1%. Immune-related adverse events were observed in 28  patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related  adverse events were more frequent in patients who received 10 mg/kg ipilimumab  than in those who received 3 mg/kg ipilimumab. The median overall survival from  the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4  months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level,  and an absolute lymphocyte count >/= 1000 cells/muL at week 7 were associated  significantly with survival. CONCLUSIONS: In this multicenter, retrospective  analysis of 4 hospitals in the United States and Europe of patients with uveal  melanoma, durable responses to ipilimumab and manageable toxicity were observed.CI  - Copyright (c) 2013 American Cancer Society.
CANIT0000200	23913718	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	39	N/A	A multicentre, retrospective cohort study	ECOG performance status (0 vs 1-2; log-rank P < .0001) was associated with improved survival.	Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab.	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2013 Oct 15	 Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective  review of the Dana-Farber Cancer Institute, Massachusetts General Hospital,  Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne  experience.	 Cancer	 BACKGROUND: Uveal melanoma exhibits a high incidence of metastases; and, to date,  there is no systemic therapy that clearly improves outcomes. The anticytotoxic  T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard  of care for metastatic melanoma; however, the clinical activity of CTLA-4  inhibition in patients with metastatic uveal melanoma is poorly defined. METHODS:  To assess ipilimumab in this setting, the authors performed a multicenter,  retrospective analysis of 4 hospitals in the United States and Europe. Clinical  characteristics, toxicities, and radiographic disease burden, as determined by  central, blinded radiology review, were evaluated. RESULTS: Thirty-nine patients   with uveal melanoma were identified, including 34 patients who received 3 mg/kg  ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response  criteria and modified World Health Organization criteria were used to assess the   response rate (RR) and the combined response plus stable disease (SD) rate after   12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6  months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at  week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1  complete response and 1 late partial response (at 100 weeks after initial SD) for  an immune-related RR of 5.1%. Immune-related adverse events were observed in 28  patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related  adverse events were more frequent in patients who received 10 mg/kg ipilimumab  than in those who received 3 mg/kg ipilimumab. The median overall survival from  the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4  months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level,  and an absolute lymphocyte count >/= 1000 cells/muL at week 7 were associated  significantly with survival. CONCLUSIONS: In this multicenter, retrospective  analysis of 4 hospitals in the United States and Europe of patients with uveal  melanoma, durable responses to ipilimumab and manageable toxicity were observed.CI  - Copyright (c) 2013 American Cancer Society.
CANIT0000201	23924790	Clinical research	Previously treated pancreatic cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	CTLA-4 (P16410); GM-CSF (P04141); 	CTLA-4; GM-CSF	Ipilimumab plus GM-CSF cell-based vaccines	Ipilimumab	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386); 	15	15	A phase Ib, open-label, randomized study	Checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study.	Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events.	N/A	N/A	N/A	N/A	N/A	 2013 Sep	 Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells  transfected with a GM-CSF gene in previously treated pancreatic cancer.	 J Immunother	 Preclinical reports support the concept of synergy between cancer vaccines and  immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T  lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully  combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has  been tested as a single agent in patients with pancreatic ductal adenocarcinoma  (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated  ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30  patients with previously treated advanced PDA were randomized (1:1). Induction  doses were administered every 3 weeks for a total of 4 doses followed by  maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of  stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses.   In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization   (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these  patients, disease stabilization occurred after an initial period of progression.   The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072)  and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20%  of patients in each arm had grade 3/4 immune-related adverse events. Among  patients with OS > 4.3 months, there was an increase in the peak  mesothelin-specific T cells (P = 0.014) and enhancement of the T-cell repertoire   (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the   potential for clinical benefit and should be evaluated in a larger study.
CANIT0000202	23942774	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Ipilimumab plus gp100 vaccine	Immune checkpoint therapy	Gp100 vaccine (NCIT:C29068); ipilimumab (DB06186); 	137	403	A phase III clinical trial	Ipilimumab results in survival of  2 years in one-fifth of pretreated patients with 2 years potential follow-up in a phase III trial. New onset, low-grade events starting after administration of the last dose were infrequent.	Safety among patients with  2 years' survival was comparable with the overall study population, with the onset of new ipilimumab-related toxic effect (all grades) reported in 6 of 78 (8%) patients.	N/A	N/A	N/A	N/A	N/A	 2013 Oct	 Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more   than 2 years following treatment in a phase III trial (MDX010-20).	 Ann Oncol	 BACKGROUND: In a phase III trial (ClinicalTrials.gov registration ID:  NCT00094653), ipilimumab significantly improved survival versus a vaccine control  in pretreated patients with metastatic melanoma. Here, we characterize outcomes  of those patients who survived >/= 2 years. METHODS: Patients were randomized (3   : 1 : 1) to receive ipilimumab 3 mg/kg + gp100 vaccine, ipilimumab 3 mg/kg +  placebo, or gp100 vaccine alone. Baseline demographic data, duration of survival,  responses, and safety among patients with >/= 2 years' survival were analyzed.  RESULTS: Among 676 randomized patients, 474 and 259 patients had at least 2 or 3   years of potential follow-up, respectively, and were eligible for analysis. Among  these, 94 (20%) and 42 (16%) survived >/= 2 and >/= 3 years, respectively.  Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with  ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus  gp100. Safety among patients with >/= 2 years' survival was comparable with the  overall study population, with the onset of new ipilimumab-related toxic effect  (all grades) reported in 6 of 78 (8%) patients. CONCLUSIONS: Ipilimumab results  in survival of >/= 2 years in one-fifth of pretreated patients with 2 years  potential follow-up in a phase III trial. New onset, low-grade events starting  after administration of the last dose were infrequent. TRIAL REGISTRATION ID:  NCT00094653.
CANIT0000203	24025700	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); BRAF (P15056); 	CTLA-4; BRAF	Ipilimumab plus vemurafenib	N/A	Immune checkpoint therapy plus Target therapy	Vemurafenib (DB08881); ipilimumab (DB06186); 	1	N/A	Case	N/A	Cumulative dermatologic toxicity	N/A	N/A	N/A	N/A	N/A	 2013 Dec	 Cumulative dermatologic toxicity with ipilimumab and vemurafenib responsive to  corticosteroids.	 Melanoma Res	 Dermatologic toxicity is a known reaction of ipilimumab and vemurafenib. Because   of the lack of effective treatments and aggressive nature of melanoma, treatments  are often discontinued and new treatments are initiated in rapid succession. We  report what we believe to be the first case of cumulative dermatologic toxicity  secondary to rapid-sequential treatment with ipilimumab and vemurafenib for  metastatic melanoma that responded to high-dose steroids. This case highlights  the combined toxicity of these two drugs that can occur as a result of  overlapping toxicity. It also illustrates the need for a substantial wash out  period between rapid cycling of these two drugs secondary to ipilimumab's long  half-life.
CANIT0000204	24035405	Clinical research	Chemotherapy-resistant advanced malignant mesothelioma	Mesothelioma	EFO:0000588	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	29	N/A	An open-label, single-arm, phase II study	Although the effect size was small in our phase 2 trial, tremelimumab seemed to have encouraging clinical activity and an  acceptable safety and tolerability profile in previously treated patients with  advanced malignant mesothelioma.	An acceptable safety and tolerability profile	N/A	N/A	N/A	N/A	N/A	 2013 Oct	 Tremelimumab for patients with chemotherapy-resistant advanced malignant  mesothelioma: an open-label, single-arm, phase 2 trial.	 Lancet Oncol	 BACKGROUND: Monoclonal antibodies to cytotoxic T-lymphocyte antigen 4 (CTLA4)  have therapeutic activity in different tumour types. We aimed to investigate the   efficacy, safety, and immunological activity of the anti-CTLA4 monoclonal  antibody, tremelimumab, in advanced malignant mesothelioma. METHODS: In our  open-label, single-arm, phase 2 study, we enrolled patients aged 18 years or  older with measurable, unresectable malignant mesothelioma and progressive  disease after a first-line platinum-based regimen. Eligible patients had to have   a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group  performance status of 2 or less, and no history of autoimmune disease. Patients  received tremelimumab 15 mg/kg intravenously once every 90 days until progressive  disease or severe toxicity. The primary endpoint was the proportion of patients  who achieved an objective response (complete or partial response), with a target   response rate of 17% according to the modified Response Evaluation Criteria in  Solid Tumors (RECIST) for pleural malignant mesothelioma or standard RECIST 1.0  for peritoneal malignant mesothelioma. Analyses were done according to intention   to treat. This trial is registered with EudraCT, number 2008-005171-95, and  ClinicalTrials.gov, number NCT01649024. FINDINGS: Between May 27, 2009, and Jan  10, 2012, we enrolled 29 patients. All patients received at least one dose of  tremelimumab (median two doses, range one to nine). No patients had a complete  response and two patients (7%) had a durable partial response (one lasting 6  months and one lasting 18 months); one partial response occurred after initial  progressive disease. Thus, the study did not reach its primary endpoint. However,  we noted disease control in nine (31%) patients and a median progression-free  survival of 6.2 months (95% CI 1.3-11.1) and a median overall survival of 10.7  months (0.0-21.9). 27 patients (93%) had at least one grade 1-2  treatment-emergent adverse event (mainly cutaneous rash, pruritus, colitis, or  diarrhoea), and four patients (14%) had at least one grade 3-4 treatment-emergent  adverse event (two gastrointestinal, one neurological, two hepatic, and one  pancreatic). INTERPRETATION: Although the effect size was small in our phase 2  trial, tremelimumab seemed to have encouraging clinical activity and an  acceptable safety and tolerability profile in previously treated patients with  advanced malignant mesothelioma. FUNDING: Associazione Italiana per la Ricerca  sul Cancro, Istituto Toscano Tumori, Pfizer, and Fondazione Buzzi Unicem.CI  - Copyright (c) 2013 Elsevier Ltd. All rights reserved.
CANIT0000205	24041689	Basic research	Murine melanoma cancer cell line, B16, and renal cell carcinoma cell line, RENCA. B7.1 and B7.2 stable CHO cells	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	PVAC-1-hCTLA-4 DNA vaccine 	N/A	Tumor vaccine	PVAC-1-hCTLA-4 DNA vaccine (NCIT:C39619); 	Cell lines/ animal models	N/A	Basic research	Immunization with the resulting construct, pVAC-1-hCTLA-4,  elicited antibody specific to human CTLA-4 with cross reactivity to murine  CTLA-4, which was sufficient for inhibiting B16F10 tumor growth in c57BL/6 mice  in the absence of measurable toxicity. Coupling liposome with pVAC-1-mCTLA-4  could break tolerance to self-antigen in BALB/c mice and induce potent immunity  against murine CTLA-4, and suppress growth of subcutaneous renal cell carcinoma	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2013 Oct 18	 A DNA vaccine against cytotoxic T-lymphocyte associated antigen-4 (CTLA-4)  prevents tumor growth.	 Biochem Biophys Res Commun	 Co-stimulatory signaling pathway triggered by the binding of B7.1/B7.2 (CD80/86)   of antigen-presenting cells (APCs) to CD28 of T cells is required for optimal  T-cell activation. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a  negative regulator of T cell activation, which competes with CD28 for B7.1/B7.2  binding with a greater affinity. Ipilimumab, a monoclonal antibody against  CTLA-4, has shown positive efficacy in a pivotal clinical trial for the treatment  of metastatic melanoma and was approved by FDA. However, the cost of monoclonal  antibody-based therapeutics might limit the number of patients treated. To  develop a novel therapeutics specifically targeting CTLA-4, we constructed a DNA   vaccine by cloning the sequence of CTLA-4 fused with a transmembrane domain  sequence of placental alkaline phosphatase (PLAP) into a mammalian expression  plasmid, pVAC-1. Immunization with the resulting construct, pVAC-1-hCTLA-4,  elicited antibody specific to human CTLA-4 with cross reactivity to murine  CTLA-4, which was sufficient for inhibiting B16F10 tumor growth in c57BL/6 mice  in the absence of measurable toxicity. Coupling liposome with pVAC-1-mCTLA-4  could break tolerance to self-antigen in BALB/c mice and induce potent immunity  against murine CTLA-4, and suppress growth of subcutaneous renal cell carcinoma  (Renca).CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
CANIT0000206	24041689	Basic research	Murine melanoma cancer cell line, B16, and renal cell carcinoma cell line, RENCA. B7.1 and B7.2 stable CHO cells	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	PVAC-1-hCTLA-4 DNA vaccine 	N/A	Tumor vaccine	PVAC-1-hCTLA-4 DNA vaccine (NCIT:C39619); 	Cell lines/ animal models	N/A	Basic research	Immunization with the resulting construct, pVAC-1-hCTLA-4,  elicited antibody specific to human CTLA-4 with cross reactivity to murine  CTLA-4, which was sufficient for inhibiting B16F10 tumor growth in c57BL/6 mice  in the absence of measurable toxicity. Coupling liposome with pVAC-1-mCTLA-4  could break tolerance to self-antigen in BALB/c mice and induce potent immunity  against murine CTLA-4, and suppress growth of subcutaneous renal cell carcinoma	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2013 Oct 18	 A DNA vaccine against cytotoxic T-lymphocyte associated antigen-4 (CTLA-4)  prevents tumor growth.	 Biochem Biophys Res Commun	 Co-stimulatory signaling pathway triggered by the binding of B7.1/B7.2 (CD80/86)   of antigen-presenting cells (APCs) to CD28 of T cells is required for optimal  T-cell activation. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a  negative regulator of T cell activation, which competes with CD28 for B7.1/B7.2  binding with a greater affinity. Ipilimumab, a monoclonal antibody against  CTLA-4, has shown positive efficacy in a pivotal clinical trial for the treatment  of metastatic melanoma and was approved by FDA. However, the cost of monoclonal  antibody-based therapeutics might limit the number of patients treated. To  develop a novel therapeutics specifically targeting CTLA-4, we constructed a DNA   vaccine by cloning the sequence of CTLA-4 fused with a transmembrane domain  sequence of placental alkaline phosphatase (PLAP) into a mammalian expression  plasmid, pVAC-1. Immunization with the resulting construct, pVAC-1-hCTLA-4,  elicited antibody specific to human CTLA-4 with cross reactivity to murine  CTLA-4, which was sufficient for inhibiting B16F10 tumor growth in c57BL/6 mice  in the absence of measurable toxicity. Coupling liposome with pVAC-1-mCTLA-4  could break tolerance to self-antigen in BALB/c mice and induce potent immunity  against murine CTLA-4, and suppress growth of subcutaneous renal cell carcinoma  (Renca).CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
CANIT0000207	24067875	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Immune-related adverse reaction is one of the common side effects of ipilimumab. Ipilimumab-induced hepatitis and colitis has been previously reported in the literature. This is the first ever case report of ipilimumab-induced granulomatous interstitial nephritis.	Granulomatous interstitial nephritis	N/A	N/A	N/A	N/A	N/A	 2015 May-Jun	 Ipilimumab granulomatous interstitial nephritis.	 Am J Ther	 Drug-induced interstitial nephritis is a recognized cause of acute and chronic  renal failure. Some of them lead to the formation of granulomata. T-cell-mediated  immune response is implicated in the pathogenesis. Here, we describe the case of   a 74-year-old male patient with metastatic melanoma who was referred to our  clinic with a history of rash and worsening renal function. Because of subacute  onset, progressively worsening renal function in the presence of skin rash,  elevated liver enzymes, and in the background of exposure, medication-induced  interstitial nephritis was suspected. He received 3 doses of ipilimumab, a novel   drug used in the treatment of metastatic melanoma within 3 months before the  onset of renal failure. A renal biopsy was done, which showed granulomatous  interstitial nephritis. Renal biopsy findings, temporal relation between renal  failure and exposure to medication, and review of the literature supported a  diagnosis of ipilimumab-induced renal failure. He was started on steroids, and  renal function recovered in the next 1 month. Immune-related adverse reaction is   one of the common side effects of ipilimumab. Ipilimumab-induced hepatitis and  colitis has been previously reported in the literature. This is the first ever  case report of ipilimumab-induced granulomatous interstitial nephritis.
CANIT0000208	24107912	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Serum S100B levels correlate with clinical benefit in a metastatic melanoma patient treated by CTLA-4 blockade.	N/A	N/A	N/A	S100B (P04271); 	Pretreatment serum S100B levels	Gene expression signature in serum	2013	 Serum S100B levels correlate with clinical benefit in a metastatic melanoma  patient treated by CTLA-4 blockade: a case report.	 Onkologie	 BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an  immunoregulatory molecule expressed by activated T cells. In patients with  metastatic melanoma, anti-CTLA-4 antibody therapy with ipilimumab achieves  durable cancer regression in approximately 10-15% of patients. In the face of  complex and sometimes delayed tumor response patterns, prognostic and predictive   biomarkers are needed to monitor therapy outcomes and to identify early potential  long-term survivors who might also benefit from therapy re-induction. CASE  REPORT: The clinical case of a 49-year-old male patient with metastatic melanoma   and unfavorable prognostic factors is presented. The time course of the serum  biomarker S100B during initial anti-CTLA-4 therapy correlated very well with the   clinical situation and, in the present case, proved its potential value as an  early biomarker of a subsequently observed radiological response in this stage IV  melanoma patient. The observed clinical response lasted for more than 24 months.   CONCLUSIONS: Further efforts are required to better understand the patterns of  response and the immunological tumor response in patients undergoing CTLA-4  blockade. A validation of S100B as a marker to identify early long-term  responders among patients treated with ipilimumab is warranted.CI  - (c) 2013 S. Karger GmbH, Freiburg.
CANIT0000209	24122241	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	7	N/A	Case	N/A	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2013 Nov	 Hypophysitis caused by ipilimumab in cancer patients: hormone replacement or  immunosuppressive therapy.	 Exp Clin Endocrinol Diabetes	 Ipilimumab is besides the BRAF inhibitor vemurafenib the first officially  approved medical treatment for metastatic melanoma, which results in improved  survival. Ipilimumab leads to a release of a CTLA4-mediated inhibition of T-cell   immunoreactions. Therefore, patients may also suffer from immune-related adverse   events affecting different organs, which are typically treated by high-dose  corticosteroids. Ipilimumab-induced hypophysitis (iH) has been reported in up to   17% of melanoma patients in clinical trials.Here we present 5 patients with  metastatic melanoma and 2 patients with prostate cancer who developed  hypophysitis after ipilimumab therapy. Patients were treated by high-dose  corticosteroid therapy resulting in the resolution of local inflammation but not   of pituitary deficiencies. Partial or complete hypopituitarism remained in all  patients. Pharmacotherapy with high-dose corticosteroids caused complications in   5 patients, necessitating hospitalization in 4. 2 of the 3 patients with  progressive disease died, while 3 patients had stable disease and 1 patient  showed tumor regression after discontinuation of ipilimumab.In summary, with  regard to safety and simplicity of hormonal substitution therapy we have to  scrutinize high-dose corticosteroid therapy, though it only improves inflammation  but not neuro-endocrine function and may cause further morbidity. Regression of  the tumor depends on the ipilimumab-mediated immune events, in which high-dose  and long-term corticosteroid therapy for iH appears to be counter-intuitive.  Herein, we discuss screening and the diagnostic as well as therapeutic management  of iH in metastatic cancer patients from an endocrinologic perspective.CI  - (c) J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart . New York.
CANIT0000210	24274261	Case report	Late presentation of amelanotic BRAF-negative metastatic malignant melanoma resembling clear cell sarcoma	Amelanotic melanoma	EFO:1001937	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Good response	N/A	N/A	N/A	N/A	N/A	N/A	 2013 Nov 25	 Diagnostic dilemma: late presentation of amelanotic BRAF-negative metastatic  malignant melanoma resembling clear cell sarcoma: a case report.	 Diagn Pathol	 UNLABELLED: Clear cell sarcoma is a rare cancer primarily of tendons, fascia, and  aponeuroses that can be difficult to discern from primary cutaneous malignant  melanoma. The two cancers share several histological markers, with most cases of   both cancers staining positively for S-100, HMB-45, and melanin. Primary therapy   of both cancers involves wide local excision, but while systemic therapy has  proven benefit for malignant melanoma, it has not been established for clear cell  sarcoma.We report the case of a 58 year old woman with a large, ulcerated,  fungating mass on her left lower leg. Frozen section of the mass showed a  malignant epithelioid and spindle cell tumor confined to the subcutaneous tissue.  A provisional diagnosis of soft-tissue sarcoma was made. Through in-depth study  of initial biopsy with immunohistochemistry for S-100, HMB-45, MART-1, and MITF,   along with karyotyping and FISH analysis for EWS gene rearrangement, the  diagnosis of amelanotic malignant melanoma was confirmed. The patient then  underwent systemic treatment with ipilimumab upon recurrence with good response.   VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:  http://www.diagnosticpathology.diagnomx.eu/vs/1989338475107348.
CANIT0000211	24293280	Case report	CD33-positive acute myeloid leukemia in early relapse	Acute myeloid leukemia	EFO:0000222	Blood and lymph nodes	CD33 (P20138); 	CD33; 	Gemtuzumab ozogamicin	N/A	Immune checkpoint therapy	Gemtuzumab ozogamicin (DB00056); 	1	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2014 Feb	 Successful repeated treatment of acute myeloid leukemia in early relapse with  gemtuzumab ozogamicin alone.	 Int J Hematol	 A 68-year-old female was diagnosed with acute myeloid leukemia (AML-M2 without  8/21 translocation) in December 2006. Although a complete remission (CR) was  obtained after induction chemotherapy, the first post-remission therapy was  discontinued because of severe cardiovascular complications. She had a relapse of  AML with CD33-positive myeloblasts which comprised 38.4 % of the bone marrow  cells in November 2007. She received two courses of low-dose chemotherapy because  of the previous complications. The amount of Wilm's tumor 1 (WT1) mRNA in the  peripheral blood was 13,000 copies/mug RNA after the first course of the  chemotherapy, and 4.8 % myeloblasts remained in the bone marrow after the second   course. She was treated with a single course of gemtuzumab ozogamicin (GO), with   a subsequent CR with 0.9 % marrow myeloblasts and fewer than 50 copies of WT-1  mRNA (normal level). Thereafter, she received five courses of GO monotherapy at  each occasion of early AML relapse. Hematological remission has been sustained  over a period of about 24 months with the GO monotherapy alone. This case  suggests that GO monotherapy is a useful salvage therapy for early relapse of  CD33-positive AML in situations in which standard chemotherapy is not indicated.
CANIT0000212	24309609	Clinical research	Pediatric newly diagnosed and recurrent brain tumors	Bladder cancer	EFO:0003833	Bladder	TLR3 (O15455); 	TLR3; 	Poly-ICLC	N/A	Tumor vaccine	Poly-ICLC (NCIT:C1198); 	47	N/A	A phase II clinical trial	On the basis of low toxicity and the promising LGG  response, poly-ICLC may be effective for childhood LGG, and the results justify  biomarker studies for personalization of poly-ICLC as a single agent or adjuvant.	No dose-limiting toxicities have been observed.	N/A	N/A	N/A	N/A	N/A	 2014 Aug	 Pediatric phase II trials of poly-ICLC in the management of newly diagnosed and  recurrent brain tumors.	 J Pediatr Hematol Oncol	 Brain tumors are the most common solid tumor diagnosed in childhood that account   for significant morbidity and mortality. New therapies are urgently needed;  hence, we conducted the first ever prospective open-label phase II trials of the   biological response modifier, poly-ICLC, in children with brain tumors. Poly-ICLC  is a synthetic double-stranded RNA that has direct antiviral, antineoplastic, and  immune adjuvant effects. A total of 47 children representing a variety of brain  tumor histopathologic subtypes were treated with poly-ICLC. On the basis of the  results of the initial phase II trial, an expanded prospective phase II trial in   low-grade glioma (LGG) has been initiated. MRI was used to acquire volume-based  measures of tumor response. No dose-limiting toxicities have been observed. In  the initial study 3 of 12 subjects with progressive high-grade gliomas (HGGs)  responded, and 2 of 4 children with progressive LGG experienced stable disease  for 18 to 24 months. In the follow-up LGG phase II study, 2 of 5 LGG patients  were stable over 18 months, with 1 stable for 6 months. Overall 5 of 10 LGG  patients have responded. On the basis of low toxicity and the promising LGG  response, poly-ICLC may be effective for childhood LGG, and the results justify  biomarker studies for personalization of poly-ICLC as a single agent or adjuvant.
CANIT0000213	24338272	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Good outcome	Side effects included fatigue, dyspnoea, cough, upper abdominal pain with diarrhoea, and gingival hyperplasia.	N/A	N/A	N/A	N/A	N/A	 2014 Jan	 Long-lasting complete response of metastatic melanoma to ipilimumab with analysis  of the resident immune cells.	 Med Oncol	 Even though ipilimumab is a promising antibody used for stage IV melanoma  therapy, the response varies and is difficult to predict. We here report on a  case of successful treatment with ipilimumab in dacarbazine-resistant metastatic   malignant melanoma, including a review of the literature on the long-term  treatment results. A 62-year-old patient with a history of a resected  lentigo-maligna melanoma 5 years earlier and parotideal metastasis 1 year before   was admitted with a newly detected 3.5 cm liver metastasis. Atypical liver  resection was performed (R1). Immunohistochemically, CD3+ T-lymphocytes and CD68+  macrophages were detected at the tumour margins and within the parotideal and  hepatic melanoma metastases. A sub-analysis of the liver metastasis showed  scattered FOX-P3+ regulatory T-lymphocytes as well as multiple CD8+ effector  T-cells. Chemotherapy with dacarbazine 1,000 mg/m(2)/day was administered at  4-weeks intervals for 3 months. A follow-up positron-emission computed tomography  and liver biopsy revealed melanoma metastases in the liver, lungs, and  mediastinum. Compassionate use of ipilimumab was administered at 3 mg/kg every 3   weeks for a total of four doses. After an initial increase in tumour size, most  lesions responded, but progressive axillary and cervical lymphadenopathy was  observed before complete remission was achieved. Side effects included fatigue,  dyspnoea, cough, upper abdominal pain with diarrhoea, and gingival hyperplasia.  Now, 36 months after ipilimumab therapy and 8 years after the initial melanoma  diagnosis, the tumour did not recur. It would be challenging to hypothesize that   long intervals between diagnosis and need for treatment, clinical side effects,  an initial increase in tumour size and the presence of intra-tumoural T-cells and  macrophages might predict tumour response.
CANIT0000214	24396833	Case report	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	4	N/A	Case	Enhancement of tumor-reactive cytotoxic CD4+ T cell responses	N/A	N/A	N/A	N/A	N/A	N/A	 2013 Oct	 Enhancement of tumor-reactive cytotoxic CD4+ T cell responses after ipilimumab  treatment in four advanced melanoma patients.	 Cancer Immunol Res	 CD4(+) T cells provide help to enhance and sustain cytotoxic CD8(+) T cell  responses. A direct lytic role for this cell population in mouse models further  supports the use of tumor-reactive CD4(+) T cells for cancer immunotherapy.  CTLA-4 blockade has been shown to expand antigen-specific cytotoxic CD4(+) T  cells in mouse models. We took advantage of spontaneous immunity to the NY-ESO-1   cancer-testis antigen to investigate quantitative and qualitative changes in  antigen-specific CD4(+) T cell responses after ipilimumab (anti-CTLA-4 monoclonal  antibody) treatment in advanced melanoma patients. Four NY-ESO-1 seropositive  melanoma patients were chosen upon the availability of suitable blood specimens  for characterizing the functions of NY-ESO-1 antigen-specific CD4(+) T cell  response by enzyme-linked immunospot (ELISPOT), intracellular cytokine staining  (ICS) and cytotoxicity assays. Multiple NY-ESO-1 antigen-specific CD4(+) T cell  responses with Th1 dominance were induced or enhanced after ipilimumab treatment   in peripheral blood in all four patients. NY-ESO-1 antigen-specific CD4(+) T cell  lines established from all 4 patients after ipilimumab treatment recognized  naturally processed NY-ESO-1 protein in antigen-presenting cells, expressed  master transcription factor Eomesodermin (Eomes) and secreted perforin and  Granzyme B. Finally, we demonstrated that these NY-ESO-1 antigen-specific CD4(+)   T cell lines directly lysed autologous melanoma cell lines expressing NY-ESO-1 in  an MHC class II restricted manner. Our results show that antigen specific  cytotoxic CD4(+) T cell responses are induced after ipilimumab therapy in human  cancer patients. Ipilimumab may induce the expression of lytic granules on  antigen specific cytotoxic CD4(+) T cells via Eomes, revealing a novel  consequence of immunologic checkpoint blockade.
CANIT0000215	24423086	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	74	N/A	A randomised, controlled  phase III clinical trial	The clinical activity and safety profile of ipilimumab 10 mg/kg in the EAP was similar to that seen in previous clinical trials of ipilimumab in pretreated patient populations.	Forty-five patients (60.8%) reported treatment-related adverse events of any grade, which were most commonly low-grade pruritus, pain, fever and diarrhoea. Grade 3 or 4 treatment-related AEs were reported in 8 patients (10.8%).	N/A	N/A	N/A	N/A	N/A	 2013 Oct 25	 Clinical experience with ipilimumab 10 mg/kg in patients with melanoma treated at  Italian centres as part of a European expanded access programme.	 J Exp Clin Cancer Res	 BACKGROUND: Patients with advanced melanoma are faced with a poor prognosis and,   until recently, limited treatment options. Ipilimumab, a novel immunotherapy that  blocks cytotoxic T-lymphocyte-associated antigen-4, was the first agent to  improve survival of patients with advanced melanoma in a randomised, controlled  phase 3 trial. We used data from an expanded access programme (EAP) at Italian  centres to evaluate the clinical activity and safety profile of ipilimumab 10  mg/kg in patients with advanced melanoma in a setting more similar to that of  daily practice. METHODS: Data were collected from patients enrolled in an  ipilimumab EAP across eight participating Italian centres. As per the EAP  protocol, patients had life-threatening, unresectable stage III/IV melanoma, had   failed or did not tolerate previous treatments and had no other therapeutic  option available. Treatment comprised ipilimumab 10 mg/kg every 3 weeks for a  total of four doses. If physicians believed patients would continue to derive  benefit from ipilimumab treatment, maintenance therapy with ipilimumab 10 mg/kg  was provided every 12 weeks. Tumour responses were assessed every 12 weeks using   modified World Health Organization criteria and safety continuously monitored.  RESULTS: Seventy-four pretreated patients with advanced melanoma were treated  with ipilimumab 10 mg/kg. Of these, 9 (13.0%) had an objective response,  comprising 3 patients with a complete response and 6 with a partial response.  Median overall survival was 7.0 months (95% confidence interval, 5.3-8.7) and  16.6% of patients were alive after 3 years. Forty-five patients (60.8%) reported   treatment-related adverse events of any grade, which were most commonly low-grade  pruritus, pain, fever and diarrhoea. Grade 3 or 4 treatment-related AEs were  reported in 8 patients (10.8%). CONCLUSIONS: The clinical activity and safety  profile of ipilimumab 10 mg/kg in the EAP was similar to that seen in previous  clinical trials of ipilimumab in pretreated patient populations.
CANIT0000216	24476799	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Enough to raise concerns for a nursing infant exposed to ipilimumab.	N/A	N/A	N/A	N/A	N/A	 2014 Apr	 Therapeutic monoclonal antibodies in human breast milk: a case study.	 Melanoma Res	 Recently, therapeutic monoclonal antibodies have been introduced for the  treatment of advanced melanoma and other diseases. It remains unclear whether  these drugs can be safely administered to women who are breast feeding because of  the potential hazardous side effects for nursing infants. One such therapy for  metastatic melanoma is ipilimumab, a human monoclonal antibody that blocks  cytotoxic T-lymphocyte-antigen-4, and is the preferred treatment for patients  with metastatic melanoma when other molecular therapies are not viable. This  study measured ipilimumab levels in the breast milk of a patient undergoing  treatment that were enough to raise concerns for a nursing infant exposed to  ipilimumab.
CANIT0000217	24490176	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); 	PD-1; BRAF	Nivolumab followed by vemurafenib	N/A	Immune checkpoint therapy followed by Target therapy	Vemurafenib (DB08881); nivolumab (DB09035); 	2	N/A	Case	N/A	Severe cutaneous and neurologic toxicity	N/A	N/A	N/A	N/A	N/A	 2013 Dec	 Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib   administration following anti-PD-1 therapy.	 Cancer Immunol Res	 Immune checkpoint inhibitors such as ipilimumab and targeted BRAF inhibitors have  dramatically altered the landscape of melanoma therapeutics over the past few  years. Agents targeting the programmed cell death-1/ligand (PD-1/PD-L1) axis are   now being developed and appear to be highly active clinically with favorable  toxicity profiles. We report two patients with BRAF V600E mutant melanoma who  were treated with anti-PD-1 agents as first-line therapy without significant  toxicity, followed by vemurafenib at disease progression. Both patients developed  severe hypersensitivity drug eruptions with multi-organ injury early in their  BRAF inhibitor treatment course. One patient subsequently developed acute  inflammatory demyelinating polyneuropathy (AIDP) and the other developed  anaphylaxis upon low-dose vemurafenib rechallenge. Further investigation of the  immune response during combination or sequences of melanoma therapeutics is  warranted. Furthermore, clinicians should maintain a high index of suspicion for   these toxicities when vemurafenib is administered following an anti-PD-1 agent.
CANIT0000218	24514956	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus vaccine PROSTVAC	N/A	Immune checkpoint therapy plus Tumor vaccine 	PROSTVAC vaccine (NCIT:C132990); ipilimumab (DB06186); 	24	N/A	A phase I clinical trial	There were trends toward associations for longer OS and a higher number of CTLA-4(NEG) Tregs (P = 0.005, adjusted P = 0.010).	N/A	N/A	N/A	Treg cells (CL:0000815); CTLA-4 (P16410); T-Lymphocyte (NCIT:C12476); 	CTLA-4(NEG) regulatory T-cell 	Gene expression signature on/in immune cell	 2014 Apr	 A combination trial of vaccine plus ipilimumab in metastatic castration-resistant  prostate cancer patients: immune correlates.	 Cancer Immunol Immunother	 We recently reported the clinical results of a Phase I trial combining ipilimumab  with a vaccine containing transgenes for prostate-specific antigen (PSA) and for   a triad of costimulatory molecules (PROSTVAC) in patients with metastatic  castration-resistant prostate cancer. Thirty patients were treated with  escalating ipilimumab and a fixed dose of vaccine. Of 24 chemotherapy-naive  patients, 58 % had a PSA decline. Combination therapy did not exacerbate the  immune-related adverse events associated with ipilimumab. Here, we present  updated survival data and an evaluation of 36 immune cell subsets pre- and  post-therapy. Peripheral blood mononuclear cells were collected before therapy,  at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow  cytometry for the subsets of T cells, regulatory T cells, natural killer cells,  and myeloid-derived suppressor cells. Associations between overall survival (OS)   and immune cell subsets prior to treatment, and the change in a given immune cell  subset 70 days post-initiation of therapy, were evaluated. The median OS was 2.63  years (1.77-3.45). There were trends toward associations for longer OS and  certain immune cell subsets before immunotherapy: lower PD-1(+)Tim-3(NEG)CD4EM (P  = 0.005, adjusted P = 0.010), higher PD-1(NEG)Tim-3(+)CD8 (P = 0.002, adjusted P   = 0.004), and a higher number of CTLA-4(NEG) Tregs (P = 0.005, adjusted P =  0.010). We also found that an increase in Tim-3(+) natural killer cells post-  versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P =  0.015). These results should be considered as hypothesis generating and should be  further evaluated in larger immunotherapy trials.
CANIT0000219	24514956	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus vaccine PROSTVAC	N/A	Immune checkpoint therapy plus Tumor vaccine 	PROSTVAC vaccine (NCIT:C132990); ipilimumab (DB06186); 	24	N/A	A phase I clinical trial	There were trends toward associations for longer OS and higher PD-1(NEG)Tim-3(+)CD8 (P = 0.002, adjusted P = 0.004).	N/A	N/A	N/A	Tim-3 (Q8TDQ0); CD8 (P01732); PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	PD-1(NEG)Tim-3(+)CD8 regulatory T-cell 	Gene expression signature on/in immune cell	 2014 Apr	 A combination trial of vaccine plus ipilimumab in metastatic castration-resistant  prostate cancer patients: immune correlates.	 Cancer Immunol Immunother	 We recently reported the clinical results of a Phase I trial combining ipilimumab  with a vaccine containing transgenes for prostate-specific antigen (PSA) and for   a triad of costimulatory molecules (PROSTVAC) in patients with metastatic  castration-resistant prostate cancer. Thirty patients were treated with  escalating ipilimumab and a fixed dose of vaccine. Of 24 chemotherapy-naive  patients, 58 % had a PSA decline. Combination therapy did not exacerbate the  immune-related adverse events associated with ipilimumab. Here, we present  updated survival data and an evaluation of 36 immune cell subsets pre- and  post-therapy. Peripheral blood mononuclear cells were collected before therapy,  at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow  cytometry for the subsets of T cells, regulatory T cells, natural killer cells,  and myeloid-derived suppressor cells. Associations between overall survival (OS)   and immune cell subsets prior to treatment, and the change in a given immune cell  subset 70 days post-initiation of therapy, were evaluated. The median OS was 2.63  years (1.77-3.45). There were trends toward associations for longer OS and  certain immune cell subsets before immunotherapy: lower PD-1(+)Tim-3(NEG)CD4EM (P  = 0.005, adjusted P = 0.010), higher PD-1(NEG)Tim-3(+)CD8 (P = 0.002, adjusted P   = 0.004), and a higher number of CTLA-4(NEG) Tregs (P = 0.005, adjusted P =  0.010). We also found that an increase in Tim-3(+) natural killer cells post-  versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P =  0.015). These results should be considered as hypothesis generating and should be  further evaluated in larger immunotherapy trials.
CANIT0000220	24514956	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus vaccine PROSTVAC	N/A	Immune checkpoint therapy plus Tumor vaccine 	PROSTVAC vaccine (NCIT:C132990); ipilimumab (DB06186); 	24	N/A	A phase I clinical trial	There were trends toward associations for longer OS and lower PD-1(+)Tim-3(NEG)CD4EM (P = 0.005, adjusted P = 0.010).	N/A	N/A	N/A	Tim-3 (Q8TDQ0); PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	PD-1(+)Tim-3(NEG) Effector memory T helper cells counts	Gene expression signature on/in immune cell	 2014 Apr	 A combination trial of vaccine plus ipilimumab in metastatic castration-resistant  prostate cancer patients: immune correlates.	 Cancer Immunol Immunother	 We recently reported the clinical results of a Phase I trial combining ipilimumab  with a vaccine containing transgenes for prostate-specific antigen (PSA) and for   a triad of costimulatory molecules (PROSTVAC) in patients with metastatic  castration-resistant prostate cancer. Thirty patients were treated with  escalating ipilimumab and a fixed dose of vaccine. Of 24 chemotherapy-naive  patients, 58 % had a PSA decline. Combination therapy did not exacerbate the  immune-related adverse events associated with ipilimumab. Here, we present  updated survival data and an evaluation of 36 immune cell subsets pre- and  post-therapy. Peripheral blood mononuclear cells were collected before therapy,  at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow  cytometry for the subsets of T cells, regulatory T cells, natural killer cells,  and myeloid-derived suppressor cells. Associations between overall survival (OS)   and immune cell subsets prior to treatment, and the change in a given immune cell  subset 70 days post-initiation of therapy, were evaluated. The median OS was 2.63  years (1.77-3.45). There were trends toward associations for longer OS and  certain immune cell subsets before immunotherapy: lower PD-1(+)Tim-3(NEG)CD4EM (P  = 0.005, adjusted P = 0.010), higher PD-1(NEG)Tim-3(+)CD8 (P = 0.002, adjusted P   = 0.004), and a higher number of CTLA-4(NEG) Tregs (P = 0.005, adjusted P =  0.010). We also found that an increase in Tim-3(+) natural killer cells post-  versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P =  0.015). These results should be considered as hypothesis generating and should be  further evaluated in larger immunotherapy trials.
CANIT0000221	24514956	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus vaccine PROSTVAC	N/A	Immune checkpoint therapy plus Tumor vaccine 	PROSTVAC vaccine (NCIT:C132990); ipilimumab (DB06186); 	24	N/A	A phase I clinical trial	We also found that an increase in Tim-3(+) natural killer cells post- versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P = 0.015).	N/A	N/A	N/A	Tim-3 (Q8TDQ0); Natural killer cells (NCIT:C12536); 	Tim-3(+) natural killer cells post- versus pre-vaccination	Gene expression signature on/in immune cell	 2014 Apr	 A combination trial of vaccine plus ipilimumab in metastatic castration-resistant  prostate cancer patients: immune correlates.	 Cancer Immunol Immunother	 We recently reported the clinical results of a Phase I trial combining ipilimumab  with a vaccine containing transgenes for prostate-specific antigen (PSA) and for   a triad of costimulatory molecules (PROSTVAC) in patients with metastatic  castration-resistant prostate cancer. Thirty patients were treated with  escalating ipilimumab and a fixed dose of vaccine. Of 24 chemotherapy-naive  patients, 58 % had a PSA decline. Combination therapy did not exacerbate the  immune-related adverse events associated with ipilimumab. Here, we present  updated survival data and an evaluation of 36 immune cell subsets pre- and  post-therapy. Peripheral blood mononuclear cells were collected before therapy,  at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow  cytometry for the subsets of T cells, regulatory T cells, natural killer cells,  and myeloid-derived suppressor cells. Associations between overall survival (OS)   and immune cell subsets prior to treatment, and the change in a given immune cell  subset 70 days post-initiation of therapy, were evaluated. The median OS was 2.63  years (1.77-3.45). There were trends toward associations for longer OS and  certain immune cell subsets before immunotherapy: lower PD-1(+)Tim-3(NEG)CD4EM (P  = 0.005, adjusted P = 0.010), higher PD-1(NEG)Tim-3(+)CD8 (P = 0.002, adjusted P   = 0.004), and a higher number of CTLA-4(NEG) Tregs (P = 0.005, adjusted P =  0.010). We also found that an increase in Tim-3(+) natural killer cells post-  versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P =  0.015). These results should be considered as hypothesis generating and should be  further evaluated in larger immunotherapy trials.
CANIT0000222	24516200	Basic research	Ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	BCL2 (P10415); 	BCL2; 	GX15	N/A	Immune checkpoint therapy	GX15 (NCIT:C62771); 	Cell lines	N/A	Basic research	When a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus resistant to the cytotoxic effects of the Bcl-2 inhibitor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2014 Mar 15	 Pan-Bcl-2 inhibitor, GX15-070 (obatoclax), decreases human T regulatory  lymphocytes while preserving effector T lymphocytes: a rationale for its use in  combination immunotherapy.	 J Immunol	 Bcl-2 inhibitors are currently being evaluated in clinical studies for treatment   of patients with solid tumors and hematopoietic malignancies. In this study we  explored the potential for combining the pan-Bcl-2 inhibitor GX15-070 (GX15;  obatoclax) with immunotherapeutic modalities. We evaluated the in vitro effects  of GX15 on human T cell subsets obtained from PBMCs in terms of activation,  memory, and suppressive function. Our results indicated that in healthy-donor  PBMCs, mature-activated T cells were more resistant to GX15 than early-activated   T cells, and that GX15 preserved memory but not non-memory T cell populations.  Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs),  profoundly downregulated FOXP3 and CTLA-4 in a dose-dependent manner, and  decreased their suppressive function. Treating PBMCs obtained from ovarian cancer  patients with GX15 also resulted in increased CD8(+):Treg and CD4(+):Treg ratios.  These results support preclinical studies in which mice vaccinated before  treatment with GX15 showed the greatest reduction in metastatic lung tumors as a   result of increased apoptotic resistance of mature CD8(+) T cells and decreased  Treg function brought about by GX15. Taken together, these findings suggest that   when a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as  the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede  administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus  resistant to the cytotoxic effects of the Bcl-2 inhibitor.
CANIT0000223	24554495	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	39	N/A	N/A	Involvement of the pituitary axes is a severe side effect of treatment with ipilimumab with an urgent need for the correct medical intervention.	Six patients developed a severe form of irAEs, including one case of colitis (2 %), one case of sarcoidosis (2 %) and 4 cases (10 %) of hypophysitis. Hypophysitis developed between the second and fourth cycle of ipilimumab administration and was independent of the dose used. We describe four cases of involvement of the pituitary gland during treatment with ipilimumab. When managed with vigilant monitoring and high-dose corticosteroids, the acute symptoms resolve, but lifelong hormone substitution therapy can be necessary. 	N/A	N/A	N/A	N/A	N/A	 2014 Dec	 Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect  illustrated by four case-reports.	 Endocrine	 Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen4  (CTLA-4), an inhibitory molecule typically expressed on T cells. Blockade of  CTLA-4 induces an overall activation of T cells, including an immune-mediated  anti-tumour response. Unfortunately, this broad T cell stimulation also causes  immune-related adverse events (irAEs), such as dermatitis, colitis, hepatitis and  hypophysitis. Ipilimumab is currently available in Belgium as a second line of  treatment for patients with advanced melanoma, and is used at a dose of 3 mg/kg  of body weight, although higher doses were previously used (up to 10 mg/kg). We  performed a retrospective analysis to identify melanoma patients treated with  ipilimumab at the Ghent University Hospital between 2010 and 2013. Data on  symptoms, stage and timing of ipilimumab, response and adverse events were  collected with a special attention to endocrine disturbances, going from a  limited involvement of one endocrine axis to development of a hypophysitis. We  identified a total of 39 patients with stage III (No. = 7) or stage IV (No. = 32)  melanoma, who received a dose of 3 (No. = 31) or 10 (No. = 8) mg/kg. Six patients  developed a severe form of irAEs, including one case of colitis (2 %), one case  of sarcoidosis (2 %) and 4 cases (10 %) of hypophysitis. Hypophysitis developed  between the second and fourth cycle of ipilimumab administration and was  independent of the dose used. We describe four cases of involvement of the  pituitary gland during treatment with ipilimumab. When managed with vigilant  monitoring and high-dose corticosteroids, the acute symptoms resolve, but  lifelong hormone substitution therapy can be necessary. Involvement of the  pituitary axes is a severe side effect of treatment with ipilimumab with an  urgent need for the correct medical intervention.
CANIT0000224	24563870	Case report	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Radiotherapy (NCIT:C15313); ipilimumab (DB06186); 	1	N/A	Case	Abscopal response	N/A	N/A	N/A	N/A	N/A	N/A	 2013 Dec	 An abscopal response to radiation and ipilimumab in a patient with metastatic  non-small cell lung cancer.	 Cancer Immunol Res	 A posteriori evidence suggests that radiotherapy to a targeted tumor can elicit  an immune-mediated abscopal (ab-scopus, away from the target) effect in  non-targeted tumors, when combined with an anti-cytotoxic T-lymphocyte antigen-4   monoclonal (CTLA-4) antibody. Concurrent radiotherapy and ipilimumab (a human  monoclonal anti-CTLA-4 antibody) induced immune-mediated abscopal effects in  poorly immunogenic pre-clinical tumor models and metastatic melanoma patients.  However, no such reports exist for patients with metastatic lung adenocarcinoma.   We report the first abscopal response in a treatment-refractory lung cancer  patient treated with radiotherapy and ipilimumab. A post-treatment increase in  tumor-infiltrating cytotoxic lymphocytes, tumor regression, and normalization of   tumor markers was observed. One year after treatment with concurrent radiotherapy  and ipilimumab the patient is without evidence of disease.
CANIT0000225	24577748	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); BRAF (P15056); 	CTLA-4; BRAF	Ipilimumab followed by dabrafenib or vemurafenib	N/A	Immune checkpoint therapy plus Target therapy	Poly-ICLC (NCIT:C1198); Montanide ISA 51 VG (NCIT:C84843); OLP (NCIT:C90918); 	28	N/A	A phase I clinical trial 	NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.	The vaccine was generally well tolerated with injection site reactions and fatigue that resolved.	N/A	N/A	N/A	N/A	N/A	 2012 Dec 1	 Phase I trial of overlapping long peptides from a tumor self-antigen and  poly-ICLC shows rapid induction of integrated immune response in ovarian cancer  patients.	 Clin Cancer Res	 PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T  cells after intracellular processing by antigen-presenting cells. To investigate   the safety and in vivo immunogenicity of synthetic overlapping long peptides  (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with  OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.  EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second  or third remission were enrolled sequentially in three cohorts and received at  least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2  (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP +  1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and  cellular responses were evaluated by standardized immunomonitoring techniques  (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).  RESULTS: The vaccine was generally well tolerated with injection site reactions  and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were  undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%)  and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide,  and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after  vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were  detected in all patients with greater frequency and polyclonality when  Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant   further accelerated the induction of NY-ESO-1-specific immune responses.  CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.CI  - (c)2012 AACR.
CANIT0000226	24577748	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); BRAF (P15056); 	IL2R; BRAF	IL2 followed by dabrafenib or vemurafenib	N/A	Immune cytokine plus Target therapy	Poly-ICLC (NCIT:C1198); Montanide ISA 51 VG (NCIT:C84843); OLP (NCIT:C90918); 	28	N/A	A phase I clinical trial 	NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.	The vaccine was generally well tolerated with injection site reactions and fatigue that resolved.	N/A	N/A	N/A	N/A	N/A	 2012 Dec 1	 Phase I trial of overlapping long peptides from a tumor self-antigen and  poly-ICLC shows rapid induction of integrated immune response in ovarian cancer  patients.	 Clin Cancer Res	 PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T  cells after intracellular processing by antigen-presenting cells. To investigate   the safety and in vivo immunogenicity of synthetic overlapping long peptides  (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with  OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.  EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second  or third remission were enrolled sequentially in three cohorts and received at  least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2  (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP +  1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and  cellular responses were evaluated by standardized immunomonitoring techniques  (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).  RESULTS: The vaccine was generally well tolerated with injection site reactions  and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were  undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%)  and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide,  and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after  vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were  detected in all patients with greater frequency and polyclonality when  Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant   further accelerated the induction of NY-ESO-1-specific immune responses.  CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.CI  - (c)2012 AACR.
CANIT0000227	24577748	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); 	PD-1; BRAF	CT-011 followed by dabrafenib or vemurafenib	N/A	Immune checkpoint therapy followed by Target therapy	Poly-ICLC (NCIT:C1198); Montanide ISA 51 VG (NCIT:C84843); OLP (NCIT:C90918); 	28	N/A	A phase I clinical trial 	NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.	The vaccine was generally well tolerated with injection site reactions and fatigue that resolved.	N/A	N/A	N/A	N/A	N/A	 2012 Dec 1	 Phase I trial of overlapping long peptides from a tumor self-antigen and  poly-ICLC shows rapid induction of integrated immune response in ovarian cancer  patients.	 Clin Cancer Res	 PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T  cells after intracellular processing by antigen-presenting cells. To investigate   the safety and in vivo immunogenicity of synthetic overlapping long peptides  (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with  OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.  EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second  or third remission were enrolled sequentially in three cohorts and received at  least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2  (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP +  1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and  cellular responses were evaluated by standardized immunomonitoring techniques  (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).  RESULTS: The vaccine was generally well tolerated with injection site reactions  and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were  undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%)  and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide,  and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after  vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were  detected in all patients with greater frequency and polyclonality when  Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant   further accelerated the induction of NY-ESO-1-specific immune responses.  CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.CI  - (c)2012 AACR.
CANIT0000228	24577748	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); 	PD-1; BRAF	MK-3475 followed by dabrafenib or vemurafenib	N/A	Immune checkpoint therapy followed by Target therapy	Poly-ICLC (NCIT:C1198); Montanide ISA 51 VG (NCIT:C84843); OLP (NCIT:C90918); 	28	N/A	A phase I clinical trial 	NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.	The vaccine was generally well tolerated with injection site reactions and fatigue that resolved.	N/A	N/A	N/A	N/A	N/A	 2012 Dec 1	 Phase I trial of overlapping long peptides from a tumor self-antigen and  poly-ICLC shows rapid induction of integrated immune response in ovarian cancer  patients.	 Clin Cancer Res	 PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T  cells after intracellular processing by antigen-presenting cells. To investigate   the safety and in vivo immunogenicity of synthetic overlapping long peptides  (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with  OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.  EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second  or third remission were enrolled sequentially in three cohorts and received at  least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2  (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP +  1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and  cellular responses were evaluated by standardized immunomonitoring techniques  (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).  RESULTS: The vaccine was generally well tolerated with injection site reactions  and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were  undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%)  and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide,  and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after  vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were  detected in all patients with greater frequency and polyclonality when  Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant   further accelerated the induction of NY-ESO-1-specific immune responses.  CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.CI  - (c)2012 AACR.
CANIT0000229	24577748	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); 	PD-1; BRAF	Nivolumab followed by dabrafenib or vemurafenib	N/A	Immune checkpoint therapy followed by Target therapy	Poly-ICLC (NCIT:C1198); Montanide ISA 51 VG (NCIT:C84843); OLP (NCIT:C90918); 	28	N/A	A phase I clinical trial 	NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.	The vaccine was generally well tolerated with injection site reactions and fatigue that resolved.	N/A	N/A	N/A	N/A	N/A	 2012 Dec 1	 Phase I trial of overlapping long peptides from a tumor self-antigen and  poly-ICLC shows rapid induction of integrated immune response in ovarian cancer  patients.	 Clin Cancer Res	 PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T  cells after intracellular processing by antigen-presenting cells. To investigate   the safety and in vivo immunogenicity of synthetic overlapping long peptides  (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with  OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.  EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second  or third remission were enrolled sequentially in three cohorts and received at  least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2  (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP +  1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and  cellular responses were evaluated by standardized immunomonitoring techniques  (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).  RESULTS: The vaccine was generally well tolerated with injection site reactions  and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were  undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%)  and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide,  and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after  vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were  detected in all patients with greater frequency and polyclonality when  Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant   further accelerated the induction of NY-ESO-1-specific immune responses.  CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.CI  - (c)2012 AACR.
CANIT0000230	24577748	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); BRAF (P15056); 	PD-L1; BRAF	Atezolizumab followed by dabrafenib or vemurafenib	N/A	Immune checkpoint therapy followed by Target therapy	Atezolizumab (DB11595); 	28	N/A	A phase I clinical trial 	NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.	The vaccine was generally well tolerated with injection site reactions and fatigue that resolved.	N/A	N/A	N/A	N/A	N/A	 2012 Dec 1	 Phase I trial of overlapping long peptides from a tumor self-antigen and  poly-ICLC shows rapid induction of integrated immune response in ovarian cancer  patients.	 Clin Cancer Res	 PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T  cells after intracellular processing by antigen-presenting cells. To investigate   the safety and in vivo immunogenicity of synthetic overlapping long peptides  (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with  OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations.  EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second  or third remission were enrolled sequentially in three cohorts and received at  least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2  (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP +  1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and  cellular responses were evaluated by standardized immunomonitoring techniques  (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining).  RESULTS: The vaccine was generally well tolerated with injection site reactions  and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were  undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%)  and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide,  and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after  vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were  detected in all patients with greater frequency and polyclonality when  Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant   further accelerated the induction of NY-ESO-1-specific immune responses.  CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and  rapidly induces consistent integrated immune responses (antibody, CD8(+) and  CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.CI  - (c)2012 AACR.
CANIT0000231	24577748	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	T-cell therapy (); BRAF (P15056); 	T-cell therapy; BRAF	T-cell therapy followed by dabrafenib or vemurafenib	Dabrafenib or vemurafenib followed by immunotherapy	Cell immunotherapy followed by Target therapy	Vemurafenib (DB08881); dabrafenib (DB08912); adoptive T-cell therapy (NCIT:C15351); Atezolizumab (DB11595); CT-011 (DB05916); pembrolizumab (DB09037); nivolumab (DB09035); ipilimumab (DB06186); IL2 (NCIT:C24498); 	32	242	A retrospective cohort study	In this retrospective analysis, prior treatment with IT does not appear to negatively influence response to BRAFi. Outcomes for IT with ipilimumab following BRAFi discontinuation are poor. Randomized controlled trials are needed to define if sequencing IT prior to BRAFi therapy is superior to sequencing BRAFi prior to IT.	N/A	N/A	N/A	N/A	N/A	N/A	 2014 Jun 1	 Outcomes of patients with metastatic melanoma treated with immunotherapy prior to  or after BRAF inhibitors.	 Cancer	 BACKGROUND: The immunotherapy (IT) agents ipilimumab and interleukin-2 as well as  BRAF inhibitors (BRAFi) vemurafenib and dabrafenib, with or without trametinib  (MEK inhibitors), are all FDA-approved treatments for BRAF metastatic melanoma,  but there are few studies to guide optimal sequencing. This retrospective  analysis describes the outcomes of patients treated with either BRAFi before IT  or IT before BRAFi. METHODS: A cohort of patients treated with BRAFi alone or  with MEK inhibitor was retrospectively identified. Response rate (RR), overall  survival (OS), and progression-free survival (PFS) were evaluated for the entire   cohort, subdivided by BRAFi prior to or after IT. RESULTS: RR and median PFS and   OS calculated from commencement of BRAFi following IT (N = 32) were 57%, 6.7  months (95% confidence interval [CI] = 4.3-9.1 months), and 19.6 months (95% CI =  10.0-undefined months), respectively; whereas for BRAFi initially (N = 242) were   66%, 5.6 months (95% CI = 4.7-6.8 months), and 13.4 months (95% CI = 10.1-17.0  months). Results were similar when controlled for prognostic variables. A total  of 193 patients discontinued BRAFi, with OS of 2.9 months (range of 1.8-4.4  months) from day of BRAFi discontinuation. Forty patients subsequently received  IT with ipilimumab. Only half could complete 4 doses of ipilimumab; PFS with  ipilimumab was 2.7 months (95% CI = 1.8-3.1 months) and OS was 5.0 months (95% CI  = 3.0-8.8 months). CONCLUSIONS: In this retrospective analysis, prior treatment  with IT does not appear to negatively influence response to BRAFi. Outcomes for  IT with ipilimumab following BRAFi discontinuation are poor. Randomized  controlled trials are needed to define if sequencing IT prior to BRAFi therapy is  superior to sequencing BRAFi prior to IT.CI  - (c) 2014 American Cancer Society.
CANIT0000232	24598453	Case report	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	1	N/A	Case	Near-complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2014 Apr	 Regression of metastatic clear cell kidney cancer with interleukin-2 treatment  following nivolumab (anti-PD-1) treatment.	 J Immunother	 Aldesleukin [interleukin-2 (IL-2)] induces durable complete responses in some  kidney cancer and melanoma patients. Nivolumab is an investigational antibody  drug targeting programmed death-1 (PD-1) as a treatment, demonstrating activity  in multiple cancer types. An expanding complement of immunotherapeutics raises  important issues regarding the best way to use them. There are issues beyond  identifying an agent that provides the superior front-line response: when does  one therapy potentiate another immune therapy  When is the capacity of immune  response exhausted and an approach without immune mechanism the better therapy   In this case report, we present a patient with metastatic renal cell carcinoma  with no tumor regression evident on a PD-1 blockade (given on an investigational   trial), who then achieved near-complete response to bolus high-dose IL-2 therapy,  maintaining a persistent response off therapy. This case emphasizes on the need  to develop improved predictors of response to immune therapies, especially as  they can be applied to optimize sequential immunotherapeutic modalities versus  predict when to turn to alternative targeted agents in renal cell carcinoma, and   is an example of efficacious IL-2 application as a second-line treatment.
CANIT0000233	24616309	Clinical research	Rapidly progressive melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	N/A	N/A	Spiking fevers, neuropathy, and other immune-related toxicity	N/A	N/A	N/A	N/A	N/A	 2015 Feb 20	 Antitumor granuloma formation by CD4+ T cells in a patient with rapidly  progressive melanoma experiencing spiking fevers, neuropathy, and other  immune-related toxicity after treatment with ipilimumab.	 J Clin Oncol	Unable to provide
CANIT0000234	24633336	Clinical research	Pancreatic adenocarcinoma	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	HTERT (O94807); 	HTERT; 	HTERT peptides vaccine	N/A	Tumor vaccine	Peptides of (MAGEA1; MAGEA3; WT1; P53; hTERT; VEGFR2)vaccine (NCIT:C39619); 	41	N/A	N/A	The frequency of lymphocyte subsets correlated well with  TAA-specific immune response. Overall survival was significantly longer in  patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1,  and VEGFR2 were shown to be attractive targets for immunotherapy in patients with  pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the  prognosis of these patients.	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	Tumor-associated antigens-specific cytotoxic T lymphocytes 	Gene expression signature on/in immune cell	 2014 May	 P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine  therapy in HLA-A24 positive pancreatic adenocarcinoma.	 Cancer Immunol Immunother	 Cancer vaccine therapy is one of the most attractive therapies as a new treatment  procedure for pancreatic adenocarcinoma. Recent technical advances have enabled  the identification of cytotoxic T lymphocyte (CTL) epitopes in various  tumor-associated antigens (TAAs). However, little is known about which TAA and  its epitope are the most immunogenic and useful for a cancer vaccine for  pancreatic adenocarcinoma. We examined the expression of 17 kinds of TAA in 9  pancreatic cancer cell lines and 12 pancreatic cancer tissues. CTL responses to  23 epitopes derived from these TAAs were analyzed using enzyme-linked immunospot   (ELISPOT), CTL, and tetramer assays in 41 patients, and factors affecting the  immune responses were investigated. All TAAs were frequently expressed in  pancreatic adenocarcinoma cells, except for adenocarcinoma antigens recognized by  T cells 1, melanoma-associated antigen (MAGE)-A1, and MAGE-A3. Among the epitopes  recognized by CTLs in more than two patients in the ELISPOT assay, 6 epitopes  derived from 5 TAAs, namely, MAGE-A3, p53, human telomerase reverse transcriptase  (hTERT), Wilms tumor (WT)-1, and vascular endothelial growth factor receptor  (VEGFR)2, could induce specific CTLs that showed cytotoxicity against pancreatic   cancer cell lines. The frequency of lymphocyte subsets correlated well with  TAA-specific immune response. Overall survival was significantly longer in  patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1,  and VEGFR2 were shown to be attractive targets for immunotherapy in patients with  pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the  prognosis of these patients.
CANIT0000235	24633336	Clinical research	Pancreatic adenocarcinoma	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	P53 (P04637); 	P53; 	P53 peptides vaccine	N/A	Tumor vaccine	Peptides of (MAGEA1; MAGEA3; WT1; P53; hTERT; VEGFR2)vaccine (NCIT:C39619); 	41	N/A	N/A	The frequency of lymphocyte subsets correlated well with  TAA-specific immune response. Overall survival was significantly longer in  patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1,  and VEGFR2 were shown to be attractive targets for immunotherapy in patients with  pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the  prognosis of these patients.	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	Tumor-associated antigens-specific cytotoxic T lymphocytes 	Gene expression signature on/in immune cell	 2014 May	 P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine  therapy in HLA-A24 positive pancreatic adenocarcinoma.	 Cancer Immunol Immunother	 Cancer vaccine therapy is one of the most attractive therapies as a new treatment  procedure for pancreatic adenocarcinoma. Recent technical advances have enabled  the identification of cytotoxic T lymphocyte (CTL) epitopes in various  tumor-associated antigens (TAAs). However, little is known about which TAA and  its epitope are the most immunogenic and useful for a cancer vaccine for  pancreatic adenocarcinoma. We examined the expression of 17 kinds of TAA in 9  pancreatic cancer cell lines and 12 pancreatic cancer tissues. CTL responses to  23 epitopes derived from these TAAs were analyzed using enzyme-linked immunospot   (ELISPOT), CTL, and tetramer assays in 41 patients, and factors affecting the  immune responses were investigated. All TAAs were frequently expressed in  pancreatic adenocarcinoma cells, except for adenocarcinoma antigens recognized by  T cells 1, melanoma-associated antigen (MAGE)-A1, and MAGE-A3. Among the epitopes  recognized by CTLs in more than two patients in the ELISPOT assay, 6 epitopes  derived from 5 TAAs, namely, MAGE-A3, p53, human telomerase reverse transcriptase  (hTERT), Wilms tumor (WT)-1, and vascular endothelial growth factor receptor  (VEGFR)2, could induce specific CTLs that showed cytotoxicity against pancreatic   cancer cell lines. The frequency of lymphocyte subsets correlated well with  TAA-specific immune response. Overall survival was significantly longer in  patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1,  and VEGFR2 were shown to be attractive targets for immunotherapy in patients with  pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the  prognosis of these patients.
CANIT0000236	24633336	Clinical research	Pancreatic adenocarcinoma	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	VEGFR2 (P35968); 	VEGFR2; 	VEGFR2 peptides vaccine	N/A	Tumor vaccine	Peptides of (MAGEA1; MAGEA3; WT1; P53; hTERT; VEGFR2)vaccine (NCIT:C39619); 	41	N/A	N/A	The frequency of lymphocyte subsets correlated well with  TAA-specific immune response. Overall survival was significantly longer in  patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1,  and VEGFR2 were shown to be attractive targets for immunotherapy in patients with  pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the  prognosis of these patients.	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	Tumor-associated antigens-specific cytotoxic T lymphocytes 	Gene expression signature on/in immune cell	 2014 May	 P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine  therapy in HLA-A24 positive pancreatic adenocarcinoma.	 Cancer Immunol Immunother	 Cancer vaccine therapy is one of the most attractive therapies as a new treatment  procedure for pancreatic adenocarcinoma. Recent technical advances have enabled  the identification of cytotoxic T lymphocyte (CTL) epitopes in various  tumor-associated antigens (TAAs). However, little is known about which TAA and  its epitope are the most immunogenic and useful for a cancer vaccine for  pancreatic adenocarcinoma. We examined the expression of 17 kinds of TAA in 9  pancreatic cancer cell lines and 12 pancreatic cancer tissues. CTL responses to  23 epitopes derived from these TAAs were analyzed using enzyme-linked immunospot   (ELISPOT), CTL, and tetramer assays in 41 patients, and factors affecting the  immune responses were investigated. All TAAs were frequently expressed in  pancreatic adenocarcinoma cells, except for adenocarcinoma antigens recognized by  T cells 1, melanoma-associated antigen (MAGE)-A1, and MAGE-A3. Among the epitopes  recognized by CTLs in more than two patients in the ELISPOT assay, 6 epitopes  derived from 5 TAAs, namely, MAGE-A3, p53, human telomerase reverse transcriptase  (hTERT), Wilms tumor (WT)-1, and vascular endothelial growth factor receptor  (VEGFR)2, could induce specific CTLs that showed cytotoxicity against pancreatic   cancer cell lines. The frequency of lymphocyte subsets correlated well with  TAA-specific immune response. Overall survival was significantly longer in  patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1,  and VEGFR2 were shown to be attractive targets for immunotherapy in patients with  pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the  prognosis of these patients.
CANIT0000237	24633336	Clinical research	Pancreatic adenocarcinoma	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	WT1 (P19544); 	WT1; 	WT1 peptide cancer vaccine	N/A	Tumor vaccine	Peptides of (MAGEA1; MAGEA3; WT1; P53; hTERT; VEGFR2)vaccine (NCIT:C39619); 	41	N/A	N/A	The frequency of lymphocyte subsets correlated well with  TAA-specific immune response. Overall survival was significantly longer in  patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1,  and VEGFR2 were shown to be attractive targets for immunotherapy in patients with  pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the  prognosis of these patients.	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	Tumor-associated antigens-specific cytotoxic T lymphocytes 	Gene expression signature on/in immune cell	 2014 May	 P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine  therapy in HLA-A24 positive pancreatic adenocarcinoma.	 Cancer Immunol Immunother	 Cancer vaccine therapy is one of the most attractive therapies as a new treatment  procedure for pancreatic adenocarcinoma. Recent technical advances have enabled  the identification of cytotoxic T lymphocyte (CTL) epitopes in various  tumor-associated antigens (TAAs). However, little is known about which TAA and  its epitope are the most immunogenic and useful for a cancer vaccine for  pancreatic adenocarcinoma. We examined the expression of 17 kinds of TAA in 9  pancreatic cancer cell lines and 12 pancreatic cancer tissues. CTL responses to  23 epitopes derived from these TAAs were analyzed using enzyme-linked immunospot   (ELISPOT), CTL, and tetramer assays in 41 patients, and factors affecting the  immune responses were investigated. All TAAs were frequently expressed in  pancreatic adenocarcinoma cells, except for adenocarcinoma antigens recognized by  T cells 1, melanoma-associated antigen (MAGE)-A1, and MAGE-A3. Among the epitopes  recognized by CTLs in more than two patients in the ELISPOT assay, 6 epitopes  derived from 5 TAAs, namely, MAGE-A3, p53, human telomerase reverse transcriptase  (hTERT), Wilms tumor (WT)-1, and vascular endothelial growth factor receptor  (VEGFR)2, could induce specific CTLs that showed cytotoxicity against pancreatic   cancer cell lines. The frequency of lymphocyte subsets correlated well with  TAA-specific immune response. Overall survival was significantly longer in  patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1,  and VEGFR2 were shown to be attractive targets for immunotherapy in patients with  pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the  prognosis of these patients.
CANIT0000238	24651165	Case report	Stage IIIc melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Infliximab is a life-saving intervention in patients with ipilimumab-induced diarrhea.	Diarrhea	N/A	N/A	N/A	N/A	N/A	 2014 Jun	 Early administration of infliximab for severe ipilimumab-related diarrhea in a  critically ill patient.	 Ann Pharmacother	 OBJECTIVE: To report a case of ipilimumab-associated life-threatening diarrhea  responding quickly to a single dose of infliximab. CASE SUMMARY: A 67-year-old  man presented 3 weeks after his second dose of ipilimumab with severe diarrhea,  acute kidney injury, and hypotension. After 2 days of high-dose corticosteroids  and supportive care, he continued to have 2.8 L of stool output per day (grade 4   National Cancer Institute Common Terminology Criteria for Adverse Events). The  patient was transferred to the medical intensive care unit requiring endotracheal  intubation because of concerns of worsening mental status, metabolic acidosis,  and increased work of breathing, with a serum bicarbonate concentration of <5  mmol/L. Despite aggressive fluid resuscitation and a sodium bicarbonate infusion,  he remained hypotensive and hyponatremic with persistent premature ventricular  contractions. On the evening of day 3, infliximab (5 mg/kg) was given, resulting   in a rapid decrease in diarrhea. After 48 hours, the acidosis was corrected and  electrolytes, renal function, and fluid status were improving. At discharge,  diarrhea, acute kidney injury, and acidosis had resolved, and he was discharged  on a slow steroid taper. DISCUSSION: Autoimmune colitis is a described  immune-related adverse event of ipilimumab. Prompt recognition, initiation of  steroids, and supportive therapy are key to the management of diarrhea.  Infliximab should be considered early in steroid-nonresponsive or  life-threatening diarrhea. CONCLUSION: Infliximab is a life-saving intervention  in patients with ipilimumab-induced diarrhea.
CANIT0000239	24676901	Basic research	B16 melanomas	Melanoma	EFO:0000756	Skin	HMGB1 (P09429); 	HMGB1; 	LTX-315	N/A	Tumor vaccine	LTX-315 (DB12748); 	Cell lines/ animal models	N/A	Basic research	Intratumoral treatment with LTX-315 can provide local tumor control followed by protective immune responses and has potential as a new immunotherapeutic agent.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2014 Jun	 Complete regression and systemic protective immune responses obtained in B16  melanomas after treatment with LTX-315.	 Cancer Immunol Immunother	 Malignant melanoma is the most aggressive and deadliest form of skin cancer due  to its highly metastatic potential, which calls for new and improved therapies.  Cationic antimicrobial peptides (CAPs) are naturally occurring molecules found in  most species, in which they play a significant role in the first line of defense   against pathogens, and several CAPs have shown promising potential as novel  anticancer agents. Structure-activity relationship studies on the CAP bovine  lactoferricin allowed us to de novo design short chemically modified lytic  anticancer peptides. In the present study, we investigated the in vivo antitumor   effects of LTX-315 against intradermally established B16 melanomas in syngeneic  mice. Intratumoral administration of LTX-315 resulted in tumor necrosis and the  infiltration of immune cells into the tumor parenchyma followed by complete  regression of the tumor in the majority of the animals. LTX-315 induced the  release of danger-associated molecular pattern molecules such as the high  mobility group box-1 protein in vitro and the subsequent upregulation of  proinflammatory cytokines such as interleukin (IL) 1beta, IL6 and IL18 in vivo.  Animals cured by LTX-315 treatment were protected against a re-challenge with  live B16 tumor cells both intradermally and intravenously. Together, our data  indicate that intratumoral treatment with LTX-315 can provide local tumor control  followed by protective immune responses and has potential as a new  immunotherapeutic agent.
CANIT0000240	24687600	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	2	N/A	Case	Autoimmune symptoms have to be carefully checked for patients treated with CTLA-4 inhibitors. In order to reduce the risk of sequelae, early recognition of immune-related adverse events (irAEs) and treatment initiation are crucial.	Kidney injuries	N/A	N/A	N/A	N/A	N/A	 2014 Aug	 Kidney injuries related to ipilimumab.	 Invest New Drugs	 Monoclonal antibodies directed against the immune checkpoint protein cytotoxic  T-lymphocyte antigen-4 (CTLA-4; CD152) have been investigated in metastatic  melanoma and other cancers and have shown promising results. Inhibition of CTLA-4  characteristically induces well-known side effects called immune-related adverse  events (irAEs). IrAEs mainly include colitis, dermatitis, hepatitis,  endocrinopathies; uveitis, iridocyclitis, neuropathies, and inflammatory myopathy  have occasionally been reported. Kidney involvement is rare. We report 2 cases of  acute granulomatous interstitial nephritis and present, based on literature  review, renal disorders related to Ipilimumab therapy. Autoimmune symptoms have  to be carefully checked for patients treated with CTLA-4 inhibitors. In order to   reduce the risk of sequelae, early recognition of irAEs and treatment initiation   are crucial.
CANIT0000241	24695685	Clinical research	Patients with melanoma or prostate cancer	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	20	N/A	N/A	The study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab, and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2014 Apr 2	 Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration   of CTLA-4 blocking antibody.	 Sci Transl Med	 Hypophysitis is a chronic inflammation of the pituitary gland of unknown (primary  forms) or recognizable (secondary forms) etiology, such as the use of ipilimumab   in cancer immunotherapy. Ipilimumab, which blocks the T cell inhibitory molecule   CTLA-4 (cytotoxic T lymphocyte antigen-4), induces hypophysitis in about 4% of  patients through unknown mechanisms. We first established a model of secondary  hypophysitis by repeated injections of a CTLA-4 blocking antibody into SJL/J or  C57BL/6J mice, and showed that they developed lymphocytic infiltration of the  pituitary gland and circulating pituitary antibodies. We next assessed the  prevalence of pituitary antibodies in a cohort of 20 patients with advanced  melanoma or prostate cancer, 7 with a clinical diagnosis of hypophysitis, before   and after ipilimumab administration. Pituitary antibodies, negative at baseline,   developed in the 7 patients with hypophysitis but not in the 13 without it; these  antibodies predominantly recognized thyrotropin-, follicle-stimulating hormone-,   and corticotropin-secreting cells. We then hypothesized that the injected CTLA-4   antibody could cause pituitary toxicity if bound to CTLA-4 antigen expressed  ectopically on pituitary endocrine cells. Pituitary glands indeed expressed  CTLA-4 at both RNA and protein levels, particularly in a subset of prolactin- and  thyrotropin-secreting cells. Notably, these cells became the site of complement  activation, featuring deposition of C3d and C4d components and an inflammatory  cascade akin to that seen in type II hypersensitivity. In summary, the study  offers a mechanism to explain the pituitary toxicity observed in patients  receiving ipilimumab, and highlights the utility of measuring pituitary  antibodies in this form of secondary hypophysitis.
CANIT0000242	24695685	Clinical research	Patients with melanoma or prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	20	N/A	N/A	The study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab, and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2014 Apr 2	 Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration   of CTLA-4 blocking antibody.	 Sci Transl Med	 Hypophysitis is a chronic inflammation of the pituitary gland of unknown (primary  forms) or recognizable (secondary forms) etiology, such as the use of ipilimumab   in cancer immunotherapy. Ipilimumab, which blocks the T cell inhibitory molecule   CTLA-4 (cytotoxic T lymphocyte antigen-4), induces hypophysitis in about 4% of  patients through unknown mechanisms. We first established a model of secondary  hypophysitis by repeated injections of a CTLA-4 blocking antibody into SJL/J or  C57BL/6J mice, and showed that they developed lymphocytic infiltration of the  pituitary gland and circulating pituitary antibodies. We next assessed the  prevalence of pituitary antibodies in a cohort of 20 patients with advanced  melanoma or prostate cancer, 7 with a clinical diagnosis of hypophysitis, before   and after ipilimumab administration. Pituitary antibodies, negative at baseline,   developed in the 7 patients with hypophysitis but not in the 13 without it; these  antibodies predominantly recognized thyrotropin-, follicle-stimulating hormone-,   and corticotropin-secreting cells. We then hypothesized that the injected CTLA-4   antibody could cause pituitary toxicity if bound to CTLA-4 antigen expressed  ectopically on pituitary endocrine cells. Pituitary glands indeed expressed  CTLA-4 at both RNA and protein levels, particularly in a subset of prolactin- and  thyrotropin-secreting cells. Notably, these cells became the site of complement  activation, featuring deposition of C3d and C4d components and an inflammatory  cascade akin to that seen in type II hypersensitivity. In summary, the study  offers a mechanism to explain the pituitary toxicity observed in patients  receiving ipilimumab, and highlights the utility of measuring pituitary  antibodies in this form of secondary hypophysitis.
CANIT0000243	24695951	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	95	N/A	N/A	Ipilimumab is a feasible treatment option for heavily pretreated patients with metastatic melanoma. Both disease control and survival were significantly associated with decreasing levels of C-reactive protein between baseline and the end of dosing (Week 12).	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2014 Jul	 Immunological and biological changes during ipilimumab treatment and their  potential correlation with clinical response and survival in patients with  advanced melanoma.	 Cancer Immunol Immunother	 BACKGROUND: Ipilimumab can induce durable disease control and long-term survival   in patients with metastatic melanoma. Identification of a biomarker that  correlates with clinical benefit and potentially provides an early marker of  response is an active area of research. PATIENTS AND METHODS: Ipilimumab was  available upon physician request for patients aged >/=16 years with stage III  (unresectable) or IV cutaneous, ocular or mucosal melanoma, who had failed or did  not tolerate previous treatments and had no other therapeutic option available.  Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Tumour  assessments were conducted at baseline, Week 12 and Week 24 using immune-related   response criteria. Patients were monitored continuously for adverse events (AEs),  including immune-related AEs. Candidate immunological markers were evaluated in  peripheral blood and sera samples collected at baseline and Weeks 4, 7, 10 and  12. RESULTS: Among 95 patients treated with ipilimumab 3 mg/kg, the  immune-related disease control rate at Week 24 was 38 %. With a median follow-up   of 24 months, median overall survival was 9.6 months. Both disease control and  survival were significantly associated with decreasing levels of lactate  dehydrogenase, C-reactive protein and FoxP3/regulatory T cells, and increasing  absolute lymphocyte count, between baseline and the end of dosing (Week 12).  CONCLUSION: Ipilimumab is a feasible treatment option for heavily pretreated  patients with metastatic melanoma. Changes in some immunological markers between   baseline and the fourth ipilimumab infusion appear to be associated with disease   control and survival, but verification in prospective clinical trials is  required.
CANIT0000244	24695951	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	95	N/A	N/A	Ipilimumab is a feasible treatment option for heavily pretreated patients with metastatic melanoma. Both disease control and survival were significantly associated with decreasing levels of FoxP3/regulatory T cells between baseline and the end of dosing (Week 12).	N/A	N/A	N/A	Treg cells (CL:0000815); FOXP3 (Q9BZS1); T-Lymphocyte (NCIT:C12476); 	FoxP3/regulatory T-cell counts	Cell percentage/counts in blood	 2014 Jul	 Immunological and biological changes during ipilimumab treatment and their  potential correlation with clinical response and survival in patients with  advanced melanoma.	 Cancer Immunol Immunother	 BACKGROUND: Ipilimumab can induce durable disease control and long-term survival   in patients with metastatic melanoma. Identification of a biomarker that  correlates with clinical benefit and potentially provides an early marker of  response is an active area of research. PATIENTS AND METHODS: Ipilimumab was  available upon physician request for patients aged >/=16 years with stage III  (unresectable) or IV cutaneous, ocular or mucosal melanoma, who had failed or did  not tolerate previous treatments and had no other therapeutic option available.  Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Tumour  assessments were conducted at baseline, Week 12 and Week 24 using immune-related   response criteria. Patients were monitored continuously for adverse events (AEs),  including immune-related AEs. Candidate immunological markers were evaluated in  peripheral blood and sera samples collected at baseline and Weeks 4, 7, 10 and  12. RESULTS: Among 95 patients treated with ipilimumab 3 mg/kg, the  immune-related disease control rate at Week 24 was 38 %. With a median follow-up   of 24 months, median overall survival was 9.6 months. Both disease control and  survival were significantly associated with decreasing levels of lactate  dehydrogenase, C-reactive protein and FoxP3/regulatory T cells, and increasing  absolute lymphocyte count, between baseline and the end of dosing (Week 12).  CONCLUSION: Ipilimumab is a feasible treatment option for heavily pretreated  patients with metastatic melanoma. Changes in some immunological markers between   baseline and the fourth ipilimumab infusion appear to be associated with disease   control and survival, but verification in prospective clinical trials is  required.
CANIT0000245	24695951	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	95	N/A	N/A	Ipilimumab is a feasible treatment option for heavily pretreated patients with metastatic melanoma. Both disease control and survival were significantly associated with decreasing levels of lactate dehydrogenase between baseline and the end of dosing (Week 12).	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2014 Jul	 Immunological and biological changes during ipilimumab treatment and their  potential correlation with clinical response and survival in patients with  advanced melanoma.	 Cancer Immunol Immunother	 BACKGROUND: Ipilimumab can induce durable disease control and long-term survival   in patients with metastatic melanoma. Identification of a biomarker that  correlates with clinical benefit and potentially provides an early marker of  response is an active area of research. PATIENTS AND METHODS: Ipilimumab was  available upon physician request for patients aged >/=16 years with stage III  (unresectable) or IV cutaneous, ocular or mucosal melanoma, who had failed or did  not tolerate previous treatments and had no other therapeutic option available.  Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Tumour  assessments were conducted at baseline, Week 12 and Week 24 using immune-related   response criteria. Patients were monitored continuously for adverse events (AEs),  including immune-related AEs. Candidate immunological markers were evaluated in  peripheral blood and sera samples collected at baseline and Weeks 4, 7, 10 and  12. RESULTS: Among 95 patients treated with ipilimumab 3 mg/kg, the  immune-related disease control rate at Week 24 was 38 %. With a median follow-up   of 24 months, median overall survival was 9.6 months. Both disease control and  survival were significantly associated with decreasing levels of lactate  dehydrogenase, C-reactive protein and FoxP3/regulatory T cells, and increasing  absolute lymphocyte count, between baseline and the end of dosing (Week 12).  CONCLUSION: Ipilimumab is a feasible treatment option for heavily pretreated  patients with metastatic melanoma. Changes in some immunological markers between   baseline and the fourth ipilimumab infusion appear to be associated with disease   control and survival, but verification in prospective clinical trials is  required.
CANIT0000246	24695951	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	95	N/A	N/A	Ipilimumab is a feasible treatment option for heavily pretreated patients with metastatic melanoma. Both disease control and survival were significantly associated with increasing absolute lymphocyte count between baseline and the end of dosing (Week 12).	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2014 Jul	 Immunological and biological changes during ipilimumab treatment and their  potential correlation with clinical response and survival in patients with  advanced melanoma.	 Cancer Immunol Immunother	 BACKGROUND: Ipilimumab can induce durable disease control and long-term survival   in patients with metastatic melanoma. Identification of a biomarker that  correlates with clinical benefit and potentially provides an early marker of  response is an active area of research. PATIENTS AND METHODS: Ipilimumab was  available upon physician request for patients aged >/=16 years with stage III  (unresectable) or IV cutaneous, ocular or mucosal melanoma, who had failed or did  not tolerate previous treatments and had no other therapeutic option available.  Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Tumour  assessments were conducted at baseline, Week 12 and Week 24 using immune-related   response criteria. Patients were monitored continuously for adverse events (AEs),  including immune-related AEs. Candidate immunological markers were evaluated in  peripheral blood and sera samples collected at baseline and Weeks 4, 7, 10 and  12. RESULTS: Among 95 patients treated with ipilimumab 3 mg/kg, the  immune-related disease control rate at Week 24 was 38 %. With a median follow-up   of 24 months, median overall survival was 9.6 months. Both disease control and  survival were significantly associated with decreasing levels of lactate  dehydrogenase, C-reactive protein and FoxP3/regulatory T cells, and increasing  absolute lymphocyte count, between baseline and the end of dosing (Week 12).  CONCLUSION: Ipilimumab is a feasible treatment option for heavily pretreated  patients with metastatic melanoma. Changes in some immunological markers between   baseline and the fourth ipilimumab infusion appear to be associated with disease   control and survival, but verification in prospective clinical trials is  required.
CANIT0000247	24700302	Clinical research	Advanced extremity melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); IL2R (A2N4P8); 	CTLA-4; IL2R	IL2 followed by ipilimumab	 IL2	Immune cytokine followed Immune checkpoint therapy	Ipilimumab (DB06186); IL2 (NCIT:C24498); 	6	15	A prospective, single-institution trial	Patients with  progression after regional therapy for melanoma may benefit from immunologic  therapy. In this group of patients, immune checkpoint blockade with ipilimumab  has a higher complete response rate than T cell stimulation with IL-2, with no  complete responders in the IL-2 only group. Furthermore, the complete response  rate for ipilimumab in our cohort is higher than reported response rates in the  literature for ipilimumab alone, suggesting that the effects of immunotherapy may  be bolstered by previous regional treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2014 Aug	 Immunotherapy following regional chemotherapy treatment of advanced extremity  melanoma.	 Ann Surg Oncol	 PURPOSE: Following regional chemotherapy (RC) for melanoma, approximately 75 % of  patients will progress. The role of immunotherapy after RC has not been well  established. METHODS: A prospective, single-institution database of 243 patients   with in-transit melanoma (1995-2013) was queried for patients who had progression  of disease after RC with melphalan and subsequently received systemic  immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only,   and 6 received IL-2 followed by ipilimumab. Fisher's exact test was used to  determine if there was a difference in number of complete responders after  immunotherapy. RESULTS: With IL-2 alone, all patients progressed. After  ipilimumab alone, three patients had a complete response and nine had progressive  disease. Six additional patients received IL-2 first then ipilimumab. All six  progressed on IL-2 but three went on to have a complete response to ipilimumab  while three progressed. The use of ipilimumab at any time in patients who  progressed after RC was associated with higher rate of complete response compared  to use of IL-2 alone (33 vs. 0 %; p = 0.021). CONCLUSIONS: Patients with  progression after regional therapy for melanoma may benefit from immunologic  therapy. In this group of patients, immune checkpoint blockade with ipilimumab  has a higher complete response rate than T cell stimulation with IL-2, with no  complete responders in the IL-2 only group. Furthermore, the complete response  rate for ipilimumab in our cohort is higher than reported response rates in the  literature for ipilimumab alone, suggesting that the effects of immunotherapy may  be bolstered by previous regional treatment.
CANIT0000248	24700302	Clinical research	Advanced extremity melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	 IL2	Immune checkpoint therapy	Ipilimumab (DB06186); IL2 (NCIT:C24498); 	12	15	A prospective, single-institution trial	Patients with  progression after regional therapy for melanoma may benefit from immunologic  therapy. In this group of patients, immune checkpoint blockade with ipilimumab  has a higher complete response rate than T cell stimulation with IL-2, with no  complete responders in the IL-2 only group. Furthermore, the complete response  rate for ipilimumab in our cohort is higher than reported response rates in the  literature for ipilimumab alone, suggesting that the effects of immunotherapy may  be bolstered by previous regional treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2014 Aug	 Immunotherapy following regional chemotherapy treatment of advanced extremity  melanoma.	 Ann Surg Oncol	 PURPOSE: Following regional chemotherapy (RC) for melanoma, approximately 75 % of  patients will progress. The role of immunotherapy after RC has not been well  established. METHODS: A prospective, single-institution database of 243 patients   with in-transit melanoma (1995-2013) was queried for patients who had progression  of disease after RC with melphalan and subsequently received systemic  immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only,   and 6 received IL-2 followed by ipilimumab. Fisher's exact test was used to  determine if there was a difference in number of complete responders after  immunotherapy. RESULTS: With IL-2 alone, all patients progressed. After  ipilimumab alone, three patients had a complete response and nine had progressive  disease. Six additional patients received IL-2 first then ipilimumab. All six  progressed on IL-2 but three went on to have a complete response to ipilimumab  while three progressed. The use of ipilimumab at any time in patients who  progressed after RC was associated with higher rate of complete response compared  to use of IL-2 alone (33 vs. 0 %; p = 0.021). CONCLUSIONS: Patients with  progression after regional therapy for melanoma may benefit from immunologic  therapy. In this group of patients, immune checkpoint blockade with ipilimumab  has a higher complete response rate than T cell stimulation with IL-2, with no  complete responders in the IL-2 only group. Furthermore, the complete response  rate for ipilimumab in our cohort is higher than reported response rates in the  literature for ipilimumab alone, suggesting that the effects of immunotherapy may  be bolstered by previous regional treatment.
CANIT0000249	24705492	Clinical research	Chronic lymphocytic leukemia 	Chronic lymphocytic leukemia	EFO:0000095	Blood and lymph nodes	CD20 (P11836); 	CD20; 	Fludarabine plus cyclophosphamide plus rituximab	N/A	Immune checkpoint therapy plus Target therapy	Rituximab (DB00073); cyclophosphamide (DB00531); fludarabine (DB01073); 	237	N/A	N/A	Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL	N/A	N/A	N/A	Minimal residual disease (NCIT:C3896); 	Minimal residual disease	Disease status	 2014 Jun 12	 Eradication of bone marrow minimal residual disease may prompt early treatment  discontinuation in CLL.	 Blood	 The high complete remission rate with first-line combined fludarabine,  cyclophosphamide, and rituximab (FCR) begs the question of the value of minimal  residual disease (MRD)-negative status as a treatment end point. We report on 237  patients with chronic lymphocytic leukemia who received first-line FCR. MRD was  prospectively assessed by 4-color flow cytometry in bone marrow after course 3  and at final response assessment. After course 3 and at final response  assessment, 17% and 43% of patients were MRD negative in bone marrow,  respectively. A mutated immunoglobulin heavy chain variable gene and trisomy 12  were independently associated with MRD-negative status both after 3 courses of  FCR and at final response assessment in multivariable analyses (MVAs).  MRD-negative status was independently associated with significantly longer  progression-free survival (PFS) and overall survival (OS) in MVA (P = .03 and  .02, respectively). This association was confirmed also on landmark MVA at the  time of MRD assessment (P = .04 and .05, respectively). MRD-negative patients had  comparable PFS and OS, independent of the number of courses received or interim  staging. Early MRD eradication may be a desirable goal, prompting consideration  of early discontinuation of treatment. This trial was registered at  www.clinicaltrials.gov as #NCT00759798.CI  - (c) 2014 by The American Society of Hematology.
CANIT0000250	24708900	Clinical research	Elderly patients with pretreated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	188	N/A	N/A	Ipilimumab is a feasible treatment option in elderly patients with metastatic melanoma. Ipilimumab treatment was generally well tolerated and  resulted in clinical benefit and extended survival in elderly patients treated at centres in Italy.	The safety profile of ipilimumab was consistent with that observed in the general population of the Italian EAP and treatment-related AEs generally resolved within a median of 2 weeks with treatment as per protocol-specific guidelines.	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2014 Apr 4	 Efficacy and safety of ipilimumab in elderly patients with pretreated advanced  melanoma treated at Italian centres through the expanded access programme.	 J Exp Clin Cancer Res	 BACKGROUND: Elderly patients with metastatic melanoma have different disease  characteristics and a poorer prognosis than younger patients. Data from clinical   trials and expanded access programmes (EAPs) suggest ipilimumab confers a  consistent survival benefit and has a similar safety profile across different age  groups of patients with metastatic melanoma. Here we report the efficacy and  safety of ipilimumab 3 mg/kg in elderly patients enrolled in an EAP in Italy.  METHODS: Patients aged > 70 years with pretreated melanoma received ipilimumab 3   mg/kg every 3 weeks for four doses through an EAP. Tumour response was evaluated   at baseline and after completion of induction therapy using immune-related  response criteria and patients were monitored throughout the treatment period for  adverse events (AEs), including immune-related AEs. RESULTS: The immune-related  disease control rate among 188 evaluable patients was 38%, including four  patients with an immune-related complete response, 24 with an immune-related  partial response and 44 with immune-related stable disease. Median  progression-free survival (PFS) was 4.0 months and the 1- and 2-year PFS rates  were 21% and 12%, respectively. Median overall survival (OS) was 8.9 months; 1-  and 2-year OS rates were 38% and 22%, respectively. The safety profile of  ipilimumab was consistent with that observed in the general population of the  Italian EAP and treatment-related AEs generally resolved within a median of 2  weeks with treatment as per protocol-specific guidelines. CONCLUSIONS: These  results suggest ipilimumab is a feasible treatment option in elderly patients  with metastatic melanoma. Ipilimumab treatment was generally well tolerated and  resulted in clinical benefit and extended survival in elderly patients treated at  centres in Italy.
CANIT0000251	24714771	Clinical research	Patients with melanoma, non-small cell lung carcinoma, renal cell carcinoma, colorectal cancer, prostate cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	41	N/A	A retrospective cohort study	Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2014 Oct 1	 Association of PD-1, PD-1 ligands, and other features of the tumor immune  microenvironment with response to anti-PD-1 therapy.	 Clin Cancer Res	 PURPOSE: Immunomodulatory drugs differ in mechanism-of-action from directly  cytotoxic cancer therapies. Identifying factors predicting clinical response  could guide patient selection and therapeutic optimization. EXPERIMENTAL DESIGN:   Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal  cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate  cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one  institution and had evaluable pretreatment tumor specimens. Immunoarchitectural  features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell  infiltration, and lymphocyte subpopulations, were assessed for interrelationships  and potential correlations with clinical outcomes. RESULTS: Membranous (cell  surface) PD-L1 expression by tumor cells and immune infiltrates varied  significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In  the overall cohort, PD-L1 expression was geographically associated with  infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not   always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and  immune infiltrates was significantly associated with expression of PD-1 on  lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1  expression. Tumor cell PD-L1 expression correlated with objective response to  anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy  or the highest scoring sample among multiple biopsies from individual patients.  These correlations were stronger than borderline associations of PD-1 expression   or the presence of intratumoral immune cell infiltrates with response.  CONCLUSIONS: Tumor PD-L1 expression reflects an immune-active microenvironment  and, while associated other immunosuppressive molecules, including PD-1 and  PD-L2, is the single factor most closely correlated with response to anti-PD-1  blockade. Clin Cancer Res; 20(19); 5064-74. (c)2014 AACR.CI  - (c)2014 American Association for Cancer Research.
CANIT0000252	24714771	Clinical research	Patients with melanoma, non-small cell lung carcinoma, renal cell carcinoma, colorectal cancer, prostate cancer	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	41	N/A	A retrospective cohort study	Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2014 Oct 1	 Association of PD-1, PD-1 ligands, and other features of the tumor immune  microenvironment with response to anti-PD-1 therapy.	 Clin Cancer Res	 PURPOSE: Immunomodulatory drugs differ in mechanism-of-action from directly  cytotoxic cancer therapies. Identifying factors predicting clinical response  could guide patient selection and therapeutic optimization. EXPERIMENTAL DESIGN:   Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal  cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate  cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one  institution and had evaluable pretreatment tumor specimens. Immunoarchitectural  features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell  infiltration, and lymphocyte subpopulations, were assessed for interrelationships  and potential correlations with clinical outcomes. RESULTS: Membranous (cell  surface) PD-L1 expression by tumor cells and immune infiltrates varied  significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In  the overall cohort, PD-L1 expression was geographically associated with  infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not   always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and  immune infiltrates was significantly associated with expression of PD-1 on  lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1  expression. Tumor cell PD-L1 expression correlated with objective response to  anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy  or the highest scoring sample among multiple biopsies from individual patients.  These correlations were stronger than borderline associations of PD-1 expression   or the presence of intratumoral immune cell infiltrates with response.  CONCLUSIONS: Tumor PD-L1 expression reflects an immune-active microenvironment  and, while associated other immunosuppressive molecules, including PD-1 and  PD-L2, is the single factor most closely correlated with response to anti-PD-1  blockade. Clin Cancer Res; 20(19); 5064-74. (c)2014 AACR.CI  - (c)2014 American Association for Cancer Research.
CANIT0000253	24714771	Clinical research	Patients with melanoma, non-small cell lung carcinoma, renal cell carcinoma, colorectal cancer, prostate cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	41	N/A	A retrospective cohort study	Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2014 Oct 1	 Association of PD-1, PD-1 ligands, and other features of the tumor immune  microenvironment with response to anti-PD-1 therapy.	 Clin Cancer Res	 PURPOSE: Immunomodulatory drugs differ in mechanism-of-action from directly  cytotoxic cancer therapies. Identifying factors predicting clinical response  could guide patient selection and therapeutic optimization. EXPERIMENTAL DESIGN:   Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal  cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate  cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one  institution and had evaluable pretreatment tumor specimens. Immunoarchitectural  features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell  infiltration, and lymphocyte subpopulations, were assessed for interrelationships  and potential correlations with clinical outcomes. RESULTS: Membranous (cell  surface) PD-L1 expression by tumor cells and immune infiltrates varied  significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In  the overall cohort, PD-L1 expression was geographically associated with  infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not   always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and  immune infiltrates was significantly associated with expression of PD-1 on  lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1  expression. Tumor cell PD-L1 expression correlated with objective response to  anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy  or the highest scoring sample among multiple biopsies from individual patients.  These correlations were stronger than borderline associations of PD-1 expression   or the presence of intratumoral immune cell infiltrates with response.  CONCLUSIONS: Tumor PD-L1 expression reflects an immune-active microenvironment  and, while associated other immunosuppressive molecules, including PD-1 and  PD-L2, is the single factor most closely correlated with response to anti-PD-1  blockade. Clin Cancer Res; 20(19); 5064-74. (c)2014 AACR.CI  - (c)2014 American Association for Cancer Research.
CANIT0000254	24714771	Clinical research	Patients with melanoma, non-small cell lung carcinoma, renal cell carcinoma, colorectal cancer, prostate cancer	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	41	N/A	A retrospective cohort study	Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2014 Oct 1	 Association of PD-1, PD-1 ligands, and other features of the tumor immune  microenvironment with response to anti-PD-1 therapy.	 Clin Cancer Res	 PURPOSE: Immunomodulatory drugs differ in mechanism-of-action from directly  cytotoxic cancer therapies. Identifying factors predicting clinical response  could guide patient selection and therapeutic optimization. EXPERIMENTAL DESIGN:   Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal  cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate  cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one  institution and had evaluable pretreatment tumor specimens. Immunoarchitectural  features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell  infiltration, and lymphocyte subpopulations, were assessed for interrelationships  and potential correlations with clinical outcomes. RESULTS: Membranous (cell  surface) PD-L1 expression by tumor cells and immune infiltrates varied  significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In  the overall cohort, PD-L1 expression was geographically associated with  infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not   always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and  immune infiltrates was significantly associated with expression of PD-1 on  lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1  expression. Tumor cell PD-L1 expression correlated with objective response to  anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy  or the highest scoring sample among multiple biopsies from individual patients.  These correlations were stronger than borderline associations of PD-1 expression   or the presence of intratumoral immune cell infiltrates with response.  CONCLUSIONS: Tumor PD-L1 expression reflects an immune-active microenvironment  and, while associated other immunosuppressive molecules, including PD-1 and  PD-L2, is the single factor most closely correlated with response to anti-PD-1  blockade. Clin Cancer Res; 20(19); 5064-74. (c)2014 AACR.CI  - (c)2014 American Association for Cancer Research.
CANIT0000255	24714771	Clinical research	Patients with melanoma, non-small cell lung carcinoma, renal cell carcinoma, colorectal cancer, prostate cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	41	N/A	A retrospective cohort study	Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2014 Oct 1	 Association of PD-1, PD-1 ligands, and other features of the tumor immune  microenvironment with response to anti-PD-1 therapy.	 Clin Cancer Res	 PURPOSE: Immunomodulatory drugs differ in mechanism-of-action from directly  cytotoxic cancer therapies. Identifying factors predicting clinical response  could guide patient selection and therapeutic optimization. EXPERIMENTAL DESIGN:   Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal  cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate  cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one  institution and had evaluable pretreatment tumor specimens. Immunoarchitectural  features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell  infiltration, and lymphocyte subpopulations, were assessed for interrelationships  and potential correlations with clinical outcomes. RESULTS: Membranous (cell  surface) PD-L1 expression by tumor cells and immune infiltrates varied  significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In  the overall cohort, PD-L1 expression was geographically associated with  infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not   always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and  immune infiltrates was significantly associated with expression of PD-1 on  lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1  expression. Tumor cell PD-L1 expression correlated with objective response to  anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy  or the highest scoring sample among multiple biopsies from individual patients.  These correlations were stronger than borderline associations of PD-1 expression   or the presence of intratumoral immune cell infiltrates with response.  CONCLUSIONS: Tumor PD-L1 expression reflects an immune-active microenvironment  and, while associated other immunosuppressive molecules, including PD-1 and  PD-L2, is the single factor most closely correlated with response to anti-PD-1  blockade. Clin Cancer Res; 20(19); 5064-74. (c)2014 AACR.CI  - (c)2014 American Association for Cancer Research.
CANIT0000256	24721645	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	218	N/A	N/A	Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral  blood are predictive of survival in patients with melanoma treated with  tremelimumab. Blood mRNA signatures should be further explored to define patient   subsets likely to benefit from immunotherapy.	N/A	N/A	N/A	CTSD (P07339); 	Serum CTSD expression levels	Gene expression signature in serum	 2014 Jun 15	 Blood mRNA expression profiling predicts survival in patients treated with  tremelimumab.	 Clin Cancer Res	 PURPOSE: Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb)  targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Ipilimumab  (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug  Administration (FDA). Biomarkers are needed to identify the subset of patients  who will achieve tumor control with CTLA-4 blockade. EXPERIMENTAL DESIGN:  Pretreatment peripheral blood samples from 218 patients with melanoma who were  refractory to prior therapy and receiving tremelimumab in a multicenter phase II   study were measured for 169 mRNA transcripts using reverse transcription  polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score  based on four genes that were highly predictive of survival (P < 0.001). This  signature was validated in an independent population of 260 treatment-naive  patients with melanoma enrolled in a multicenter phase III study of tremelimumab.  RESULTS: Median follow-up was 297 days for the training population and 386 days  for the test population. Expression levels of the 169 genes were closely  correlated across the two populations (r = 0.9939). A four-gene model, including   cathepsin D (CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1  (TXNRD1), and interleukin 1 receptor-associated kinase 3 (IRAK3), predicted  survival in the test population (P = 0.001 by log-rank test). This four-gene  model added to the predictive value of clinical predictors (P < 0.0001).  CONCLUSIONS: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral  blood are predictive of survival in patients with melanoma treated with  tremelimumab. Blood mRNA signatures should be further explored to define patient   subsets likely to benefit from immunotherapy.CI  - (c)2014 American Association for Cancer Research.
CANIT0000257	24721645	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	218	N/A	N/A	Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral  blood are predictive of survival in patients with melanoma treated with  tremelimumab. Blood mRNA signatures should be further explored to define patient   subsets likely to benefit from immunotherapy.	N/A	N/A	N/A	IRAK3 (Q9Y616); 	Serum IRAK3 expression levels	Gene expression signature in serum	 2014 Jun 15	 Blood mRNA expression profiling predicts survival in patients treated with  tremelimumab.	 Clin Cancer Res	 PURPOSE: Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb)  targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Ipilimumab  (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug  Administration (FDA). Biomarkers are needed to identify the subset of patients  who will achieve tumor control with CTLA-4 blockade. EXPERIMENTAL DESIGN:  Pretreatment peripheral blood samples from 218 patients with melanoma who were  refractory to prior therapy and receiving tremelimumab in a multicenter phase II   study were measured for 169 mRNA transcripts using reverse transcription  polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score  based on four genes that were highly predictive of survival (P < 0.001). This  signature was validated in an independent population of 260 treatment-naive  patients with melanoma enrolled in a multicenter phase III study of tremelimumab.  RESULTS: Median follow-up was 297 days for the training population and 386 days  for the test population. Expression levels of the 169 genes were closely  correlated across the two populations (r = 0.9939). A four-gene model, including   cathepsin D (CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1  (TXNRD1), and interleukin 1 receptor-associated kinase 3 (IRAK3), predicted  survival in the test population (P = 0.001 by log-rank test). This four-gene  model added to the predictive value of clinical predictors (P < 0.0001).  CONCLUSIONS: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral  blood are predictive of survival in patients with melanoma treated with  tremelimumab. Blood mRNA signatures should be further explored to define patient   subsets likely to benefit from immunotherapy.CI  - (c)2014 American Association for Cancer Research.
CANIT0000258	24721645	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	218	N/A	N/A	Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral  blood are predictive of survival in patients with melanoma treated with  tremelimumab. Blood mRNA signatures should be further explored to define patient   subsets likely to benefit from immunotherapy.	N/A	N/A	N/A	PLA2G7 (Q13093); 	Serum PLA2G7 expression levels	Gene expression signature in serum	 2014 Jun 15	 Blood mRNA expression profiling predicts survival in patients treated with  tremelimumab.	 Clin Cancer Res	 PURPOSE: Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb)  targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Ipilimumab  (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug  Administration (FDA). Biomarkers are needed to identify the subset of patients  who will achieve tumor control with CTLA-4 blockade. EXPERIMENTAL DESIGN:  Pretreatment peripheral blood samples from 218 patients with melanoma who were  refractory to prior therapy and receiving tremelimumab in a multicenter phase II   study were measured for 169 mRNA transcripts using reverse transcription  polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score  based on four genes that were highly predictive of survival (P < 0.001). This  signature was validated in an independent population of 260 treatment-naive  patients with melanoma enrolled in a multicenter phase III study of tremelimumab.  RESULTS: Median follow-up was 297 days for the training population and 386 days  for the test population. Expression levels of the 169 genes were closely  correlated across the two populations (r = 0.9939). A four-gene model, including   cathepsin D (CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1  (TXNRD1), and interleukin 1 receptor-associated kinase 3 (IRAK3), predicted  survival in the test population (P = 0.001 by log-rank test). This four-gene  model added to the predictive value of clinical predictors (P < 0.0001).  CONCLUSIONS: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral  blood are predictive of survival in patients with melanoma treated with  tremelimumab. Blood mRNA signatures should be further explored to define patient   subsets likely to benefit from immunotherapy.CI  - (c)2014 American Association for Cancer Research.
CANIT0000259	24721645	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	218	N/A	N/A	Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral  blood are predictive of survival in patients with melanoma treated with  tremelimumab. Blood mRNA signatures should be further explored to define patient   subsets likely to benefit from immunotherapy.	N/A	N/A	N/A	TXNRD1 (Q16881); 	Serum TXNRD1 expression levels	Gene expression signature in serum	 2014 Jun 15	 Blood mRNA expression profiling predicts survival in patients treated with  tremelimumab.	 Clin Cancer Res	 PURPOSE: Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb)  targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Ipilimumab  (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug  Administration (FDA). Biomarkers are needed to identify the subset of patients  who will achieve tumor control with CTLA-4 blockade. EXPERIMENTAL DESIGN:  Pretreatment peripheral blood samples from 218 patients with melanoma who were  refractory to prior therapy and receiving tremelimumab in a multicenter phase II   study were measured for 169 mRNA transcripts using reverse transcription  polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score  based on four genes that were highly predictive of survival (P < 0.001). This  signature was validated in an independent population of 260 treatment-naive  patients with melanoma enrolled in a multicenter phase III study of tremelimumab.  RESULTS: Median follow-up was 297 days for the training population and 386 days  for the test population. Expression levels of the 169 genes were closely  correlated across the two populations (r = 0.9939). A four-gene model, including   cathepsin D (CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1  (TXNRD1), and interleukin 1 receptor-associated kinase 3 (IRAK3), predicted  survival in the test population (P = 0.001 by log-rank test). This four-gene  model added to the predictive value of clinical predictors (P < 0.0001).  CONCLUSIONS: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral  blood are predictive of survival in patients with melanoma treated with  tremelimumab. Blood mRNA signatures should be further explored to define patient   subsets likely to benefit from immunotherapy.CI  - (c)2014 American Association for Cancer Research.
CANIT0000260	24721740	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Neutrophilic disease of the skin and intestines- simultaneous occurrence of pyoderma gangrenosum and colitis	N/A	N/A	N/A	N/A	N/A	 2014 Mar-Apr	 Neutrophilic disease of the skin and intestines after ipilimumab treatment for  malignant melanoma - simultaneous occurrence of pyoderma gangrenosum and colitis.	 Eur J Dermatol	Unable to provide
CANIT0000261	24739759	Clinical research	Advanced malignancies (21 Melanoma, 6 Ovarian, 5 Sarcoma, 4 NonCsmall cell lung cancer, 4 Colorectal, 5 Other)	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); CD205 (O60449); NY-ESO-1 (P78358); TLR3 (O15455); 	CTLA-4 ;  CD205 ;  NY-ESO-1 	CDX-1401 plus poly-ICLC followed by Immune checkpoint therapy	N/A	Tumor vaccine followed by Immune checkpoint therapy	Ipilimumab (DB06186); poly-ICLC (NCIT:C1198); CDX-1401 (DB15185); 	45	N/A	A phase I clinical trial	This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.	No dose-limiting or grade 3 toxicities were reported.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2014 Apr 16	 Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the  dendritic cell receptor DEC-205.	 Sci Transl Med	 Immune-based therapies for cancer are generating substantial interest because of   the success of immune checkpoint inhibitors. This study aimed to enhance  anticancer immunity by exploiting the capacity of dendritic cells (DCs) to  initiate T cell immunity by efficient uptake and presentation of endocytosed  material. Delivery of tumor-associated antigens to DCs using receptor-specific  monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits  robust antigen-specific immune responses in preclinical models. DEC-205 (CD205),   a molecule expressed on DCs, has been extensively studied for its role in antigen  processing and presentation. CDX-1401 is a vaccine composed of a human mAb  specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase   1 trial assessed the safety, immunogenicity, and clinical activity of escalating   doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8)   and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies  refractory to available therapies. Treatment induced humoral and cellular  immunity to NY-ESO-1 in patients with confirmed NY-ESO-1-expressing tumors across  various dose levels and adjuvant combinations. No dose-limiting or grade 3  toxicities were reported. Thirteen patients experienced stabilization of disease,  with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients  had tumor regression (~20% shrinkage in target lesions). Six of eight patients  who received immune-checkpoint inhibitors within 3 months after CDX-1401  administration had objective tumor regression. This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.
CANIT0000262	24739759	Clinical research	Advanced malignancies (21 Melanoma, 6 Ovarian, 5 Sarcoma, 4 NonCsmall cell lung cancer, 4 Colorectal, 5 Other)	Sarcoma	EFO:0000691	Soft tissue	CTLA-4 (P16410); CD205 (O60449); NY-ESO-1 (P78358); TLR3 (O15455); 	CTLA-4 ;  CD205 ;  NY-ESO-1 	CDX-1401 plus poly-ICLC followed by Immune checkpoint therapy	N/A	Tumor vaccine followed by Immune checkpoint therapy	Ipilimumab (DB06186); poly-ICLC (NCIT:C1198); CDX-1401 (DB15185); 	45	N/A	A phase I clinical trial	This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.	No dose-limiting or grade 3 toxicities were reported.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2014 Apr 16	 Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the  dendritic cell receptor DEC-205.	 Sci Transl Med	 Immune-based therapies for cancer are generating substantial interest because of   the success of immune checkpoint inhibitors. This study aimed to enhance  anticancer immunity by exploiting the capacity of dendritic cells (DCs) to  initiate T cell immunity by efficient uptake and presentation of endocytosed  material. Delivery of tumor-associated antigens to DCs using receptor-specific  monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits  robust antigen-specific immune responses in preclinical models. DEC-205 (CD205),   a molecule expressed on DCs, has been extensively studied for its role in antigen  processing and presentation. CDX-1401 is a vaccine composed of a human mAb  specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase   1 trial assessed the safety, immunogenicity, and clinical activity of escalating   doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8)   and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies  refractory to available therapies. Treatment induced humoral and cellular  immunity to NY-ESO-1 in patients with confirmed NY-ESO-1-expressing tumors across  various dose levels and adjuvant combinations. No dose-limiting or grade 3  toxicities were reported. Thirteen patients experienced stabilization of disease,  with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients  had tumor regression (~20% shrinkage in target lesions). Six of eight patients  who received immune-checkpoint inhibitors within 3 months after CDX-1401  administration had objective tumor regression. This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.
CANIT0000263	24739759	Clinical research	Advanced malignancies (21 Melanoma, 6 Ovarian, 5 Sarcoma, 4 NonCsmall cell lung cancer, 4 Colorectal, 5 Other)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); CD205 (O60449); NY-ESO-1 (P78358); TLR3 (O15455); 	CTLA-4 ;  CD205 ;  NY-ESO-1 	CDX-1401 plus poly-ICLC followed by Immune checkpoint therapy	N/A	Tumor vaccine followed by Immune checkpoint therapy	Ipilimumab (DB06186); poly-ICLC (NCIT:C1198); CDX-1401 (DB15185); 	45	N/A	A phase I clinical trial	This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.	No dose-limiting or grade 3 toxicities were reported.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2014 Apr 16	 Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the  dendritic cell receptor DEC-205.	 Sci Transl Med	 Immune-based therapies for cancer are generating substantial interest because of   the success of immune checkpoint inhibitors. This study aimed to enhance  anticancer immunity by exploiting the capacity of dendritic cells (DCs) to  initiate T cell immunity by efficient uptake and presentation of endocytosed  material. Delivery of tumor-associated antigens to DCs using receptor-specific  monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits  robust antigen-specific immune responses in preclinical models. DEC-205 (CD205),   a molecule expressed on DCs, has been extensively studied for its role in antigen  processing and presentation. CDX-1401 is a vaccine composed of a human mAb  specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase   1 trial assessed the safety, immunogenicity, and clinical activity of escalating   doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8)   and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies  refractory to available therapies. Treatment induced humoral and cellular  immunity to NY-ESO-1 in patients with confirmed NY-ESO-1-expressing tumors across  various dose levels and adjuvant combinations. No dose-limiting or grade 3  toxicities were reported. Thirteen patients experienced stabilization of disease,  with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients  had tumor regression (~20% shrinkage in target lesions). Six of eight patients  who received immune-checkpoint inhibitors within 3 months after CDX-1401  administration had objective tumor regression. This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.
CANIT0000264	24739759	Clinical research	Advanced malignancies (21 Melanoma, 6 Ovarian, 5 Sarcoma, 4 NonCsmall cell lung cancer, 4 Colorectal, 5 Other)	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); CD205 (O60449); NY-ESO-1 (P78358); TLR3 (O15455); 	CTLA-4 ;  CD205 ;  NY-ESO-1 	CDX-1401 plus poly-ICLC followed by Immune checkpoint therapy	N/A	Tumor vaccine followed by Immune checkpoint therapy	Ipilimumab (DB06186); poly-ICLC (NCIT:C1198); CDX-1401 (DB15185); 	45	N/A	A phase I clinical trial	This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.	No dose-limiting or grade 3 toxicities were reported.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2014 Apr 16	 Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the  dendritic cell receptor DEC-205.	 Sci Transl Med	 Immune-based therapies for cancer are generating substantial interest because of   the success of immune checkpoint inhibitors. This study aimed to enhance  anticancer immunity by exploiting the capacity of dendritic cells (DCs) to  initiate T cell immunity by efficient uptake and presentation of endocytosed  material. Delivery of tumor-associated antigens to DCs using receptor-specific  monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits  robust antigen-specific immune responses in preclinical models. DEC-205 (CD205),   a molecule expressed on DCs, has been extensively studied for its role in antigen  processing and presentation. CDX-1401 is a vaccine composed of a human mAb  specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase   1 trial assessed the safety, immunogenicity, and clinical activity of escalating   doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8)   and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies  refractory to available therapies. Treatment induced humoral and cellular  immunity to NY-ESO-1 in patients with confirmed NY-ESO-1-expressing tumors across  various dose levels and adjuvant combinations. No dose-limiting or grade 3  toxicities were reported. Thirteen patients experienced stabilization of disease,  with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients  had tumor regression (~20% shrinkage in target lesions). Six of eight patients  who received immune-checkpoint inhibitors within 3 months after CDX-1401  administration had objective tumor regression. This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.
CANIT0000265	24739759	Clinical research	Advanced malignancies (21 Melanoma, 6 Ovarian, 5 Sarcoma, 4 NonCsmall cell lung cancer, 4 Colorectal, 5 Other)	Ovarian carcinoma	EFO:0001075	Ovary	CTLA-4 (P16410); CD205 (O60449); NY-ESO-1 (P78358); TLR3 (O15455); 	CTLA-4 ;  CD205 ;  NY-ESO-1 	CDX-1401 plus poly-ICLC followed by Immune checkpoint therapy	N/A	Tumor vaccine followed by Immune checkpoint therapy	Ipilimumab (DB06186); poly-ICLC (NCIT:C1198); CDX-1401 (DB15185); 	45	N/A	A phase I clinical trial	This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.	No dose-limiting or grade 3 toxicities were reported.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2014 Apr 16	 Induction of antigen-specific immunity with a vaccine targeting NY-ESO-1 to the  dendritic cell receptor DEC-205.	 Sci Transl Med	 Immune-based therapies for cancer are generating substantial interest because of   the success of immune checkpoint inhibitors. This study aimed to enhance  anticancer immunity by exploiting the capacity of dendritic cells (DCs) to  initiate T cell immunity by efficient uptake and presentation of endocytosed  material. Delivery of tumor-associated antigens to DCs using receptor-specific  monoclonal antibodies (mAbs) in the presence of DC-activating agents elicits  robust antigen-specific immune responses in preclinical models. DEC-205 (CD205),   a molecule expressed on DCs, has been extensively studied for its role in antigen  processing and presentation. CDX-1401 is a vaccine composed of a human mAb  specific for DEC-205 fused to the full-length tumor antigen NY-ESO-1. This phase   1 trial assessed the safety, immunogenicity, and clinical activity of escalating   doses of CDX-1401 with the Toll-like receptor (TLR) agonists resiquimod (TLR7/8)   and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies  refractory to available therapies. Treatment induced humoral and cellular  immunity to NY-ESO-1 in patients with confirmed NY-ESO-1-expressing tumors across  various dose levels and adjuvant combinations. No dose-limiting or grade 3  toxicities were reported. Thirteen patients experienced stabilization of disease,  with a median duration of 6.7 months (range, 2.4+ to 13.4 months). Two patients  had tumor regression (~20% shrinkage in target lesions). Six of eight patients  who received immune-checkpoint inhibitors within 3 months after CDX-1401  administration had objective tumor regression. This first-in-human study of a  protein vaccine targeting DCs demonstrates its feasibility, safety, and  biological activity and provides rationale for combination immunotherapy  strategies including immune checkpoint blockade.
CANIT0000266	24777678	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	5	N/A	N/A	Ipilimumab treatment results in an early decrease in the frequency of circulating granulocytic myeloid-derived suppressor cells as well as their Arginase1 production.	N/A	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); 	Frequency of granulocytic monocytic myeloid-derived suppressor cells	Cell percentage/counts in blood	 2013 Sep	 Ipilimumab treatment results in an early decrease in the frequency of circulating  granulocytic myeloid-derived suppressor cells as well as their Arginase1  production.	 Cancer Immunol Res	 Blocking the immune checkpoint molecule CTL antigen-4 (CTLA-4) with ipilimumab  has proven to induce long-lasting clinical responses in patients with metastatic   melanoma. To study the early response that takes place after CTLA-4 blockade,  peripheral blood immune monitoring was conducted in five patients undergoing  ipilimumab treatment at baseline, three and nine weeks after administration of  the first dose. Along with T-cell population analysis, this work was primarily  focused on an in-depth study of the myeloid-derived suppressor cell (MDSC)  populations. Ipilimumab treatment resulted in lower frequencies of regulatory T  cells along with reduced expression levels of PD-1 at the nine-week time point.  Three weeks after the initial ipilimumab dose, the frequency of granulocytic  MDSCs was significantly reduced and was followed by a reduction in the frequency   of arginase1-producing CD3(-) cells, indicating an indirect in trans effect that   should be taken into account for future evaluations of ipilimumab mechanisms of  action.CI  - (c)2013 AACR.
CANIT0000267	24778276	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	176	N/A	N/A	Pretreatment VEGF >/= 43 pg/mL was  associated with decreased OS (median OS 6.6 vs. 12.9 months, P = 0.006; 7.4 vs.  14.3 months, P = 0.037 for 3 mg/kg; and 6.2 vs. 10.9 months, P = 0.048 for 10  mg/kg). There was no correlation between VEGF changes and clinical outcome. Serum  VEGF may be a predictive biomarker for ipilimumab treatment and is worthy of  prospective investigation with various forms of immunologic checkpoint blockade.	N/A	N/A	N/A	VEGF (P15692); 	Serum VEGF expression levels	Gene expression signature in serum	 2014 Feb	 Pretreatment serum VEGF is associated with clinical response and overall survival  in advanced melanoma patients treated with ipilimumab.	 Cancer Immunol Res	 Ipilimumab, an antibody that blocks CTL antigen 4 (CTLA-4), improves overall  survival (OS) for patients with metastatic melanoma. Given its role in  angiogenesis and immune evasion, serum VEGF levels were evaluated for association  with clinical benefit in ipilimumab-treated patients. Sera were collected from  176 patients treated at 3 (n = 98) or 10 mg/kg (n = 68). The VEGF levels before  treatment and at induction completion (week 12) were analyzed using the Meso  Scale Discovery kit. The association of the levels of VEGF with clinical  responses and OS were assessed using the Fisher exact and Kaplan-Meier log-rank  tests. VEGF as a continuous variable was associated with OS (P = 0.002). Using 43  pg/mL as the cutoff pretreatment VEGF value defined by maximally selected  log-rank statistics, pretreatment VEGF values correlated with clinical benefit at  week 24 (P = 0.019; 159 patients evaluable). Pretreatment VEGF >/= 43 pg/mL was  associated with decreased OS (median OS 6.6 vs. 12.9 months, P = 0.006; 7.4 vs.  14.3 months, P = 0.037 for 3 mg/kg; and 6.2 vs. 10.9 months, P = 0.048 for 10  mg/kg). There was no correlation between VEGF changes and clinical outcome. Serum  VEGF may be a predictive biomarker for ipilimumab treatment and is worthy of  prospective investigation with various forms of immunologic checkpoint blockade.CI  - (c)2014 AACR.
CANIT0000268	24795352	Case report	Metastatic, castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Case	To the best of our knowledge, this is the first case of a durable complete remission in advanced CRPC induced by an immunotherapeutic agent.	Autoimmune hepatitis, autoimmune colitis, and thyroiditis	N/A	N/A	N/A	N/A	N/A	 2014 May	 Sustained complete response to CTLA-4 blockade in a patient with metastatic,  castration-resistant prostate cancer.	 Cancer Immunol Res	 We present the case of a man with metastatic, castration-resistant prostate  cancer, who had a complete prostate-specific antigen (PSA) response after 2(1/2)   doses of ipilimumab. His treatment course was complicated by diarrhea and  autoimmune hepatitis, both of which resolved within 4 months. Sera and biopsy  specimens were accessed, and sera from pretreatment and day 113 were analyzed.  Augmented antibody responses were detected against 11 potential tumor antigens,  with responses ranging from 5- to 20-fold in day 113 sera compared with baseline.  Genes that were targets of a strong antibody response (arbitrarily set at 10-fold  or greater increase) were analyzed by real-time PCR for expression in the tumor  biopsy cDNA. Of the top 5 genes, only 3-hydroxyisobutyryl-CoA hydrolase (HIBCH)  could be identified in the amplified tumor biopsy cDNA. Using an antibody to  HIBCH, immunohistochemical analysis documented strong expression of the protein.   Together, these data suggest that an augmented antibody response to HIBCH, an  antigen that was expressed by the patient's prostate cancer, could have  contributed to the clinical response. After 16 months of PSA stability, he  discontinued his androgen-suppression therapy. With the return of his  testosterone, his PSA increased slightly, likely originating from his intact  prostate. He has been disease free for the past 6 years without any additional  therapy.
CANIT0000269	24801836	Case report	Exceptionally advanced facial embryonal rhabdomyosarcoma with extension to the brain	Embryonal rhabdomyosarcoma	EFO:0000437	Soft tissue	TLR3 (O15455); 	TLR3; 	Poly-ICLC	N/A	Tumor vaccine	Poly-ICLC (NCIT:C1198); 	1	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2014 Aug	 Therapeutic in situ autovaccination against solid cancers with intratumoral  poly-ICLC: case report, hypothesis, and clinical trial.	 Cancer Immunol Res	 Pathogen-associated molecular patterns (PAMP) are stand-alone innate and adaptive  immunomodulators and critical vaccine components. We present a strategy of  sequential intratumoral (i.t.) and intramuscular (i.m.) injections of the  stabilized dsRNA viral mimic and PAMP, polyinosinic-polycytidylic  acid-polylysine-carboxymethylcellulose (poly-ICLC, Hiltonol; Oncovir). We report   the first treated patient, a young man with an exceptionally advanced facial  embryonal rhabdomyosarcoma with extension to the brain. After treatment, the  patient showed tumor inflammation consistent with immunotherapy, followed by  gradual, marked tumor regression, with extended survival. Sequential i.t. and  i.m. poly-ICLC injections mimicking a viral infection can induce an effective, in  situ, personalized systemic therapeutic autovaccination against tumor antigens   of a patient. We postulate a three-step immunomodulatory process: (i)  innate-immune local tumor killing induced by i.t. poly-ICLC; (ii) activation of  dendritic cells with Th1 cell- and CTL-weighted priming against the released  tumor antigens; and (iii) i.m. poly-ICLC maintenance of the systemic antitumor  immune response via chemokine induction, facilitation of CTL killing through the   induction of costimulators such as OX40, inflammasome activation, and increase in  the T-effector/Treg ratio. These results support the use of certain simple and  inexpensive i.t. PAMPs to favorably stimulate effective immunity against solid  cancers. A phase II clinical trial testing the hypothesis presented has begun  accrual (clinicaltrials.gov, NCT01984892).CI  - (c)2014 American Association for Cancer Research.
CANIT0000270	24812130	Case report	Metastatic BRAF(V600)-mutant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Akt Inhibitor MK2206 (NCIT:C90581); selumetinib (DB11689); ipilimumab (DB06186); 	1	N/A	Case	He was referred to hospice care and subsequently died.	N/A	N/A	N/A	N/A	N/A	N/A	 2014 May	 BRAFV600E-mutant melanoma presenting with cardiac involvement.	 J Natl Compr Canc Netw	 Melanoma is an aggressive skin cancer with historically limited treatment  options. Approximately 50% of melanomas harbor BRAF(V600) mutations. This report   describes a 32-year-old man with metastatic BRAF(V600)-mutant melanoma who  presented with cardiac involvement. Recently developed treatment options for  patients with BRAF-mutant melanoma include BRAF inhibitors (vemurafenib,  dabrafenib), MEK inhibitors (trametinib), and immune-based therapeutics  (interleukin-2 or ipilimumab), but the most effective strategy for first-line  therapy is heavily debated. Opinions vary for treatment selection, but the  general consensus recommends immune-based therapies initially for asymptomatic  patients with low-volume disease, and BRAF inhibitors for those with highly  symptomatic or rapidly progressing disease. In this case, melanoma with cardiac  involvement, although clinically uncommon, presents challenging management  decisions.
CANIT0000271	24814274	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Bilateral orbital inflammatory syndrome	Bilateral orbital inflammatory syndrome	N/A	N/A	N/A	N/A	N/A	 2015 May-Jun	 A case report of orbital inflammatory syndrome secondary to ipilimumab.	 Ophthalmic Plast Reconstr Surg	 Ipilimumab is a monoclonal antibody to cytotoxic T-lymphocyte antigen-4, a  negative regulator of T-cell-mediated immune response. Ipilimumab is approved by   the US Food and Drug Administration for the treatment of advanced melanoma.  However, its use frequently has been associated with immune-related side effects,  which can be explained by its mechanism of action. More common adverse effects  include dermatitis, colitis, hepatitis, and endocrinopathies, but many less  common immune-related adverse effects that involve various tissues and organ  systems have been reported with more widespread use of ipilimumab since its  approval in 2011. A case of bilateral orbital inflammatory syndrome secondary to   ipilimumab, in a patient undergoing adjuvant treatment for metastatic melanoma,  is reported.
CANIT0000272	24831977	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Radiotherapy followed by Ipilimumab	Radiotherapy followed by placebo	Radiotherapy followed by Immune checkpoint therapy	Radiotherapy (NCIT:C15313); ipilimumab (DB06186); 	393	396	A multicentre, randomised, double-blind, phase III trial.	Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation.	The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group.	N/A	N/A	N/A	N/A	N/A	 2014 Jun	 Ipilimumab versus placebo after radiotherapy in patients with metastatic  castration-resistant prostate cancer that had progressed after docetaxel  chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.	 Lancet Oncol	 BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic   T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the   use of ipilimumab after radiotherapy in patients with metastatic  castration-resistant prostate cancer that progressed after docetaxel  chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3  trial in which men with at least one bone metastasis from castration-resistant  prostate cancer that had progressed after docetaxel treatment were randomly  assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one  fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up   to four doses. Non-progressing patients could continue to receive ipilimumab at  10 mg/kg or placebo as maintenance therapy every 3 months until disease  progression, unacceptable toxic effect, or death. Patients were randomly assigned  to either treatment group via a minimisation algorithm, and stratified by Eastern  Cooperative Oncology Group performance status, alkaline phosphatase  concentration, haemoglobin concentration, and investigator site. Patients and  investigators were masked to treatment allocation. The primary endpoint was  overall survival, assessed in the intention-to-treat population. This trial is  registered with ClinicalTrials.gov, number NCT00861614. FINDINGS: From May 26,  2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and  400 to placebo), all of whom were included in the intention-to-treat analysis.  Median overall survival was 11.2 months (95% CI 9.5-12.7) with ipilimumab and  10.0 months (8.3-11.0) with placebo (hazard ratio [HR] 0.85, 0.72-1.00; p=0.053).  However, the assessment of the proportional hazards assumption showed that it was  violated (p=0.0031). A piecewise hazard model showed that the HR changed over  time: the HR for 0-5 months was 1.46 (95% CI 1.10-1.95), for 5-12 months was 0.65  (0.50-0.85), and beyond 12 months was 0.60 (0.43-0.86). The most common grade 3-4  adverse events were immune-related, occurring in 101 (26%) patients in the  ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent   grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the  ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs  35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%)  deaths occurred because of toxic effects of the study drug, all in the ipilimumab  group. INTERPRETATION: Although there was no significant difference between the  ipilimumab group and the placebo group in terms of overall survival in the  primary analysis, there were signs of activity with the drug that warrant further  investigation. FUNDING: Bristol-Myers Squibb.CI  - Copyright (c) 2014 Elsevier Ltd. All rights reserved.
CANIT0000273	24832153	Clinical research	Pancreatic (No. = 53), prostate (No. = 35) or colon (No. = 8) cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	GM-CSF	N/A	Tumor vaccine	GM-CSF (DB05386)	96	N/A	N/A	GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival.	N/A	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2015 Jan 1	 Development of thyroglobulin antibodies after GVAX immunotherapy is associated  with prolonged survival.	 Int J Cancer	 Cancer immunotherapy induces a variety of autoinflammatory responses, including  those against the thyroid gland, which can be exploited to predict clinical  outcomes. Considering the paucity of information about thyroid autoimmunity in  patients receiving cancer vaccines, we designed our study to assess the  development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX  (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and  correlated seroconversion with survival. Using both in house and commercial ELISA  assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No. =  35) or colon (No. = 8) cancer, before and after treatment with GVAX only (No. =  34), GVAX plus ipilimumab (No. = 42) or ipilimumab (No. = 20), and correlated  their levels with patient's survival, disease status and T-cell surface markers.   Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin  were also measured. TgAbs specifically developed after GVAX, independent of the  underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer)  and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus  ipilimumab). This TgAbs seroconversion could be detected mainly by the in house  assay, suggesting that the thyroglobulin epitopes recognized by the antibodies  induced by GVAX are different from the epitopes seen in the classic form of  Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with  significantly prolonged survival (p = 0.01 for pancreas and p = 0.005 for  prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of  TgAbs that recognize a unique antigenic repertoire and associate with prolonged  survival.CI  - (c) 2014 UICC.
CANIT0000274	24832153	Clinical research	Pancreatic (No. = 53), prostate (No. = 35) or colon (No. = 8) cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	96	N/A	N/A	GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival.	N/A	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2015 Jan 1	 Development of thyroglobulin antibodies after GVAX immunotherapy is associated  with prolonged survival.	 Int J Cancer	 Cancer immunotherapy induces a variety of autoinflammatory responses, including  those against the thyroid gland, which can be exploited to predict clinical  outcomes. Considering the paucity of information about thyroid autoimmunity in  patients receiving cancer vaccines, we designed our study to assess the  development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX  (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and  correlated seroconversion with survival. Using both in house and commercial ELISA  assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No. =  35) or colon (No. = 8) cancer, before and after treatment with GVAX only (No. =  34), GVAX plus ipilimumab (No. = 42) or ipilimumab (No. = 20), and correlated  their levels with patient's survival, disease status and T-cell surface markers.   Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin  were also measured. TgAbs specifically developed after GVAX, independent of the  underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer)  and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus  ipilimumab). This TgAbs seroconversion could be detected mainly by the in house  assay, suggesting that the thyroglobulin epitopes recognized by the antibodies  induced by GVAX are different from the epitopes seen in the classic form of  Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with  significantly prolonged survival (p = 0.01 for pancreas and p = 0.005 for  prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of  TgAbs that recognize a unique antigenic repertoire and associate with prolonged  survival.CI  - (c) 2014 UICC.
CANIT0000275	24832153	Clinical research	Pancreatic (No. = 53), prostate (No. = 35) or colon (No. = 8) cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus GM-CSF	N/A	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386)	96	N/A	N/A	GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival.	N/A	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2015 Jan 1	 Development of thyroglobulin antibodies after GVAX immunotherapy is associated  with prolonged survival.	 Int J Cancer	 Cancer immunotherapy induces a variety of autoinflammatory responses, including  those against the thyroid gland, which can be exploited to predict clinical  outcomes. Considering the paucity of information about thyroid autoimmunity in  patients receiving cancer vaccines, we designed our study to assess the  development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX  (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and  correlated seroconversion with survival. Using both in house and commercial ELISA  assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No. =  35) or colon (No. = 8) cancer, before and after treatment with GVAX only (No. =  34), GVAX plus ipilimumab (No. = 42) or ipilimumab (No. = 20), and correlated  their levels with patient's survival, disease status and T-cell surface markers.   Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin  were also measured. TgAbs specifically developed after GVAX, independent of the  underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer)  and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus  ipilimumab). This TgAbs seroconversion could be detected mainly by the in house  assay, suggesting that the thyroglobulin epitopes recognized by the antibodies  induced by GVAX are different from the epitopes seen in the classic form of  Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with  significantly prolonged survival (p = 0.01 for pancreas and p = 0.005 for  prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of  TgAbs that recognize a unique antigenic repertoire and associate with prolonged  survival.CI  - (c) 2014 UICC.
CANIT0000276	24832153	Clinical research	Pancreatic (No. = 53), prostate (No. = 35) or colon (No. = 8) cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	CTLA-4 (P16410); 	CTLA-4; 	GM-CSF	N/A	Tumor vaccine	GM-CSF (DB05386)	96	N/A	N/A	GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival.	N/A	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2015 Jan 1	 Development of thyroglobulin antibodies after GVAX immunotherapy is associated  with prolonged survival.	 Int J Cancer	 Cancer immunotherapy induces a variety of autoinflammatory responses, including  those against the thyroid gland, which can be exploited to predict clinical  outcomes. Considering the paucity of information about thyroid autoimmunity in  patients receiving cancer vaccines, we designed our study to assess the  development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX  (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and  correlated seroconversion with survival. Using both in house and commercial ELISA  assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No. =  35) or colon (No. = 8) cancer, before and after treatment with GVAX only (No. =  34), GVAX plus ipilimumab (No. = 42) or ipilimumab (No. = 20), and correlated  their levels with patient's survival, disease status and T-cell surface markers.   Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin  were also measured. TgAbs specifically developed after GVAX, independent of the  underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer)  and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus  ipilimumab). This TgAbs seroconversion could be detected mainly by the in house  assay, suggesting that the thyroglobulin epitopes recognized by the antibodies  induced by GVAX are different from the epitopes seen in the classic form of  Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with  significantly prolonged survival (p = 0.01 for pancreas and p = 0.005 for  prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of  TgAbs that recognize a unique antigenic repertoire and associate with prolonged  survival.CI  - (c) 2014 UICC.
CANIT0000277	24832153	Clinical research	Pancreatic (No. = 53), prostate (No. = 35) or colon (No. = 8) cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	96	N/A	N/A	GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival.	N/A	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2015 Jan 1	 Development of thyroglobulin antibodies after GVAX immunotherapy is associated  with prolonged survival.	 Int J Cancer	 Cancer immunotherapy induces a variety of autoinflammatory responses, including  those against the thyroid gland, which can be exploited to predict clinical  outcomes. Considering the paucity of information about thyroid autoimmunity in  patients receiving cancer vaccines, we designed our study to assess the  development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX  (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and  correlated seroconversion with survival. Using both in house and commercial ELISA  assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No. =  35) or colon (No. = 8) cancer, before and after treatment with GVAX only (No. =  34), GVAX plus ipilimumab (No. = 42) or ipilimumab (No. = 20), and correlated  their levels with patient's survival, disease status and T-cell surface markers.   Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin  were also measured. TgAbs specifically developed after GVAX, independent of the  underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer)  and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus  ipilimumab). This TgAbs seroconversion could be detected mainly by the in house  assay, suggesting that the thyroglobulin epitopes recognized by the antibodies  induced by GVAX are different from the epitopes seen in the classic form of  Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with  significantly prolonged survival (p = 0.01 for pancreas and p = 0.005 for  prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of  TgAbs that recognize a unique antigenic repertoire and associate with prolonged  survival.CI  - (c) 2014 UICC.
CANIT0000278	24832153	Clinical research	Pancreatic (No. = 53), prostate (No. = 35) or colon (No. = 8) cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus GM-CSF	N/A	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386)	96	N/A	N/A	GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival.	N/A	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2015 Jan 1	 Development of thyroglobulin antibodies after GVAX immunotherapy is associated  with prolonged survival.	 Int J Cancer	 Cancer immunotherapy induces a variety of autoinflammatory responses, including  those against the thyroid gland, which can be exploited to predict clinical  outcomes. Considering the paucity of information about thyroid autoimmunity in  patients receiving cancer vaccines, we designed our study to assess the  development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX  (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and  correlated seroconversion with survival. Using both in house and commercial ELISA  assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No. =  35) or colon (No. = 8) cancer, before and after treatment with GVAX only (No. =  34), GVAX plus ipilimumab (No. = 42) or ipilimumab (No. = 20), and correlated  their levels with patient's survival, disease status and T-cell surface markers.   Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin  were also measured. TgAbs specifically developed after GVAX, independent of the  underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer)  and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus  ipilimumab). This TgAbs seroconversion could be detected mainly by the in house  assay, suggesting that the thyroglobulin epitopes recognized by the antibodies  induced by GVAX are different from the epitopes seen in the classic form of  Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with  significantly prolonged survival (p = 0.01 for pancreas and p = 0.005 for  prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of  TgAbs that recognize a unique antigenic repertoire and associate with prolonged  survival.CI  - (c) 2014 UICC.
CANIT0000279	24832153	Clinical research	Pancreatic (No. = 53), prostate (No. = 35) or colon (No. = 8) cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	GM-CSF	N/A	Tumor vaccine	GM-CSF (DB05386)	96	N/A	N/A	GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival.	N/A	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2015 Jan 1	 Development of thyroglobulin antibodies after GVAX immunotherapy is associated  with prolonged survival.	 Int J Cancer	 Cancer immunotherapy induces a variety of autoinflammatory responses, including  those against the thyroid gland, which can be exploited to predict clinical  outcomes. Considering the paucity of information about thyroid autoimmunity in  patients receiving cancer vaccines, we designed our study to assess the  development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX  (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and  correlated seroconversion with survival. Using both in house and commercial ELISA  assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No. =  35) or colon (No. = 8) cancer, before and after treatment with GVAX only (No. =  34), GVAX plus ipilimumab (No. = 42) or ipilimumab (No. = 20), and correlated  their levels with patient's survival, disease status and T-cell surface markers.   Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin  were also measured. TgAbs specifically developed after GVAX, independent of the  underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer)  and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus  ipilimumab). This TgAbs seroconversion could be detected mainly by the in house  assay, suggesting that the thyroglobulin epitopes recognized by the antibodies  induced by GVAX are different from the epitopes seen in the classic form of  Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with  significantly prolonged survival (p = 0.01 for pancreas and p = 0.005 for  prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of  TgAbs that recognize a unique antigenic repertoire and associate with prolonged  survival.CI  - (c) 2014 UICC.
CANIT0000280	24832153	Clinical research	Pancreatic (No. = 53), prostate (No. = 35) or colon (No. = 8) cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	96	N/A	N/A	GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival.	N/A	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2015 Jan 1	 Development of thyroglobulin antibodies after GVAX immunotherapy is associated  with prolonged survival.	 Int J Cancer	 Cancer immunotherapy induces a variety of autoinflammatory responses, including  those against the thyroid gland, which can be exploited to predict clinical  outcomes. Considering the paucity of information about thyroid autoimmunity in  patients receiving cancer vaccines, we designed our study to assess the  development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX  (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and  correlated seroconversion with survival. Using both in house and commercial ELISA  assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No. =  35) or colon (No. = 8) cancer, before and after treatment with GVAX only (No. =  34), GVAX plus ipilimumab (No. = 42) or ipilimumab (No. = 20), and correlated  their levels with patient's survival, disease status and T-cell surface markers.   Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin  were also measured. TgAbs specifically developed after GVAX, independent of the  underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer)  and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus  ipilimumab). This TgAbs seroconversion could be detected mainly by the in house  assay, suggesting that the thyroglobulin epitopes recognized by the antibodies  induced by GVAX are different from the epitopes seen in the classic form of  Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with  significantly prolonged survival (p = 0.01 for pancreas and p = 0.005 for  prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of  TgAbs that recognize a unique antigenic repertoire and associate with prolonged  survival.CI  - (c) 2014 UICC.
CANIT0000281	24832153	Clinical research	Pancreatic (No. = 53), prostate (No. = 35) or colon (No. = 8) cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus GM-CSF	N/A	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386)	96	N/A	N/A	GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival.	N/A	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2015 Jan 1	 Development of thyroglobulin antibodies after GVAX immunotherapy is associated  with prolonged survival.	 Int J Cancer	 Cancer immunotherapy induces a variety of autoinflammatory responses, including  those against the thyroid gland, which can be exploited to predict clinical  outcomes. Considering the paucity of information about thyroid autoimmunity in  patients receiving cancer vaccines, we designed our study to assess the  development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX  (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and  correlated seroconversion with survival. Using both in house and commercial ELISA  assays, we measured TgAbs in patients with pancreatic (No. = 53), prostate (No. =  35) or colon (No. = 8) cancer, before and after treatment with GVAX only (No. =  34), GVAX plus ipilimumab (No. = 42) or ipilimumab (No. = 20), and correlated  their levels with patient's survival, disease status and T-cell surface markers.   Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin  were also measured. TgAbs specifically developed after GVAX, independent of the  underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer)  and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus  ipilimumab). This TgAbs seroconversion could be detected mainly by the in house  assay, suggesting that the thyroglobulin epitopes recognized by the antibodies  induced by GVAX are different from the epitopes seen in the classic form of  Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with  significantly prolonged survival (p = 0.01 for pancreas and p = 0.005 for  prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of  TgAbs that recognize a unique antigenic repertoire and associate with prolonged  survival.CI  - (c) 2014 UICC.
CANIT0000282	24885479	Clinical research	Pretreated metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); GVAX (DB04901); 	855	N/A	N/A	Outside of a clinical trial setting, ipilimumab is a   feasible treatment option in patients with pretreated metastatic melanoma,  regardless of BRAF and NRAS mutational status. Data from this large cohort of  patients support clinical trial evidence that ipilimumab can induce durable  disease control and long-term survival in patients who have failed to respond to   prior treatment.	Overall, 33% of patients reported an immune-related AE (irAE). The frequency of irAEs was not associated with response to ipilimumab.	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2014 May 7	 Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data   from an expanded access programme cohort.	 J Transl Med	 BACKGROUND: Ipilimumab improves survival in patients with advanced melanoma. The   activity and safety of ipilimumab outside of a clinical trial was assessed in an   expanded access programme (EAP). METHODS: Ipilimumab was available upon physician  request for patients aged 16 or over with pretreated stage III (unresectable)/IV   melanoma, for whom no other therapeutic option was available. Patients received  ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or   an objective response to ipilimumab were eligible for retreatment upon disease  progression. Tumour assessments were conducted at baseline and week 12. Patients   were monitored for adverse events (AEs) within 3 to 4 days of each scheduled  visit. RESULTS: Of 855 patients participating in the EAP in Italy, 833 were  evaluable for response. Of these, 13% had an objective immune response, and the  immune-related disease control rate was 34%. Median progression-free survival and  overall survival were 3.7 and 7.2 months, respectively. Efficacy was independent   of BRAF and NRAS mutational status. Overall, 33% of patients reported an  immune-related AE (irAE). The frequency of irAEs was not associated with response  to ipilimumab. CONCLUSIONS: Outside of a clinical trial setting, ipilimumab is a   feasible treatment option in patients with pretreated metastatic melanoma,  regardless of BRAF and NRAS mutational status. Data from this large cohort of  patients support clinical trial evidence that ipilimumab can induce durable  disease control and long-term survival in patients who have failed to respond to   prior treatment.
CANIT0000283	24885479	Clinical research	Pretreated metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); GVAX (DB04901); 	855	N/A	N/A	Outside of a clinical trial setting, ipilimumab is a   feasible treatment option in patients with pretreated metastatic melanoma,  regardless of BRAF and NRAS mutational status. Data from this large cohort of  patients support clinical trial evidence that ipilimumab can induce durable  disease control and long-term survival in patients who have failed to respond to   prior treatment.	Overall, 33% of patients reported an immune-related AE (irAE). The frequency of irAEs was not associated with response to ipilimumab.	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	 2014 May 7	 Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data   from an expanded access programme cohort.	 J Transl Med	 BACKGROUND: Ipilimumab improves survival in patients with advanced melanoma. The   activity and safety of ipilimumab outside of a clinical trial was assessed in an   expanded access programme (EAP). METHODS: Ipilimumab was available upon physician  request for patients aged 16 or over with pretreated stage III (unresectable)/IV   melanoma, for whom no other therapeutic option was available. Patients received  ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or   an objective response to ipilimumab were eligible for retreatment upon disease  progression. Tumour assessments were conducted at baseline and week 12. Patients   were monitored for adverse events (AEs) within 3 to 4 days of each scheduled  visit. RESULTS: Of 855 patients participating in the EAP in Italy, 833 were  evaluable for response. Of these, 13% had an objective immune response, and the  immune-related disease control rate was 34%. Median progression-free survival and  overall survival were 3.7 and 7.2 months, respectively. Efficacy was independent   of BRAF and NRAS mutational status. Overall, 33% of patients reported an  immune-related AE (irAE). The frequency of irAEs was not associated with response  to ipilimumab. CONCLUSIONS: Outside of a clinical trial setting, ipilimumab is a   feasible treatment option in patients with pretreated metastatic melanoma,  regardless of BRAF and NRAS mutational status. Data from this large cohort of  patients support clinical trial evidence that ipilimumab can induce durable  disease control and long-term survival in patients who have failed to respond to   prior treatment.
CANIT0000284	24903767	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	New-onset mediastinal and central nervous system sarcoidosis. The condition was successfully treated with corticosteroids	N/A	N/A	N/A	N/A	N/A	2014	 New-onset mediastinal and central nervous system sarcoidosis in a patient with  metastatic melanoma undergoing CTLA4 monoclonal antibody treatment.	 Oncol Res Treat	 BACKGROUND: Ipilimumab, a cytotoxic monoclonal antibody that inhibits cytotoxic T  lymphocyte-associated antigen-4 (CTLA-4), has been established as an effective  therapy in the management of advanced melanoma. Immune-mediated adverse events  are a common side effect. CASE REPORT: A 37-year-old male patient was diagnosed  with nodal and osseous metastatic melanoma 15 months after the initial surgical  treatment for lower limb melanoma. Therapy with the anti-CTLA-4 antibody,  ipilimumab, was started. Follow-up staging imaging after treatment initiation  showed symmetrical bihilar adenopathy. Transbronchial biopsy showed sarcoidosis.   The patient had associated systemic symptoms of fatigue, joint pains, anorexia  and weight loss. Brain magnetic resonance imaging (MRI), which was performed for   the investigation of headaches, showed abnormal enhancing tissue in the sella  turcica and adjacent to the pituitary infundibulum, consistent with  neurosarcoidosis. The condition was successfully treated with corticosteroids.  CONCLUSIONS: We report a case of immunotherapy-induced mediastinal/hilar  sarcoidosis, with pituitary involvement, mimicking tumour progression. This  highlights the need for awareness amongst radiologists and oncologists of the  mechanism of action and potential side effects of new immunotherapies.CI  - (c) 2014 S. Karger GmbH, Freiburg.
CANIT0000285	24907635	Clinical research	Metastatic pancreatic cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab plus gemcitabine	N/A	Immune checkpoint therapy plus Chemotherapy	Gemcitabine (DB00441); tremelimumab (DB11771); 	34	N/A	A phase I dose escalation trial	Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer.	No dose-limiting toxicities related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). 	N/A	N/A	N/A	N/A	N/A	 2014 Sep	 A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with   gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer.	 Ann Oncol	 BACKGROUND: Tremelimumab (CP-675,206) is a fully human monoclonal antibody  binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that  stimulates the immune system by blocking the CTLA4-negative regulatory signal.  Combination with standard chemotherapy may strengthen antitumor therapy. This is   a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating  the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab  combined with gemcitabine in patients with metastatic pancreatic cancer. PATIENTS  AND METHODS: Gemcitabine (1000 mg/m(2) on days 1, 8, and 15 of each 28-day  cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or  15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18  patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting  toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks  after the first dose of tremelimumab. RESULTS: From June 2008 to August 2011, 34   patients were enrolled and received at least one dose of tremelimumab. No DLTs  related to tremelimumab were observed at any dose, even when the maximum dose  established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4  toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a  serious drug-related event (diarrhea with dehydration). The median overall  survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of  treatment, two patients achieved partial response. Both patients received  tremelimumab 15-mg/kg group (n = 2/19, 10.5%). CONCLUSION: Tremelimumab plus  gemcitabine demonstrated a safety and tolerability profile, warranting further  study in patients with metastatic pancreatic cancer. CLINICALTRIALSGOV ID:  NCT00556023.CI  - (c) The Author 2014. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000286	24986059	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	Case	N/A	Serious haematological toxicity, but it is manageable and can be reversed with standard corticosteroid treatment	N/A	N/A	N/A	N/A	N/A	 2014 Jul 1	 Serious haematological toxicity during and after ipilimumab treatment: a case  series.	 J Med Case Rep	 INTRODUCTION: Immunotherapy with the anti-cytotoxic T-lymphocyte antigen-4  monoclonal antibody ipilimumab has been shown to improve overall survival in  previously treated and treatment-naive patients with unresectable stage III or IV  melanoma. Consistent with its proposed immunomodulating mechanism of action, the   most common toxicities associated with ipilimumab therapy are immune-related in  nature and include those related to the skin and gastrointestinal tract, with  endocrine and hepatic events also frequent. Other rare adverse events, including   haematological aberrations, may also occur and can have serious consequences if  unrecognised. Here we describe three patients who developed serious  haematological adverse events during or after treatment with ipilimumab. CASE  PRESENTATION: Three Caucasian patients (two women aged 68 and 49 years and one  man aged 70 years) with metastatic melanoma experienced anaemia and/or leukopenia  (neutropenia) with toxicity of various grades during or after treatment with  ipilimumab, without significant changes to other haematological values. Two of  the patients stopped treatment after the third ipilimumab dose, one because of  severe anaemia that required blood transfusion and the other due to febrile  neutropenia that was treated with antibiotics and granulocyte-macrophage  colony-stimulating factor stimulation. The third patient developed anaemia and  leukopenia after treatment during the follow-up period. The results of  autoimmunity tests performed were positive and corticosteroids were used to treat  these events as per side-effects treatment algorithms specifically developed for   the management of immune-related adverse events associated with ipilimumab, an  approach that was safe and effective. CONCLUSIONS: Haematological toxicity is a  rare but potentially serious immune-related side effect of ipilimumab therapy.  However, if promptly recognised and treated, haematological toxicity is  manageable and can be reversed with standard corticosteroid treatment as  recommended for other ipilimumab immune-related side effects.
CANIT0000287	24987057	Clinical research	Refractory gastrointestinal malignancies	Gastrointestinal stromal tumor	Orphanet:44890	Stomach	P53 (P04637); 	P53; 	MVA-P53 vaccine	N/A	Tumor vaccine	MVA-P53 vaccine (NCIT:C116868); 	12	N/A	A phase I clinical trial 	P53MVA was well tolerated and induced robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8(+) T-cell responses	Gene expression signature on/in immune cell	 2014 Sep 1	 p53MVA therapy in patients with refractory gastrointestinal malignancies elevates  p53-specific CD8+ T-cell responses.	 Clin Cancer Res	 PURPOSE: To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine  delivering wild-type human p53 (p53MVA) in patients with refractory  gastrointestinal cancers. EXPERIMENTAL DESIGN: Three patients were vaccinated  with 1.0x10(8) plaque-forming unit (pfu) p53MVA followed by nine patients at  5.6x10(8) pfu. Toxicity was classified using the NCI Common Toxicity Criteria and  clinical responses were assessed by CT scan. Peripheral blood samples were  collected pre- and post-immunization for immunophenotyping, monitoring of  p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in  vitro. RESULTS: p53MVA immunization was well tolerated at both doses, with no  adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition   of a p53 overlapping peptide library were detectable after the first  immunization, particularly in the CD8+ T-cell compartment (P=0.03). However, in  most patients, this did not expand further with the second and third  immunization. The frequency of PD1+ T cells detectable in patients' peripheral  blood mononuclear cells (PBMC) was significantly higher than in healthy controls.  Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation  with the peak CD8+ p53 response (P=0.02) and antibody blockade of PD1 in vitro  increased the p53 immune responses detected after the second or third  immunizations. Induction of strong T-cell and antibody responses to the MVA  backbone were also apparent. CONCLUSION: p53MVA was well tolerated and induced  robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint  inhibition could help sustain immune responses and lead to enhanced clinical  benefit.CI  - (c)2014 American Association for Cancer Research.
CANIT0000288	25008236	Basic research	Human Burkitts lymphoma cell line (Daudi)	Burkitts lymphoma	EFO:0000309	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Basic research	Expansion of ATC in the presence of ipilimumab significantly improves not only the T cell proliferation but it also enhances cytokine secretion and the specific cytotoxicity of T cells armed with bispecific antibodies.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2014 Jul 9	 Ipilimumab augments antitumor activity of bispecific antibody-armed T cells.	 J Transl Med	 BACKGROUND: Ipilimumab is an antagonistic monoclonal antibody against cytotoxic  T-lymphocyte antigen-4 (CTLA-4) that enhances antitumor immunity by inhibiting  immunosuppressive activity of regulatory T cells (Treg). In this study, we  investigated whether inhibiting Treg activity with ipilimumab during ex vivo T  cell expansion could augment anti-CD3-driven T cell proliferation and enhance  bispecific antibody (BiAb)-redirected antitumor cytotoxicity of activated T cells  (ATC). METHODS: PBMC from healthy individuals were stimulated with anti-CD3  monoclonal antibody with or without ipilimumab and expanded for 10-14 days. ATC  were harvested and armed with anti-CD3 x anti-EGFR BiAb (EGFRBi) or anti-CD3 x  anti-CD20 BiAb (CD20Bi) to test for redirected cytotoxicity against COLO356/FG  pancreatic cancer cell line or Burkitt's lymphoma cell line (Daudi). RESULTS: In   PBMC from healthy individuals, the addition of ipilimumab at the initiation of  culture significantly enhanced T cell proliferation (p = 0.0029). ATC grown in  the presence of ipilimumab showed significantly increased mean tumor-specific  cytotoxicity at effector:target (E:T) ratio of 25:1 directed at COLO356/FG and  Daudi by 37.71% (p < 0.0004) and 27.5% (p < 0.0004), respectively, and increased   the secretion of chemokines (CCL2, CCL3, CCL4,CCL5, CXCL9, and  granulocyte-macrophage colony stimulating factor(GM-CSF)) and cytokines  (IFN-gamma, IL-2R, IL-12, and IL-13), while reducing IL-10 secretion.  CONCLUSIONS: Expansion of ATC in the presence of ipilimumab significantly  improves not only the T cell proliferation but it also enhances cytokine  secretion and the specific cytotoxicity of T cells armed with bispecific  antibodies.
CANIT0000289	25008236	Basic research	Human pancreatic cancer cell line	Pancreatic carcinoma	EFO:0002618	Pancreas	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Basic research	Expansion of ATC in the presence of ipilimumab significantly improves not only the T cell proliferation but it also enhances cytokine secretion and the specific cytotoxicity of T cells armed with bispecific antibodies.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2014 Jul 9	 Ipilimumab augments antitumor activity of bispecific antibody-armed T cells.	 J Transl Med	 BACKGROUND: Ipilimumab is an antagonistic monoclonal antibody against cytotoxic  T-lymphocyte antigen-4 (CTLA-4) that enhances antitumor immunity by inhibiting  immunosuppressive activity of regulatory T cells (Treg). In this study, we  investigated whether inhibiting Treg activity with ipilimumab during ex vivo T  cell expansion could augment anti-CD3-driven T cell proliferation and enhance  bispecific antibody (BiAb)-redirected antitumor cytotoxicity of activated T cells  (ATC). METHODS: PBMC from healthy individuals were stimulated with anti-CD3  monoclonal antibody with or without ipilimumab and expanded for 10-14 days. ATC  were harvested and armed with anti-CD3 x anti-EGFR BiAb (EGFRBi) or anti-CD3 x  anti-CD20 BiAb (CD20Bi) to test for redirected cytotoxicity against COLO356/FG  pancreatic cancer cell line or Burkitt's lymphoma cell line (Daudi). RESULTS: In   PBMC from healthy individuals, the addition of ipilimumab at the initiation of  culture significantly enhanced T cell proliferation (p = 0.0029). ATC grown in  the presence of ipilimumab showed significantly increased mean tumor-specific  cytotoxicity at effector:target (E:T) ratio of 25:1 directed at COLO356/FG and  Daudi by 37.71% (p < 0.0004) and 27.5% (p < 0.0004), respectively, and increased   the secretion of chemokines (CCL2, CCL3, CCL4,CCL5, CXCL9, and  granulocyte-macrophage colony stimulating factor(GM-CSF)) and cytokines  (IFN-gamma, IL-2R, IL-12, and IL-13), while reducing IL-10 secretion.  CONCLUSIONS: Expansion of ATC in the presence of ipilimumab significantly  improves not only the T cell proliferation but it also enhances cytokine  secretion and the specific cytotoxicity of T cells armed with bispecific  antibodies.
CANIT0000290	25034862	Clinical research	Ipilimumab-refractory advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	173	N/A	A phase I clinical trial 	The results suggest that  pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an  effective treatment in patients for whom there are few effective treatment  options.	Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient.	N/A	N/A	N/A	N/A	N/A	 2014 Sep 20	 Anti-programmed-death-receptor-1 treatment with pembrolizumab in  ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a  phase 1 trial.	 Lancet	 BACKGROUND: The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab  has shown potent antitumour activity at different doses and schedules in patients  with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2  mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced   melanoma. METHODS: In an open-label, international, multicentre expansion cohort   of a phase 1 trial, patients (aged >/=18 years) with advanced melanoma whose  disease had progressed after at least two ipilimumab doses were randomly assigned  with a computer-generated allocation schedule (1:1 final ratio) to intravenous  pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease  progression, intolerable toxicity, or consent withdrawal. Primary endpoint was  overall response rate (ORR) assessed with the Response Evaluation Criteria In  Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was  done on the full-analysis set (all treated patients with measurable disease at  baseline). This study is registered with ClinicalTrials.gov, number NCT01295827.   FINDINGS: 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84).   Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81  patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%,   95% CI -14 to 13; p=0.96). Treatment was well tolerated, with similar safety  profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most   common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg  groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and   rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in  the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse  event reported in more than one patient. INTERPRETATION: The results suggest that  pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an  effective treatment in patients for whom there are few effective treatment  options. FUNDING: Merck Sharp and Dohme.CI  - Copyright (c) 2014 Elsevier Ltd. All rights reserved.
CANIT0000291	25052849	Clinical research	Prostate cancer	Prostate cancer	MONDO:0008315	Prostate	HER2 (P04626); 	HER2; 	AE37 vaccine	N/A	Tumor vaccine	AE37 vaccine (NCIT:C91719); 	23	N/A	A retrospective cohort study	DTH reactions were a stronger indicator for patients' overall survival (OS) than preexistent or vaccine-induced IFN- immunity.	N/A	N/A	N/A	Delayed type hypersensitivity response (NCIT:C3115); 	Delayed-type hypersensitivity reactions	Disease status	 2014 Nov	 AE37 peptide vaccination in prostate cancer: identification of biomarkers in the   context of prognosis and prediction.	 Cancer Immunol Immunother	 A fundamental challenge in administering immunotherapies for cancer is the  establishment of biomarkers that can predict patients' responsiveness to  treatment. In this study, our aim was to predict the immunologic and clinical  responses of vaccination therapy with an Ii-key-modified HER-2/neu peptide  (Ii-key/HER-2(776-790) or AE37), applied in our recent phase I study in patients   with prostate cancer. To this end, we retrospectively analyzed our data derived  from immunologic determinations before, during and after primary series of  vaccinations with AE37, as well as after one AE37 booster injection. Using the  obtained data, we then observed the relationship between the immunologic  parameters and clinical outcome of patients. We found that preexisting levels of   transforming growth factor beta (TGF-beta) had an inverse correlation with in  vivo and in vitro immunologic responses to the AE37 vaccine which were measured  as delayed-type hypersensitivity (DTH) and interferon gamma (IFN-gamma)  production in response to the native HER-2(776-790) (or AE36) peptide,  respectively. Patients with preexistent IFNG immunity to AE36 developed  positive DTH reactions after primary vaccinations and booster. Moreover, we could  detect a direct correlation between IFNG production and DTH reactions in  response to AE36 challenge in our vaccinated patients. DTH reactions were a  stronger indicator for patients' overall survival (OS) than preexistent or  vaccine-induced IFNG immunity. In contrast, we found that preexisting  TGF-beta levels were correlated with shorter patients' OS. These retrospective  analyses suggest that the above biomarkers at the time-points measured offer  promise for evaluating immunologic and clinical responses to AE37-based  vaccinations.
CANIT0000292	25052849	Clinical research	Prostate cancer	Prostate cancer	MONDO:0008315	Prostate	HER2 (P04626); 	HER2; 	AE37 vaccine	N/A	Tumor vaccine	AE37 vaccine (NCIT:C91719); 	23	N/A	A retrospective cohort study	Preexisting levels of transforming growth factor beta (TGF-b) had an inverse correlation with in vivo and in vitro immunologic responses to the AE37 vaccine. Preexisting transforming growth factor beta (TGF-b) levels were correlated with shorter patients' OS.	N/A	N/A	N/A	TGFB (P01137); 	Serum TGFB expression levels	Gene expression signature in serum	 2014 Nov	 AE37 peptide vaccination in prostate cancer: identification of biomarkers in the   context of prognosis and prediction.	 Cancer Immunol Immunother	 A fundamental challenge in administering immunotherapies for cancer is the  establishment of biomarkers that can predict patients' responsiveness to  treatment. In this study, our aim was to predict the immunologic and clinical  responses of vaccination therapy with an Ii-key-modified HER-2/neu peptide  (Ii-key/HER-2(776-790) or AE37), applied in our recent phase I study in patients   with prostate cancer. To this end, we retrospectively analyzed our data derived  from immunologic determinations before, during and after primary series of  vaccinations with AE37, as well as after one AE37 booster injection. Using the  obtained data, we then observed the relationship between the immunologic  parameters and clinical outcome of patients. We found that preexisting levels of   transforming growth factor beta (TGF-beta) had an inverse correlation with in  vivo and in vitro immunologic responses to the AE37 vaccine which were measured  as delayed-type hypersensitivity (DTH) and interferon gamma (IFN-gamma)  production in response to the native HER-2(776-790) (or AE36) peptide,  respectively. Patients with preexistent IFNG immunity to AE36 developed  positive DTH reactions after primary vaccinations and booster. Moreover, we could  detect a direct correlation between IFNG production and DTH reactions in  response to AE36 challenge in our vaccinated patients. DTH reactions were a  stronger indicator for patients' overall survival (OS) than preexistent or  vaccine-induced IFNG immunity. In contrast, we found that preexisting  TGF-beta levels were correlated with shorter patients' OS. These retrospective  analyses suggest that the above biomarkers at the time-points measured offer  promise for evaluating immunologic and clinical responses to AE37-based  vaccinations.
CANIT0000293	25075567	Clinical research	Unresectable stage III or IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	198	N/A	A retrospective cohort study	The occurrence of irAE correlated significantly with the probability of response to therapy and prolonged OS. In this named-patient program including heavily pretreated patients, the efficacy and tolerability of ipilimumab 3 mg/kg corresponds with findings from the confirmatory clinical trial.	Immune-related adverse events (irAE) were reported in 30% of all treated patients, the occurrence of irAE correlated significantly with the probability of response to therapy and prolonged OS.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2014 Sep	 Effectiveness and tolerability of ipilimumab: experiences from 198 patients  included in a named-patient program in various daily-practice settings and  multiple institutions.	 J Immunother	 BACKGROUND: Ipilimumab is an approved anti-cytotoxic T-lymphocyte-associated  antigen-4 monoclonal antibody introducing immune responses in melanoma patients.   Treatment experiences from named-patient programs support the evaluation of the  efficacy and tolerability of new medicines under usual circumstances of health  care practice. Here, the largest ever reported cohort treated with ipilimumab 3  mg/kg alone is described. METHODS: This report retrospectively analyzes data of  198 patients who were followed up in 15 hospital centers in Germany between April  2010 and March 2013. Patients had received prior therapy for unresectable stage  III or IV melanoma before receiving ipilimumab (4 doses of 3 mg/kg every 21 d).  Routine staging and tumor response evaluation procedures were applied. RESULTS:  Of the patients, 119 received the planned 4-course therapy schedule; in further  79 patients, the number of doses was reduced mainly because of toxicity or fast  progression. In all, 196 patients were eligible for evaluation of the efficacy of  ipilimumab under routine care conditions. Median overall survival (OS) was 6.8  months [95% confidence interval, 5.6-10.3] from the start of therapy. OS differed  significantly among patients who received 4 doses (n=119) and those receiving <4   doses (n=79) (14.2 vs. 2.0 mo; P<0.0001). The overall response rate (ORR) of 11%   was in the same range as reported from previous clinical trials; and stable  disease (SD) was observed in 11% resulting in a disease control rate (ORR+SD) of   22%. In 23 of the 79 patients with reduced dosing, dose omission was most  probably caused by toxicity, whereas 56 patients had progressive disease before  receiving all 4 treatment cycles. Immune-related adverse events (irAE) were  reported in 30% of all treated patients, the occurrence of irAE correlated  significantly with the probability of response to therapy and prolonged OS.  CONCLUSION: In this named-patient program including heavily pretreated patients,   the efficacy and tolerability of ipilimumab 3 mg/kg corresponds with findings  from the confirmatory clinical trial.
CANIT0000294	25078147	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	154	N/A	A  multicenter clinical trial	Male gender was risk factors for Ipi-induced hypophysitis (IH).	Ipi-induced hypophysitis (IH) was diagnosed in 17 patients (11%). Male gender (P = .02) and older age (P = .005), but not the cumulative dose of Ipi, were risk factors for IH. All patients with IH had anterior hypopituitarism (none had diabetes insipidus). Hypopituitarism was persistent in most individuals (76%). Diffuse pituitary enlargement was observed exclusively in all cases of IH and, upon retrospective review of magnetic resonance imaging scans, this finding preceded the clinical diagnosis of hypophysitis in eight patients. Pituitary enlargement resolved rapidly (within 40 d in seven of seven patients).	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2014 Nov	 Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large  cohort of patients with metastatic melanoma.	 J Clin Endocrinol Metab	 CONTEXT: Ipilimumab (Ipi) is approved by the Food and Drug Administration for the  treatment of unresectable or metastatic melanoma. Little is known about  Ipi-induced hypophysitis (IH), an important treatment complication. OBJECTIVE:  The objectives of the study were as follows: 1) to examine the prevalence of IH,   2) to characterize the clinical course and treatment outcomes in IH, 3) to  identify the risk factors for the development of IH, and 4) to determine optimal   strategies for the management of IH. DESIGN: This was a retrospective review.  SETTING: The study was conducted at a tertiary referral center. SUBJECTS: One  hundred fifty-four adult patients with metastatic melanoma were evaluated at  Massachusetts General Hospital and were treated with Ipi between March 2008 and  December 2013. INTERVENTION(S): The intervention included treatment with Ipi.  MAIN OUTCOME MEASURE(S): Pituitary magnetic resonance imaging, pituitary hormone   assessment, and patient survival were measured. RESULTS: IH was diagnosed in 17  patients (11%). Male gender (P = .02) and older age (P = .005), but not the  cumulative dose of Ipi, were risk factors for IH. All patients with IH had  anterior hypopituitarism (none had diabetes insipidus). Hypopituitarism was  persistent in most individuals (76%). Diffuse pituitary enlargement was observed   exclusively in all cases of IH and, upon retrospective review of magnetic  resonance imaging scans, this finding preceded the clinical diagnosis of  hypophysitis in eight patients. Pituitary enlargement resolved rapidly (within 40  d in seven of seven patients). Median survival in patients with IH was 19.4 vs  8.8 months (P = .05) in the remainder of the cohort. CONCLUSIONS: Male gender and  older age are risk factors for IH. Pituitary enlargement is sensitive and  specific for IH in the appropriate setting, can precede the clinical diagnosis,  and resolves rapidly. Anterior pituitary function recovery is uncommon. The  incidence of hypophysitis may positively predict survival in melanoma patients  treated with Ipi.
CANIT0000295	25078147	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	154	N/A	A  multicenter clinical trial	Not the cumulative dose of Ipi was risk factors for Ipi-induced hypophysitis (IH).	Ipi-induced hypophysitis (IH) was diagnosed in 17 patients (11%). Male gender (P = .02) and older age (P = .005), but not the cumulative dose of Ipi, were risk factors for IH. All patients with IH had anterior hypopituitarism (none had diabetes insipidus). Hypopituitarism was persistent in most individuals (76%). Diffuse pituitary enlargement was observed exclusively in all cases of IH and, upon retrospective review of magnetic resonance imaging scans, this finding preceded the clinical diagnosis of hypophysitis in eight patients. Pituitary enlargement resolved rapidly (within 40 d in seven of seven patients).	N/A	N/A	Treatment doses (NCIT:C25488); 	Cumulative dose of Ipilimumab	Exposure factors/status	 2014 Nov	 Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large  cohort of patients with metastatic melanoma.	 J Clin Endocrinol Metab	 CONTEXT: Ipilimumab (Ipi) is approved by the Food and Drug Administration for the  treatment of unresectable or metastatic melanoma. Little is known about  Ipi-induced hypophysitis (IH), an important treatment complication. OBJECTIVE:  The objectives of the study were as follows: 1) to examine the prevalence of IH,   2) to characterize the clinical course and treatment outcomes in IH, 3) to  identify the risk factors for the development of IH, and 4) to determine optimal   strategies for the management of IH. DESIGN: This was a retrospective review.  SETTING: The study was conducted at a tertiary referral center. SUBJECTS: One  hundred fifty-four adult patients with metastatic melanoma were evaluated at  Massachusetts General Hospital and were treated with Ipi between March 2008 and  December 2013. INTERVENTION(S): The intervention included treatment with Ipi.  MAIN OUTCOME MEASURE(S): Pituitary magnetic resonance imaging, pituitary hormone   assessment, and patient survival were measured. RESULTS: IH was diagnosed in 17  patients (11%). Male gender (P = .02) and older age (P = .005), but not the  cumulative dose of Ipi, were risk factors for IH. All patients with IH had  anterior hypopituitarism (none had diabetes insipidus). Hypopituitarism was  persistent in most individuals (76%). Diffuse pituitary enlargement was observed   exclusively in all cases of IH and, upon retrospective review of magnetic  resonance imaging scans, this finding preceded the clinical diagnosis of  hypophysitis in eight patients. Pituitary enlargement resolved rapidly (within 40  d in seven of seven patients). Median survival in patients with IH was 19.4 vs  8.8 months (P = .05) in the remainder of the cohort. CONCLUSIONS: Male gender and  older age are risk factors for IH. Pituitary enlargement is sensitive and  specific for IH in the appropriate setting, can precede the clinical diagnosis,  and resolves rapidly. Anterior pituitary function recovery is uncommon. The  incidence of hypophysitis may positively predict survival in melanoma patients  treated with Ipi.
CANIT0000296	25078147	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	154	N/A	A  multicenter clinical trial	Older age was risk factors for Ipi-induced hypophysitis (IH).	Ipi-induced hypophysitis (IH) was diagnosed in 17 patients (11%). Male gender (P = .02) and older age (P = .005), but not the cumulative dose of Ipi, were risk factors for IH. All patients with IH had anterior hypopituitarism (none had diabetes insipidus). Hypopituitarism was persistent in most individuals (76%). Diffuse pituitary enlargement was observed exclusively in all cases of IH and, upon retrospective review of magnetic resonance imaging scans, this finding preceded the clinical diagnosis of hypophysitis in eight patients. Pituitary enlargement resolved rapidly (within 40 d in seven of seven patients).	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2014 Nov	 Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large  cohort of patients with metastatic melanoma.	 J Clin Endocrinol Metab	 CONTEXT: Ipilimumab (Ipi) is approved by the Food and Drug Administration for the  treatment of unresectable or metastatic melanoma. Little is known about  Ipi-induced hypophysitis (IH), an important treatment complication. OBJECTIVE:  The objectives of the study were as follows: 1) to examine the prevalence of IH,   2) to characterize the clinical course and treatment outcomes in IH, 3) to  identify the risk factors for the development of IH, and 4) to determine optimal   strategies for the management of IH. DESIGN: This was a retrospective review.  SETTING: The study was conducted at a tertiary referral center. SUBJECTS: One  hundred fifty-four adult patients with metastatic melanoma were evaluated at  Massachusetts General Hospital and were treated with Ipi between March 2008 and  December 2013. INTERVENTION(S): The intervention included treatment with Ipi.  MAIN OUTCOME MEASURE(S): Pituitary magnetic resonance imaging, pituitary hormone   assessment, and patient survival were measured. RESULTS: IH was diagnosed in 17  patients (11%). Male gender (P = .02) and older age (P = .005), but not the  cumulative dose of Ipi, were risk factors for IH. All patients with IH had  anterior hypopituitarism (none had diabetes insipidus). Hypopituitarism was  persistent in most individuals (76%). Diffuse pituitary enlargement was observed   exclusively in all cases of IH and, upon retrospective review of magnetic  resonance imaging scans, this finding preceded the clinical diagnosis of  hypophysitis in eight patients. Pituitary enlargement resolved rapidly (within 40  d in seven of seven patients). Median survival in patients with IH was 19.4 vs  8.8 months (P = .05) in the remainder of the cohort. CONCLUSIONS: Male gender and  older age are risk factors for IH. Pituitary enlargement is sensitive and  specific for IH in the appropriate setting, can precede the clinical diagnosis,  and resolves rapidly. Anterior pituitary function recovery is uncommon. The  incidence of hypophysitis may positively predict survival in melanoma patients  treated with Ipi.
CANIT0000297	25124688	Clinical research	EBV-positive nasopharyngeal carcinoma	Nasopharyngeal squamous cell carcinoma	EFO:1000058	Head and neck	LMP2 (P13285); EBNA1 (P03211); 	LMP2; EBNA1	MVA-EL vaccine	N/A	Tumor vaccine	MVA-EBNA1/LMP2 Vaccine (NCIT:C91076); 	16	N/A	A phase I clinical trial 	MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5  10(8) pfu) is recommended for investigation in current phase IB and II trials.	N/A	N/A	N/A	Epstein-Barr Virus (NCIT:C14204); 	EBV-positive	Microbiota	 2014 Oct 1	 A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV)   target antigens: a phase I trial in UK patients with EBV-positive cancer.	 Clin Cancer Res	 PURPOSE: Epstein-Barr virus (EBV) is associated with several cancers in which the  tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising  a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these  tumor antigens. A phase I trial was conducted to demonstrate the safety and  immunogenicity of MVA-EL across a range of doses. EXPERIMENTAL DESIGN: Sixteen  patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma  (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at   dose levels between 5 x 10(7) and 5 x 10(8) plaque-forming units (pfu). Blood  samples were taken at screening, after each vaccine cycle, and during the  post-vaccination period. T-cell responses were measured using IFNG ELISpot  assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides.  Polychromatic flow cytometry was used to characterize functionally responsive  T-cell populations. RESULTS: Vaccination was generally well tolerated. Immunity  increased after vaccination to at least one antigen in 8 of 14 patients (7/14,  EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV  strains associated with different ethnic groups. Immunophenotypic analysis  revealed that vaccination induced differentiation and functional diversification   of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and  CD8 compartments, respectively. CONCLUSIONS: MVA-EL is safe and immunogenic  across diverse ethnicities and thus suitable for use in trials against different   EBV-positive cancers globally as well as in South-East Asia where NPC is most  common. The highest dose (5 x 10(8) pfu) is recommended for investigation in  current phase IB and II trials.CI  - (c)2014 American Association for Cancer Research.
CANIT0000298	25168392	Basic research	Orthotopic renal carcinoma model	Renal carcinoma	EFO:0002890	Kidney	TLR9 (Q9NR96); MUC1 (P15941); 	TLR9; MUC1	MVA-MUC1 vaccine through intravenous (i.v.) administration	MVA-MUC1 vaccine through subcutaneously (s.c.) administration	Immune checkpoint therapy plus Tumor vaccine 	MVA-MUC1 vaccine (NCIT:C2241); 	Cell lines/ animal models	N/A	Basic research	This study supports the clinical evaluation of MVA-based immunotherapies via the i.v. route.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2014 Dec	 Intravenous injection of MVA virus targets CD8+ lymphocytes to tumors to control   tumor growth upon combinatorial treatment with a TLR9 agonist.	 Cancer Immunol Res	 Effector T-cell access to tumor tissue is a limiting step for clinical efficacy  of antigen-specific T cell-based immunotherapies. Ectopic mouse tumor models, in   which a subcutaneously (s.c.) implanted tumor is treated with s.c. or  intramuscular therapeutic immunization, may not be optimal for targeting effector  T cells to an organ-borne tumor. We used an orthotopic renal carcinoma model to  evaluate the impact of injection routes on therapeutic efficacy of a Modified  Vaccinia virus Ankara viral vector expressing the human mucin 1 tumor-associated   xeno-antigen (MVA-MUC1). We show that intravenous (i.v.) administration of  MVA-MUC1 displayed enhanced efficacy when compared with s.c. injection.  Therapeutic efficacy of MVA-MUC1 was further enhanced by i.v. injection of a TLR9  agonist. In all cases, infiltration of tumor-bearing kidney by CD8(+) lymphocytes  was associated with control of tumor growth. Biodistribution experiments indicate  that, following i.v. injection, MVA-encoded antigens are quickly expressed in  visceral organs and, in particular, in splenic antigen-presenting cells, compared  with those following s.c. injection. This appears to result in a faster  generation of MUC1-specific CD8(+) T cells. Lymphocytes infiltrating  tumor-bearing kidneys are characterized by an effector memory phenotype and  express PD-1 and Tim3 immune checkpoint molecules. Therapeutic efficacy was  associated with a modification of the tumor microenvironment toward a Th1-type  immune response and recruitment of activated lymphocytes. This study supports the  clinical evaluation of MVA-based immunotherapies via the i.v. route.CI  - (c)2014 American Association for Cancer Research.
CANIT0000299	25168392	Basic research	Orthotopic renal carcinoma model	Renal carcinoma	EFO:0002890	Kidney	TLR9 (Q9NR96); MUC1 (P15941); 	TLR9; MUC1	TLR9 agonist plus MVA-MUC1 vaccine	MVA-MUC1 vaccine	Immune checkpoint therapy plus Tumor vaccine 	TLR-9 agonist (NCIT:C74083); MVA-MUC1 vaccine (NCIT:C2241); 	Cell lines/ animal models	N/A	Basic research	Therapeutic efficacy of MVA-MUC1 was further enhanced by i.v. injection of a TLR9 agonist.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2014 Dec	 Intravenous injection of MVA virus targets CD8+ lymphocytes to tumors to control   tumor growth upon combinatorial treatment with a TLR9 agonist.	 Cancer Immunol Res	 Effector T-cell access to tumor tissue is a limiting step for clinical efficacy  of antigen-specific T cell-based immunotherapies. Ectopic mouse tumor models, in   which a subcutaneously (s.c.) implanted tumor is treated with s.c. or  intramuscular therapeutic immunization, may not be optimal for targeting effector  T cells to an organ-borne tumor. We used an orthotopic renal carcinoma model to  evaluate the impact of injection routes on therapeutic efficacy of a Modified  Vaccinia virus Ankara viral vector expressing the human mucin 1 tumor-associated   xeno-antigen (MVA-MUC1). We show that intravenous (i.v.) administration of  MVA-MUC1 displayed enhanced efficacy when compared with s.c. injection.  Therapeutic efficacy of MVA-MUC1 was further enhanced by i.v. injection of a TLR9  agonist. In all cases, infiltration of tumor-bearing kidney by CD8(+) lymphocytes  was associated with control of tumor growth. Biodistribution experiments indicate  that, following i.v. injection, MVA-encoded antigens are quickly expressed in  visceral organs and, in particular, in splenic antigen-presenting cells, compared  with those following s.c. injection. This appears to result in a faster  generation of MUC1-specific CD8(+) T cells. Lymphocytes infiltrating  tumor-bearing kidneys are characterized by an effector memory phenotype and  express PD-1 and Tim3 immune checkpoint molecules. Therapeutic efficacy was  associated with a modification of the tumor microenvironment toward a Th1-type  immune response and recruitment of activated lymphocytes. This study supports the  clinical evaluation of MVA-based immunotherapies via the i.v. route.CI  - (c)2014 American Association for Cancer Research.
CANIT0000300	25185693	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); BRAF (P15056); 	CTLA-4; BRAF	Ipilimumab plus dacarbazine followed by vemurafenib	N/A	Immune checkpoint therapy followed by Target therapy	Ipilimumab (DB06186); vemurafenib (DB08881); dacarbazine (DB00851); 	1	N/A	Case	Dramatic response of vemurafenib-induced cutaneous lesions	N/A	N/A	N/A	N/A	N/A	N/A	 2014 Oct	 Dramatic response of vemurafenib-induced cutaneous lesions upon switch to dual  BRAF/MEK inhibition in a metastatic melanoma patient.	 Melanoma Res	 BRAF inhibitory therapy is the mainstream treatment for BRAF mutant advanced  melanoma. However vemurafenib, a type I mutant BRAF V600 inhibitor, induces an  array of proliferative skin disorders from keratosis pilaris-like and  keratoacanthoma-like lesions to locally aggressive cutaneous squamous cell  carcinoma (cuSCC). Dual BRAF/MEK inhibition is known to lower the incidence of  such manifestations, but it is not known whether it can counteract established  lesions. Here we show, for the first time, a dramatic response and a restitution   ad integro upon dual inhibition of a widespread proliferative affection induced  by BRAF monotherapy. A 75-year-old woman was diagnosed with a BRAF V600E mutated   metastatic melanoma. Following dacarbazine (DTIC) and ipilimumab, the patient was  started on 960 mg twice daily vemurafenib (Zelboraf), which resulted in complete   response, but the patient also developed grade IV skin toxicity. Despite  dose-reduction to 720 mg twice daily the side effects persisted. We hypothesized   that a switch to double inhibition of the mitogen-activated protein kinase  pathway with dabrafenib and trametinib could lead to improvement of the skin  lesions, while preserving tumor control. The patient was closely followed for  changes in skin lesions. We witnessed a rapid regression followed by complete  disappearance of all side effects of vemurafenib except for grade I fatigue. The   biopsied skin lesions show regression of established keratoacanthoma-like lesions  with signs of apoptosis. Switching from the current standard of care vemurafenib   therapy to the double BRAF/MEK inhibition in BRAF mutant melanoma patients  results in rapid disappearance of established proliferative skin disorders.
CANIT0000301	25207976	Case report	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Thyroid function tests should be performed for all patients prior to their commencement of Ipilimumab. Thyroid-like eye disease may develop in patients treated with Ipilimumab even if they remain euthyroid.	Thyroid-like ophthalmopathy	N/A	N/A	N/A	N/A	N/A	 2014 Dec	 Thyroid-like ophthalmopathy in a euthyroid patient receiving Ipilimumab.	 Orbit	 A 68-year-old lady with metastatic malignant melanoma was treated with  Ipilimumab. She presented to Eye Casualty unable to move her eyes. Physical  examination confirmed ophthalmoplegia and identified proptosis bilaterally.  Radiological imaging showed bilateral enlargement of all the extra-ocular muscles  suggestive of thyroid eye disease. Laboratory investigations found this patient  to be euthyroid. A diagnosis of thyroid-like orbitopathy secondary to Ipilimumab   therapy was made. Thyroid function tests should be performed for all patients  prior to their commencement of Ipilimumab. Thyroid-like eye disease may develop  in patients treated with Ipilimumab even if they remain euthyroid.
CANIT0000302	25227926	Case report	Metastatic melanoma and Behcets disease	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	1	N/A	Case	Complete remission	N/A	N/A	N/A	N/A	N/A	N/A	 2014 Dec	 Successful treatment with Ipilimumab and Interleukin-2 in two patients with  metastatic melanoma and systemic autoimmune disease.	 Cancer Immunol Immunother	 Two patients were treated with immunotherapy for metastatic malignant melanoma  (MM) despite suffering from systemic autoimmune disease, i.e., ulcerative colitis  (UC) and Behcets disease (BD), respectively. Both patients benefitted from the  treatment. The patient with UC achieved partial remission of all measurable  parameters after treatment with Ipilimumab, while the patient with BD achieved a   complete remission of MM after treatment with Interleukin-2 (IL-2) and  Interferon-alpha (IFN-alpha). Moreover, no aggravation of symptoms related to the  autoimmune diseases was seen during treatment, in contrast, clinical indications   of improvement were observed. These two cases illustrate that the presence of  autoimmune disease does not necessarily predict increased autoimmune toxicity in   connection with immunotherapy. They also raise the question of whether autoimmune  disease should continue to be an absolute exclusion criterion for treatment of MM  with immunotherapy. Consequently, given the poor prognosis of refractory MM,  immunotherapies need to be taken into consideration even in cases of autoimmune  comorbidity due to the potential long-term benefit that these therapies offer to   MM patients.
CANIT0000303	25227926	Case report	Metastatic melanoma and ulcerative colitis	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Partial remission	N/A	N/A	N/A	N/A	N/A	N/A	 2014 Dec	 Successful treatment with Ipilimumab and Interleukin-2 in two patients with  metastatic melanoma and systemic autoimmune disease.	 Cancer Immunol Immunother	 Two patients were treated with immunotherapy for metastatic malignant melanoma  (MM) despite suffering from systemic autoimmune disease, i.e., ulcerative colitis  (UC) and Behcets disease (BD), respectively. Both patients benefitted from the  treatment. The patient with UC achieved partial remission of all measurable  parameters after treatment with Ipilimumab, while the patient with BD achieved a   complete remission of MM after treatment with Interleukin-2 (IL-2) and  Interferon-alpha (IFN-alpha). Moreover, no aggravation of symptoms related to the  autoimmune diseases was seen during treatment, in contrast, clinical indications   of improvement were observed. These two cases illustrate that the presence of  autoimmune disease does not necessarily predict increased autoimmune toxicity in   connection with immunotherapy. They also raise the question of whether autoimmune  disease should continue to be an absolute exclusion criterion for treatment of MM  with immunotherapy. Consequently, given the poor prognosis of refractory MM,  immunotherapies need to be taken into consideration even in cases of autoimmune  comorbidity due to the potential long-term benefit that these therapies offer to   MM patients.
CANIT0000304	25232180	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	40	N/A	N/A	The observation that anti-CTLA-4 treatment induces a significant number of newly detected T cell responses-but only infrequently boosts preexisting immune responses-provides strong evidence for anti-CTLA-4 therapy-enhanced T cell priming as a component of the clinical mode of action.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Melanoma-specific CD8 T-cell responses	Gene expression signature on/in immune cell	 2014 Sep 17	 Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response.	 Sci Transl Med	 Anti-CTLA-4 treatment improves the survival of patients with advanced-stage  melanoma. However, although the anti-CTLA-4 antibody ipilimumab is now an  approved treatment for patients with metastatic disease, it remains unknown by  which mechanism it boosts tumor-specific T cell activity. In particular, it is  unclear whether treatment amplifies previously induced T cell responses or  whether it induces new tumor-specific T cell reactivities. Using a combination  ultraviolet (UV)-induced peptide exchange and peptide-major histocompatibility  complex (pMHC) combinatorial coding, we monitored immune reactivity against a  panel of 145 melanoma-associated epitopes in a cohort of patients receiving  anti-CTLA-4 treatment. Comparison of pre- and posttreatment T cell reactivities  in peripheral blood mononuclear cell samples of 40 melanoma patients demonstrated  that anti-CTLA-4 treatment induces a significant increase in the number of  detectable melanoma-specific CD8 T cell responses (P = 0.0009). In striking  contrast, the magnitude of both virus-specific and melanoma-specific T cell  responses that were already detected before start of therapy remained unaltered  by treatment (P = 0.74). The observation that anti-CTLA-4 treatment induces a  significant number of newly detected T cell responses-but only infrequently  boosts preexisting immune responses-provides strong evidence for anti-CTLA-4  therapy-enhanced T cell priming as a component of the clinical mode of action.CI  - Copyright (c) 2014, American Association for the Advancement of Science.
CANIT0000305	25263811	Clinical research	Lymphoma	Lymphoma	EFO:0000574	Blood and lymph nodes	N/A (N/A); 	N/A; 	Hematopoietic stem cell transplantation	N/A	Cell immunotherapy	Hematopoietic stem cell transplantation (NCIT:C15431); 	296	N/A	N/A	Out of the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/= 25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.	Increased death risk in patients with bloodstream infection by Gram-negative	N/A	N/A	Gram-negative infection (NCIT:C2890); 	Bloodstream infection by Gram-negative	Microbiota	 2014 Dec	 Risk factor for death in hematopoietic stem cell transplantation: are biomarkers   useful to foresee the prognosis in this population of patients 	 Infection	 BACKGROUND: The morbidity and mortality in hematopoietic stem cell  transplantation (HSCT) occur due to infectious complications and constitute the  major clinical problems in HSCT recipients. The role of the use of biomarkers in   post-HSCT patients is still controversial. OBJECTIVES: To assess the serum values  of biomarkers interleukin 6 (IL-6), procalcitonin (PCT) and C-reactive protein  (CRP) and risk factors for post-HSCT death. PATIENTS AND METHODS: Prospective  study conducted in patients submitted to HSCT at a university hospital.  Biomarkers (IL-6, PCT and CRP) were assessed on the day afebrile neutropenia was   detected, in the febrile event, 24 and 72 h after fever onset and 48 h or 5 days   if fever persisted. Patients were compared as to the death outcome within 30 days  from the HSCT. Variables with p < 0.15 were included in the multivariate analysis  model (MVA) that were performed for all patients included in the study and  separated for autologous and allogeneic HSCT patients. RESULTS: 296 patients with  ages ranging between 15 and 70 years, neutropenic, submitted to HSCT, being 216  (73%) autologous and 80 (20%) allogeneic were assessed. One hundred and ninety  (64.2%) patients presented fever after the transplantation and infection  microbiologically controlled in 78 (26.4%). Twenty-three cases (7.8%) evolved to   death. The risk factors associated with death in the bivariate analysis were age,  allogeneic transplantation, unrelated transplantation, GVHD, bloodstream  infection by Gram-negative, IL-6 >140 pg/mL and CRP >/= 120 mg/L and the  protective ones were lymphoma and hospital outpatient support. The independent  variables in the MVA associated with death were allogeneic and unrelated  transplantation, blood stream infection (BSI) by Gram-negative, LDH >/= 390 UI/L,  urea >/= 25 mg/dL and CRP >/= 120 mg/L for HSCT transplanted patients and BSI due  to Gram-negative and CRP >/= 120 mg/L for allogeneic HSCT, however, CRP >/= 120  mg/L did not remain in the model when urea >/= 25 mg/L was included. No  independent risk factor was found for autologous patients. CONCLUSIONS: Out of  the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with   death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/=  25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to  Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.
CANIT0000306	25263811	Clinical research	Lymphoma	Lymphoma	EFO:0000574	Blood and lymph nodes	N/A (N/A); 	N/A; 	Hematopoietic stem cell transplantation	N/A	Cell immunotherapy	Hematopoietic stem cell transplantation (NCIT:C15431); 	296	N/A	N/A	Out of the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/= 25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.	Increased death risk in patients with CRP  120 mg/L	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2014 Dec	 Risk factor for death in hematopoietic stem cell transplantation: are biomarkers   useful to foresee the prognosis in this population of patients 	 Infection	 BACKGROUND: The morbidity and mortality in hematopoietic stem cell  transplantation (HSCT) occur due to infectious complications and constitute the  major clinical problems in HSCT recipients. The role of the use of biomarkers in   post-HSCT patients is still controversial. OBJECTIVES: To assess the serum values  of biomarkers interleukin 6 (IL-6), procalcitonin (PCT) and C-reactive protein  (CRP) and risk factors for post-HSCT death. PATIENTS AND METHODS: Prospective  study conducted in patients submitted to HSCT at a university hospital.  Biomarkers (IL-6, PCT and CRP) were assessed on the day afebrile neutropenia was   detected, in the febrile event, 24 and 72 h after fever onset and 48 h or 5 days   if fever persisted. Patients were compared as to the death outcome within 30 days  from the HSCT. Variables with p < 0.15 were included in the multivariate analysis  model (MVA) that were performed for all patients included in the study and  separated for autologous and allogeneic HSCT patients. RESULTS: 296 patients with  ages ranging between 15 and 70 years, neutropenic, submitted to HSCT, being 216  (73%) autologous and 80 (20%) allogeneic were assessed. One hundred and ninety  (64.2%) patients presented fever after the transplantation and infection  microbiologically controlled in 78 (26.4%). Twenty-three cases (7.8%) evolved to   death. The risk factors associated with death in the bivariate analysis were age,  allogeneic transplantation, unrelated transplantation, GVHD, bloodstream  infection by Gram-negative, IL-6 >140 pg/mL and CRP >/= 120 mg/L and the  protective ones were lymphoma and hospital outpatient support. The independent  variables in the MVA associated with death were allogeneic and unrelated  transplantation, blood stream infection (BSI) by Gram-negative, LDH >/= 390 UI/L,  urea >/= 25 mg/dL and CRP >/= 120 mg/L for HSCT transplanted patients and BSI due  to Gram-negative and CRP >/= 120 mg/L for allogeneic HSCT, however, CRP >/= 120  mg/L did not remain in the model when urea >/= 25 mg/L was included. No  independent risk factor was found for autologous patients. CONCLUSIONS: Out of  the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with   death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/=  25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to  Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.
CANIT0000307	25263811	Clinical research	Lymphoma	Lymphoma	EFO:0000574	Blood and lymph nodes	N/A (N/A); 	N/A; 	Hematopoietic stem cell transplantation	N/A	Cell immunotherapy	Hematopoietic stem cell transplantation (NCIT:C15431); 	296	N/A	N/A	Out of the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/= 25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.	Increased death risk in patients with LDH  390 UI/L	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2014 Dec	 Risk factor for death in hematopoietic stem cell transplantation: are biomarkers   useful to foresee the prognosis in this population of patients 	 Infection	 BACKGROUND: The morbidity and mortality in hematopoietic stem cell  transplantation (HSCT) occur due to infectious complications and constitute the  major clinical problems in HSCT recipients. The role of the use of biomarkers in   post-HSCT patients is still controversial. OBJECTIVES: To assess the serum values  of biomarkers interleukin 6 (IL-6), procalcitonin (PCT) and C-reactive protein  (CRP) and risk factors for post-HSCT death. PATIENTS AND METHODS: Prospective  study conducted in patients submitted to HSCT at a university hospital.  Biomarkers (IL-6, PCT and CRP) were assessed on the day afebrile neutropenia was   detected, in the febrile event, 24 and 72 h after fever onset and 48 h or 5 days   if fever persisted. Patients were compared as to the death outcome within 30 days  from the HSCT. Variables with p < 0.15 were included in the multivariate analysis  model (MVA) that were performed for all patients included in the study and  separated for autologous and allogeneic HSCT patients. RESULTS: 296 patients with  ages ranging between 15 and 70 years, neutropenic, submitted to HSCT, being 216  (73%) autologous and 80 (20%) allogeneic were assessed. One hundred and ninety  (64.2%) patients presented fever after the transplantation and infection  microbiologically controlled in 78 (26.4%). Twenty-three cases (7.8%) evolved to   death. The risk factors associated with death in the bivariate analysis were age,  allogeneic transplantation, unrelated transplantation, GVHD, bloodstream  infection by Gram-negative, IL-6 >140 pg/mL and CRP >/= 120 mg/L and the  protective ones were lymphoma and hospital outpatient support. The independent  variables in the MVA associated with death were allogeneic and unrelated  transplantation, blood stream infection (BSI) by Gram-negative, LDH >/= 390 UI/L,  urea >/= 25 mg/dL and CRP >/= 120 mg/L for HSCT transplanted patients and BSI due  to Gram-negative and CRP >/= 120 mg/L for allogeneic HSCT, however, CRP >/= 120  mg/L did not remain in the model when urea >/= 25 mg/L was included. No  independent risk factor was found for autologous patients. CONCLUSIONS: Out of  the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with   death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/=  25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to  Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.
CANIT0000308	25263811	Clinical research	Lymphoma	Lymphoma	EFO:0000574	Blood and lymph nodes	N/A (N/A); 	N/A; 	Hematopoietic stem cell transplantation	N/A	Cell immunotherapy	Hematopoietic stem cell transplantation (NCIT:C15431); 	296	N/A	N/A	Out of the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/= 25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.	Increased death risk in patients with unrelated transplantation	N/A	N/A	Type of transplantation (NCIT:C15342); 	Type of transplantation (allogeneic and unrelated)	Exposure factors/status	 2014 Dec	 Risk factor for death in hematopoietic stem cell transplantation: are biomarkers   useful to foresee the prognosis in this population of patients 	 Infection	 BACKGROUND: The morbidity and mortality in hematopoietic stem cell  transplantation (HSCT) occur due to infectious complications and constitute the  major clinical problems in HSCT recipients. The role of the use of biomarkers in   post-HSCT patients is still controversial. OBJECTIVES: To assess the serum values  of biomarkers interleukin 6 (IL-6), procalcitonin (PCT) and C-reactive protein  (CRP) and risk factors for post-HSCT death. PATIENTS AND METHODS: Prospective  study conducted in patients submitted to HSCT at a university hospital.  Biomarkers (IL-6, PCT and CRP) were assessed on the day afebrile neutropenia was   detected, in the febrile event, 24 and 72 h after fever onset and 48 h or 5 days   if fever persisted. Patients were compared as to the death outcome within 30 days  from the HSCT. Variables with p < 0.15 were included in the multivariate analysis  model (MVA) that were performed for all patients included in the study and  separated for autologous and allogeneic HSCT patients. RESULTS: 296 patients with  ages ranging between 15 and 70 years, neutropenic, submitted to HSCT, being 216  (73%) autologous and 80 (20%) allogeneic were assessed. One hundred and ninety  (64.2%) patients presented fever after the transplantation and infection  microbiologically controlled in 78 (26.4%). Twenty-three cases (7.8%) evolved to   death. The risk factors associated with death in the bivariate analysis were age,  allogeneic transplantation, unrelated transplantation, GVHD, bloodstream  infection by Gram-negative, IL-6 >140 pg/mL and CRP >/= 120 mg/L and the  protective ones were lymphoma and hospital outpatient support. The independent  variables in the MVA associated with death were allogeneic and unrelated  transplantation, blood stream infection (BSI) by Gram-negative, LDH >/= 390 UI/L,  urea >/= 25 mg/dL and CRP >/= 120 mg/L for HSCT transplanted patients and BSI due  to Gram-negative and CRP >/= 120 mg/L for allogeneic HSCT, however, CRP >/= 120  mg/L did not remain in the model when urea >/= 25 mg/L was included. No  independent risk factor was found for autologous patients. CONCLUSIONS: Out of  the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with   death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/=  25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to  Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.
CANIT0000309	25263811	Clinical research	Lymphoma	Lymphoma	EFO:0000574	Blood and lymph nodes	N/A (N/A); 	N/A; 	Hematopoietic stem cell transplantation	N/A	Cell immunotherapy	Hematopoietic stem cell transplantation (NCIT:C15431); 	296	N/A	N/A	Out of the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/= 25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.	Increased death risk in patients with urea  25 mg/L	N/A	N/A	Urea (NCIT:C29531); 	Urea levels	Metabolite	 2014 Dec	 Risk factor for death in hematopoietic stem cell transplantation: are biomarkers   useful to foresee the prognosis in this population of patients 	 Infection	 BACKGROUND: The morbidity and mortality in hematopoietic stem cell  transplantation (HSCT) occur due to infectious complications and constitute the  major clinical problems in HSCT recipients. The role of the use of biomarkers in   post-HSCT patients is still controversial. OBJECTIVES: To assess the serum values  of biomarkers interleukin 6 (IL-6), procalcitonin (PCT) and C-reactive protein  (CRP) and risk factors for post-HSCT death. PATIENTS AND METHODS: Prospective  study conducted in patients submitted to HSCT at a university hospital.  Biomarkers (IL-6, PCT and CRP) were assessed on the day afebrile neutropenia was   detected, in the febrile event, 24 and 72 h after fever onset and 48 h or 5 days   if fever persisted. Patients were compared as to the death outcome within 30 days  from the HSCT. Variables with p < 0.15 were included in the multivariate analysis  model (MVA) that were performed for all patients included in the study and  separated for autologous and allogeneic HSCT patients. RESULTS: 296 patients with  ages ranging between 15 and 70 years, neutropenic, submitted to HSCT, being 216  (73%) autologous and 80 (20%) allogeneic were assessed. One hundred and ninety  (64.2%) patients presented fever after the transplantation and infection  microbiologically controlled in 78 (26.4%). Twenty-three cases (7.8%) evolved to   death. The risk factors associated with death in the bivariate analysis were age,  allogeneic transplantation, unrelated transplantation, GVHD, bloodstream  infection by Gram-negative, IL-6 >140 pg/mL and CRP >/= 120 mg/L and the  protective ones were lymphoma and hospital outpatient support. The independent  variables in the MVA associated with death were allogeneic and unrelated  transplantation, blood stream infection (BSI) by Gram-negative, LDH >/= 390 UI/L,  urea >/= 25 mg/dL and CRP >/= 120 mg/L for HSCT transplanted patients and BSI due  to Gram-negative and CRP >/= 120 mg/L for allogeneic HSCT, however, CRP >/= 120  mg/L did not remain in the model when urea >/= 25 mg/L was included. No  independent risk factor was found for autologous patients. CONCLUSIONS: Out of  the biomarkers assessed, only CRP >/= 120 mg/L was independently associated with   death. Other risk factors found were: type of transplantation (allogeneic and  unrelated), bloodstream infection by Gram-negative, LDH >/= 390 UI/L and urea >/=  25 mg/dL. For allogeneic patients only CRP >/= 120 mg/L and BSI due to  Gram-negative were risk factors for death; however, CRP did not remain in the  model when urea >/= 25 mg/L was included.
CANIT0000310	25321335	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	This case adds to the expanding literature regarding immune-related adverse events associated with ipilimumab. To our knowledge, drug-induced dermatomyositis from ipilimumab has not previously been reported.	We describe a woman undergoing treatment with ipilimumab for metastatic melanoma who developed classic cutaneous findings of dermatomyositis along with proximal muscle weakness and elevated muscle enzymes.	N/A	N/A	N/A	N/A	N/A	 2015 Feb	 Drug-associated dermatomyositis following ipilimumab therapy: a novel  immune-mediated adverse event associated with cytotoxic T-lymphocyte antigen 4  blockade.	 JAMA Dermatol	 IMPORTANCE: Ipilimumab, a human monoclonal antibody targeted against cytotoxic  T-lymphocyte antigen 4, has shown promise in the treatment of metastatic  melanoma. However, given its mechanism of action, immune-related adverse effects   have been reported with this therapy. Despite increasing reports of  immune-related adverse effects related to ipilimumab therapy, dermatomyositis  associated with this agent has not previously been reported. OBSERVATIONS: We  describe a woman undergoing treatment with ipilimumab for metastatic melanoma who  developed classic cutaneous findings of dermatomyositis along with proximal  muscle weakness and elevated muscle enzymes. CONCLUSIONS AND RELEVANCE: This case  adds to the expanding literature regarding immune-related adverse events  associated with ipilimumab. To our knowledge, drug-induced dermatomyositis from  ipilimumab has not previously been reported. Physicians should be aware of these   potential immune-related adverse events and consider drug-associated  dermatomyositis in the differential diagnosis in patients receiving ipilimumab  who present with a cutaneous eruption or muscle weakness.
CANIT0000311	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Breast cancer	MONDO:0007254	Breast	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000312	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Esophageal carcinoma	EFO:0002916	Esophagus	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000313	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Laryngeal carcinoma	MONDO:0002358	Head and neck	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000314	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Liposarcoma	EFO:0000569	Soft tissue	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000315	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Non-small cell lung carcinoma	EFO:0003060	Lung	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000316	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Ovarian carcinoma	EFO:0001075	Ovary	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000317	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Pancreatic carcinoma	EFO:0002618	Pancreas	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000318	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Rectum cancer	EFO:1000657	Intestines	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000319	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Thymic cancer	MONDO:0002586	Thymus	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000320	25327557	Clinical research	Metastatic solid tumors(10 non-small cell lung carcinoma, 8 Breast cancer, 2 Laryngeal cancer, 2 Esophageal cancer, 2 Ovarian cancer, 1Uterine cancer, 1 Thymus cancer, 1 Liposarcoma cancer, 1 Rectal cancer, 1 pancreatic carcinoma)	Uterine cancer	MONDO:0002715	Uterus	IDO1 (P14902); 	IDO1; 	Indoximod plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Docetaxel (DB01248); indoximod (DB12827); 	27	N/A	A phase I clinical trial 	Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.	DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).	N/A	N/A	N/A	N/A	N/A	 2014 Sep 30	 A first in man phase I trial of the oral immunomodulator, indoximod, combined  with docetaxel in patients with metastatic solid tumors.	 Oncotarget	 BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to  create a state of immunosuppression. Indoximod is an IDO pathway inhibitor.  Preclinical studies demonstrated that indoximod combined with chemotherapy was  synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed  to study the combination of docetaxel and indoximod. METHODS: Docetaxel was  administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2  for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO  twice daily continuously for levels 1-5, respectively. Serum drug levels were  measured. RESULTS: Twenty-seven patients were treated, with 22 evaluable for  response. DLTs included grade 3 dehydration (level 1), hypotension(level 4),  mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the  recommended phase II dose. The most frequent adverse events were fatigue (58.6%),  anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%).  There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug   interactions were noted. CONCLUSIONS: Docetaxel plus indoximod was well tolerated  with no increase in expected toxicities or pharmacokinetic interactions. It was  active in a pretreated population of patients with metastatic solid tumors.
CANIT0000321	25345808	Basic research	Mouse tumor models	Cancer	EFO:0000311	Other	TLR3 (O15455); MRC1 (P22897); 	TLR3; MRC1	Poly-CpG plus B11-hCG	B11-hCG	Tumor vaccine plus Immune cytokine	CpG-ODN (NCIT:C62280); B11-hCG (DB09126); 	HMR-Tg mice	HMR-Tg mice	Basic research	This study provides insight into the mechanisms by which adjuvants can augment immune responses to B11-hCGbeta and have implications for the rationale design of clinical studies combining MR-targeted vaccination with TLR agonists.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2015 Nov	 Toll-like receptor agonists shape the immune responses to a mannose  receptor-targeted cancer vaccine.	 Cell Mol Immunol	 Previous studies have documented that selective delivery of protein antigens to  cells expressing mannose receptor (MR) can lead to enhanced immune responses. We   postulated that agents that influenced the MR expression level, and the  activation and migration status of MR-expressing antigen presenting cells, would   modulate immune responses to MR-targeted vaccines. To address this question, we  investigated the effect of clinically used adjuvants in human MR transgenic  (hMR-Tg) mice immunized with an MR-targeting cancer vaccine composed of the human  anti-MR monoclonal antibody B11 fused with the oncofetal protein, human chorionic  gonadotropin beta chain (hCGbeta), and referred to as B11-hCGbeta. We found that   humoral responses to low doses of B11-hCGbeta could be enhanced by prior  administration of GM-CSF, which upregulated MR expression in vivo. However,  co-administration of the Toll-like receptor (TLR) agonists, poly-ICLC and/or CpG   with B11-hCGbeta was required to elicit Th1 immunity, as measured by  antigen-specific T-cell production of IFN-gamma. The TLR agonists were shown to  increase the number of vaccine-containing cells in the draining lymph nodes of  immunized hMR-Tg mice. In particular, with B11-hCGbeta and poly-ICLC, a dramatic   increase in vaccine-positive cells was observed in the T-cell areas of the lymph   nodes, compared to the vaccine alone or combined with GM-CSF. Importantly, the  absence of the TLR agonists during the priming immunization led to  antigen-specific tolerance. Therefore, this study provides insight into the  mechanisms by which adjuvants can augment immune responses to B11-hCGbeta and  have implications for the rationale design of clinical studies combining  MR-targeted vaccination with TLR agonists.
CANIT0000322	25345808	Basic research	Mouse tumor models	Cancer	EFO:0000311	Other	TLR3 (O15455); MRC1 (P22897); 	TLR3; MRC1	Poly-ICLC plus B11-hCG 	B11-hCG	Tumor vaccine plus Immune cytokine	Poly-ICLC (NCIT:C1198); B11-hCG (DB09126); 	HMR-Tg mice	HMR-Tg mice	Basic research	This study provides insight into the mechanisms by which adjuvants can augment immune responses to B11-hCGbeta and have implications for the rationale design of clinical studies combining MR-targeted vaccination with TLR agonists.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2015 Nov	 Toll-like receptor agonists shape the immune responses to a mannose  receptor-targeted cancer vaccine.	 Cell Mol Immunol	 Previous studies have documented that selective delivery of protein antigens to  cells expressing mannose receptor (MR) can lead to enhanced immune responses. We   postulated that agents that influenced the MR expression level, and the  activation and migration status of MR-expressing antigen presenting cells, would   modulate immune responses to MR-targeted vaccines. To address this question, we  investigated the effect of clinically used adjuvants in human MR transgenic  (hMR-Tg) mice immunized with an MR-targeting cancer vaccine composed of the human  anti-MR monoclonal antibody B11 fused with the oncofetal protein, human chorionic  gonadotropin beta chain (hCGbeta), and referred to as B11-hCGbeta. We found that   humoral responses to low doses of B11-hCGbeta could be enhanced by prior  administration of GM-CSF, which upregulated MR expression in vivo. However,  co-administration of the Toll-like receptor (TLR) agonists, poly-ICLC and/or CpG   with B11-hCGbeta was required to elicit Th1 immunity, as measured by  antigen-specific T-cell production of IFN-gamma. The TLR agonists were shown to  increase the number of vaccine-containing cells in the draining lymph nodes of  immunized hMR-Tg mice. In particular, with B11-hCGbeta and poly-ICLC, a dramatic   increase in vaccine-positive cells was observed in the T-cell areas of the lymph   nodes, compared to the vaccine alone or combined with GM-CSF. Importantly, the  absence of the TLR agonists during the priming immunization led to  antigen-specific tolerance. Therefore, this study provides insight into the  mechanisms by which adjuvants can augment immune responses to B11-hCGbeta and  have implications for the rationale design of clinical studies combining  MR-targeted vaccination with TLR agonists.
CANIT0000323	25396683	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	101	N/A	A retrospective cohort study	These data suggest that survival was improved in patients who were amenable to local therapies (LTs); however, they had better prognostic markers at diagnosis of metastatic disease.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Metastatic disease	Disease status	 2015 Feb	 The Mayo Clinic experience with the use of kinase inhibitors, ipilimumab,  bevacizumab, and local therapies in the treatment of metastatic uveal melanoma.	 Melanoma Res	 Uveal melanoma is the most common neoplasm of the adult eye. Many patients will  develop metastatic disease, for which there is no standard of care. Therefore, we  sought to review our experience with treating this neoplasm. We retrospectively  reviewed all of the cases of metastatic uveal melanoma seen at the Mayo Clinic,  Rochester, Minnesota, USA, between 1 January 2000 and 1 August 2013. Overall  survival rates were compared among patients treated with local therapies (LTs),  ipilumumab, bevacizumab, or kinase inhibitors. A total of 101 patients were  included in the study, among whom 59% were male; the median age was 62 years  (interquartile range 54-71), and 92% had an Eastern Cooperative Oncology Group  performance status of 0-1. Treatment with LT was associated with increased median  overall survival: 26 months (n=46; interquartile range 20-44) versus 9.1 months  (n=55; 4.1-20, P<0.0001). No significant survival benefit was seen with the use  of bevacizumab (25 vs. 12 months; P=0.09), ipilimumab (28 vs. 13 months; P=0.07),  or kinase inhibitors (24 vs. 13 months; P=0.06). Multivariate analysis showed LT   as the only therapy to significantly improve survival (risk ratio 0.23,  P=0.0003). However, these patients had better markers of prognosis at the time of  treatment. These data suggest that survival was improved in patients who were  amenable to LTs; however, they had better prognostic markers at diagnosis of  metastatic disease. Ongoing prospective clinical trials will define the roles of   these novel agents in this patient population.
CANIT0000324	25396684	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	64	N/A	N/A	Objective tumor responses to ipi-based immunotherapy can still be obtained after progression has occurred upon treatment with a BRAFi.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Feb	 Objective responses can be obtained by CTLA-4 inhibition in metastatic melanoma  after BRAF inhibitor failure.	 Melanoma Res	 The aim of this study was to determine the activity of ipilimumab (ipi)-based  therapy after treatment failure with a BRAF inhibitor (BRAFi). Sixty-four  patients with unresectable stage III or stage IV BRAF V600-mutant melanoma who  were treated sequentially with a BRAFi and ipi-based therapy [ipi as monotherapy   or ipi in combination with an autologous mRNA electroporated dendritic cell  vaccine (TriMixDC-MEL)] were identified. Thirty-three patients had been treated  with a BRAFi before ipi-based therapy (BRAFi-first), and 31 patients had been  treated with ipi-based therapy first (ipi-first). In patients treated with a  BRAFi first (n=33), the best response on sequential ipi-based therapy was three  complete responses and six partial responses (best objective response rate of  27%). In patients treated with ipi-based therapy first (n=31), the best response   on ipi-based therapy was 0 complete response and four partial responses (best  objective response rate of 13%). The response rate did not differ significantly  between the two groups (P=0.14). The median overall survival from the start of  ipi-based therapy was 10 months (95% confidence interval: 5.7-14.3) in the  BRAFi-first group and 12.3 months (95% confidence interval: 7.4-17.2) in the  ipi-first group (P=0.34). We report that objective tumor responses to ipi-based  immunotherapy can still be obtained after progression has occurred upon treatment  with a BRAFi. A part of this observation might be related to the results obtained  with a combination of ipi and TriMixDC-MEL.
CANIT0000325	25409260	Clinical research	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	64	N/A	N/A	Better outcome in patients with high mutational load	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2014 Dec 4	 Genetic basis for clinical response to CTLA-4 blockade in melanoma.	 N Engl J Med	 BACKGROUND: Immune checkpoint inhibitors are effective cancer treatments, but  molecular determinants of clinical benefit are unknown. Ipilimumab and  tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4).  Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4  blockade activates T cells and enables them to destroy tumor cells. METHODS: We  obtained tumor tissue from patients with melanoma who were treated with  ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and  matched blood samples. Somatic mutations and candidate neoantigens generated from  these mutations were characterized. Neoantigen peptides were tested for the  ability to activate lymphocytes from ipilimumab-treated patients. RESULTS:  Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were  characterized with the use of massively parallel sequencing. A discovery set  consisted of 11 patients who derived a long-term clinical benefit and 14 patients  who derived a minimal benefit or no benefit. Mutational load was associated with   the degree of clinical benefit (P=0.01) but alone was not sufficient to predict  benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA  typing, we identified candidate tumor neoantigens for each patient. We elucidated  a neoantigen landscape that is specifically present in tumors with a strong  response to CTLA-4 blockade. We validated this signature in a second set of 39  patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted  neoantigens activated T cells from the patients treated with ipilimumab.  CONCLUSIONS: These findings define a genetic basis for benefit from CTLA-4  blockade in melanoma and provide a rationale for examining exomes of patients for  whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund  and others.).
CANIT0000326	25409260	Clinical research	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	64	N/A	N/A	Better outcome in patients with neoepitope signature	N/A	N/A	N/A	Neoantigen load (NCIT:C154155); 	Neoepitope signature	Gene expression signature on/in tumor cell	 2014 Dec 4	 Genetic basis for clinical response to CTLA-4 blockade in melanoma.	 N Engl J Med	 BACKGROUND: Immune checkpoint inhibitors are effective cancer treatments, but  molecular determinants of clinical benefit are unknown. Ipilimumab and  tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4).  Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4  blockade activates T cells and enables them to destroy tumor cells. METHODS: We  obtained tumor tissue from patients with melanoma who were treated with  ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and  matched blood samples. Somatic mutations and candidate neoantigens generated from  these mutations were characterized. Neoantigen peptides were tested for the  ability to activate lymphocytes from ipilimumab-treated patients. RESULTS:  Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were  characterized with the use of massively parallel sequencing. A discovery set  consisted of 11 patients who derived a long-term clinical benefit and 14 patients  who derived a minimal benefit or no benefit. Mutational load was associated with   the degree of clinical benefit (P=0.01) but alone was not sufficient to predict  benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA  typing, we identified candidate tumor neoantigens for each patient. We elucidated  a neoantigen landscape that is specifically present in tumors with a strong  response to CTLA-4 blockade. We validated this signature in a second set of 39  patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted  neoantigens activated T cells from the patients treated with ipilimumab.  CONCLUSIONS: These findings define a genetic basis for benefit from CTLA-4  blockade in melanoma and provide a rationale for examining exomes of patients for  whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund  and others.).
CANIT0000327	25416723	Clinical research	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	15	N/A	N/A	Ipilimumab-induced hypophysitis is a common side-effect with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies improved, except for corticotroph function. Patients receiving these  immunomodulatory therapies should be closely monitored especially by systematic  baseline hormone measurements after the third infusion and remain at a risk of adrenal insufficiency in the long-term.	Hypophysitis	N/A	N/A	Hormone measurement (NCIT:C74742); 	Baseline hormone measurements	Gene expression signature in serum	 2015 Feb	 Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of  the anti-CTLA-4 antibody in melanoma.	 Eur J Endocrinol	 OBJECTIVE: Few data are published on the long-term follow-up of  ipilimumab-induced hypophysitis, a cytotoxic T-lymphocyte antigen 4 antibody. We   characterized hypophysitis in terms of clinical signs, endocrinological profile,   and imaging at diagnosis and during a long-term follow-up. DESIGN AND PATIENTS:  Fifteen patients, treated for malignant melanoma and who presented  ipilimumab-induced hypophysitis, were observed between June 2006 and August 2012   in Timone Hospital, Marseille. METHODS: Symptoms, pituitary function, and  pituitary imaging at diagnosis of hypophysitis and during the follow-up were  recorded. RESULTS: Of 131 patients treated with ipilimumab or a placebo, 15  patients (10 mg/kg in 11/15) presented with hypophysitis (>/=11.5%) at 9.5+/-5.9   weeks (mean+/-s.d.) after treatment start, occurring in 66% after the third  infusion. The main initial symptoms were headache (n=13) and asthenia (n=11). All  patients but one had at least one hormonal defect: thyrotroph (n=13), gonadotroph  (n=12), or corticotroph (n=11) deficiencies. None had diabetes insipidus.  Pituitary imaging showed a moderately enlarged gland in 12 patients. Clinical  symptoms improved rapidly on high-dose glucocorticoids (n=11) or physiological  replacement doses (n=4). At the end of follow-up (median 33.6 months, range  7-53.5), corticotroph deficiency remained in 13 patients, 11 recovered thyrotroph  and ten gonadotroph functions. Pituitary imaging remained abnormal in 11  patients. CONCLUSION: Ipilimumab-induced hypophysitis is a common side-effect  with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies   improved, except for corticotroph function. Patients receiving these  immunomodulatory therapies should be closely monitored especially by systematic  baseline hormone measurements after the third infusion and remain at a risk of  adrenal insufficiency in the long-term.CI  - (c) 2015 European Society of Endocrinology.
CANIT0000328	25424847	Clinical research	WHO grade 2 low-grade glioma	Glioma	EFO:0005543	Brain	TLR3 (O15455); glioma-associated antigen epitopes (N/A)	TLR3; glioma-associated antigen epitopes	Vaccination with glioma-associated antigen peptides plus poly-ICLC	N/A	Tumor vaccine	Poly-ICLC (NCIT:C1198); peptide-based vaccines (NCIT:C120475); 	23	N/A	A phase I clinical trial	The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade 2 glioma patients.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Jan 15	 Induction of robust type-I CD8+ T-cell responses in WHO grade 2 low-grade glioma   patients receiving peptide-based vaccines in combination with poly-ICLC.	 Clin Cancer Res	 PURPOSE: WHO grade 2 low-grade gliomas (LGG) with high risk factors for  recurrence are mostly lethal despite current treatments. We conducted a phase I  study to evaluate the safety and immunogenicity of subcutaneous vaccinations with  synthetic peptides for glioma-associated antigen (GAA) epitopes in HLA-A2(+)  adults with high-risk LGGs in the following three cohorts: (i) patients without  prior progression, chemotherapy, or radiotherapy (RT); (ii) patients without  prior progression or chemotherapy but with prior RT; and (iii) recurrent  patients. EXPERIMENTAL DESIGN: GAAs were IL13Ralpha2, EphA2, WT1, and Survivin.  Synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks  for eight courses with intramuscular injections of poly-ICLC, followed by q12  week booster vaccines. RESULTS: Cohorts 1, 2, and 3 enrolled 12, 1, and 10  patients, respectively. No regimen-limiting toxicity was encountered except for  one case with grade 3 fever, fatigue, and mood disturbance (cohort 1). ELISPOT  assays demonstrated robust IFNG responses against at least three of the four   GAA epitopes in 10 and 4 cases of cohorts 1 and 3, respectively. Cohort 1  patients demonstrated significantly higher IFNG responses than cohort 3  patients. Median progression-free survival (PFS) periods since the first vaccine   are 17 months in cohort 1 (range, 10-47+) and 12 months in cohort 3 (range,  3-41+). The only patient with large astrocytoma in cohort 2 has been  progression-free for more than 67 months since diagnosis. CONCLUSION: The current  regimen is well tolerated and induces robust GAA-specific responses in WHO grade   2 glioma patients. These results warrant further evaluations of this approach.  Clin Cancer Res; 21(2); 286-94. (c)2014 AACR.CI  - (c)2014 American Association for Cancer Research.
CANIT0000329	25428505	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	46	N/A	N/A	Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Pre-existing CD8(+) T-cell 	Gene expression signature on/in immune cell	 2014 Nov 27	 PD-1 blockade induces responses by inhibiting adaptive immune resistance.	 Nature	 Therapies that target the programmed death-1 (PD-1) receptor have shown  unprecedented rates of durable clinical responses in patients with various cancer  types. One mechanism by which cancer tissues limit the host immune response is  via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on  antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show  that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin  are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may  predict response to therapy. We analysed samples from 46 patients with metastatic  melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using  quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and  next-generation sequencing for T-cell antigen receptors (TCRs). In serially  sampled tumours, patients responding to treatment showed proliferation of  intratumoral CD8(+) T cells that directly correlated with radiographic reduction   in tumour size. Pre-treatment samples obtained from responding patients showed  higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour  margin and inside tumours, with close proximity between PD-1 and PD-L1, and a  more clonal TCR repertoire. Using multivariate analysis, we established a  predictive model based on CD8 expression at the invasive margin and validated the  model in an independent cohort of 15 patients. Our findings indicate that tumour   regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells  that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.
CANIT0000330	25452452	Clinical research	Metastatic Renal Cell Carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	168	N/A	A randomized Phase II Trial	Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response  relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting.	The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs.	N/A	N/A	N/A	N/A	N/A	 2015 May 1	 Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II  Trial.	 J Clin Oncol	 PURPOSE: Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune  checkpoint inhibitor antibody that restores T-cell immune activity. This phase II  trial assessed the antitumor activity, dose-response relationship, and safety of   nivolumab in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND  METHODS: Patients with clear-cell mRCC previously treated with agents targeting  the vascular endothelial growth factor pathway were randomly assigned (blinded  ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3  weeks. The primary objective was to evaluate the dose-response relationship as  measured by progression-free survival (PFS); secondary end points included  objective response rate (ORR), overall survival (OS), and safety. RESULTS: A  total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2-  (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had   received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2  months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS   was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8   months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most  common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%,  respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related  AEs. CONCLUSION: Nivolumab demonstrated antitumor activity with a manageable  safety profile across the three doses studied in mRCC. No dose-response  relationship was detected as measured by PFS. These efficacy and safety results  in mRCC support study in the phase III setting.CI  - (c) 2014 by American Society of Clinical Oncology.
CANIT0000331	25464388	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Nivolumab followed by ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	3	N/A	Case	N/A	Atypical severe immune-related adverse effects	N/A	N/A	N/A	N/A	N/A	 2015 Apr	 Atypical severe immune-related adverse effects resulting from sequenced  immunotherapy in melanoma.	 Melanoma Res	 We report unusual severe toxicity in three patients treated at our institution  with sequenced immunotherapy for metastatic melanoma. These three patients  illustrate the unusual potential toxicity of sequential administration of  anti-programmed cell death 1 followed by ipilimumab, and the need for careful  monitoring of these toxicities associated with sequential immunotherapies. Data  from forthcoming trials and national databases such as MELBASE, recently  implemented in France, will be helpful in providing further insights into the  risks and benefits of sequential immunotherapy schedules.CI  - Copyright (c) 2015 Wolters Kluwer Health, Inc. All rights reserved.
CANIT0000332	25464388	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Pembrolizumab followed by ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); 	3	N/A	Case	N/A	Atypical severe immune-related adverse effects	N/A	N/A	N/A	N/A	N/A	 2015 Apr	 Atypical severe immune-related adverse effects resulting from sequenced  immunotherapy in melanoma.	 Melanoma Res	 We report unusual severe toxicity in three patients treated at our institution  with sequenced immunotherapy for metastatic melanoma. These three patients  illustrate the unusual potential toxicity of sequential administration of  anti-programmed cell death 1 followed by ipilimumab, and the need for careful  monitoring of these toxicities associated with sequential immunotherapies. Data  from forthcoming trials and national databases such as MELBASE, recently  implemented in France, will be helpful in providing further insights into the  risks and benefits of sequential immunotherapy schedules.CI  - Copyright (c) 2015 Wolters Kluwer Health, Inc. All rights reserved.
CANIT0000333	25482239	Clinical research	Relapsed or refractory Hodgkin's lymphoma that had already been heavily treated	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	23	N/A	N/A	Nivolumab had substantial therapeutic activity and an acceptable safety profile  in patients with previously heavily treated relapsed or refractory Hodgkin's  lymphoma.	Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively.	N/A	N/A	N/A	N/A	N/A	 2015 Jan 22	 PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.	 N Engl J Med	 BACKGROUND: Preclinical studies suggest that Reed-Sternberg cells exploit the  programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's  lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1  ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase  (JAK)-signal transducer and activator of transcription (STAT) signaling. We  hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune  evasion in patients with relapsed or refractory Hodgkin's lymphoma. METHODS: In  this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma  that had already been heavily treated received nivolumab (at a dose of 3 mg per  kilogram of body weight) every 2 weeks until they had a complete response, tumor   progression, or excessive toxic effects. Study objectives were measurement of  safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and  PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. RESULTS: Of   the 23 study patients, 78% were enrolled in the study after a relapse following  autologous stem-cell transplantation and 78% after a relapse following the  receipt of brentuximab vedotin. Drug-related adverse events of any grade and of  grade 3 occurred in 78% and 22% of patients, respectively. An objective response   was reported in 20 patients (87%), including 17% with a complete response and 70%  with a partial response; the remaining 3 patients (13%) had stable disease. The  rate of progression-free survival at 24 weeks was 86%; 11 patients were  continuing to participate in the study. Reasons for discontinuation included  stem-cell transplantation (in 6 patients), disease progression (in 4 patients),  and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from   10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression   of these ligands. Reed-Sternberg cells showed nuclear positivity of  phosphorylated STAT3, indicative of active JAK-STAT signaling. CONCLUSIONS:  Nivolumab had substantial therapeutic activity and an acceptable safety profile  in patients with previously heavily treated relapsed or refractory Hodgkin's  lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number,   NCT01592370.).
CANIT0000334	25500362	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	45	N/A	A retrospective cohort study	OS was not different between patients with brain metastases at baseline and those without (p = 0.10).	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2015 Jan-Feb	 Single-center study under a French Temporary Authorization for Use (TAU) protocol  for ipilimumab in metastatic melanoma: negative impact of baseline  corticosteroids.	 Eur J Dermatol	 UNLABELLED: Ipilimumab is an anti-CTLA-4 antibody which has recently been  approved in Europe as a monotherapy in the treatment of metastatic melanoma. We  report a single-center study among patients treated within a Temporary  Authorization for Use (TAU) protocol. We also performed a review of the  literature involving expanded access program studies with a focus on factors  associated with overall survival (OS). PATIENTS AND METHODS: This retrospective,   observational study included patients between June 2010 and July 2011 with a  diagnosis of non-resectable stage III or IV melanoma with at least one previous  line of chemotherapy. Treatment consisted of four courses of ipilimumab at a dose  of 3mg/kg every three weeks. RESULTS: 45 patients were included, among whom 23  (51%) had brain metastases. 33 (71%) of the patients completed the induction  phase. The best overall response rate (BORR) was 13% and median overall survival   (OS) was 8 months (95%CI: 7 to 12). OS was not different between patients with  brain metastases at baseline and those without (p = 0.10), regardless of BRAF  V600E status (p = 0.61). OS was poorer in patients who were being treated with  corticoids at baseline (p<0.001) or with LDH at baseline > 500 UI/ml (p = 0.008).  CONCLUSION: A subset of patients most likely to benefit from ipilimumab should be  defined. In our series we found a negative association of baseline  corticosteroids with OS. Unlike high LDH levels, BRAF V600 E status and brain  metastases should not be barriers to the initiation of treatment.
CANIT0000335	25500362	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	45	N/A	A retrospective cohort study	OS was not different regardless of BRAF V600E status (p = 0.61).	N/A	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2015 Jan-Feb	 Single-center study under a French Temporary Authorization for Use (TAU) protocol  for ipilimumab in metastatic melanoma: negative impact of baseline  corticosteroids.	 Eur J Dermatol	 UNLABELLED: Ipilimumab is an anti-CTLA-4 antibody which has recently been  approved in Europe as a monotherapy in the treatment of metastatic melanoma. We  report a single-center study among patients treated within a Temporary  Authorization for Use (TAU) protocol. We also performed a review of the  literature involving expanded access program studies with a focus on factors  associated with overall survival (OS). PATIENTS AND METHODS: This retrospective,   observational study included patients between June 2010 and July 2011 with a  diagnosis of non-resectable stage III or IV melanoma with at least one previous  line of chemotherapy. Treatment consisted of four courses of ipilimumab at a dose  of 3mg/kg every three weeks. RESULTS: 45 patients were included, among whom 23  (51%) had brain metastases. 33 (71%) of the patients completed the induction  phase. The best overall response rate (BORR) was 13% and median overall survival   (OS) was 8 months (95%CI: 7 to 12). OS was not different between patients with  brain metastases at baseline and those without (p = 0.10), regardless of BRAF  V600E status (p = 0.61). OS was poorer in patients who were being treated with  corticoids at baseline (p<0.001) or with LDH at baseline > 500 UI/ml (p = 0.008).  CONCLUSION: A subset of patients most likely to benefit from ipilimumab should be  defined. In our series we found a negative association of baseline  corticosteroids with OS. Unlike high LDH levels, BRAF V600 E status and brain  metastases should not be barriers to the initiation of treatment.
CANIT0000336	25500362	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	45	N/A	A retrospective cohort study	OS was poorer in patients who were being treated with corticoids at baseline (p<0.001).	N/A	N/A	N/A	Corticosteroids (NCIT:C211); 	Treated with corticoids at baseline	Metabolite	 2015 Jan-Feb	 Single-center study under a French Temporary Authorization for Use (TAU) protocol  for ipilimumab in metastatic melanoma: negative impact of baseline  corticosteroids.	 Eur J Dermatol	 UNLABELLED: Ipilimumab is an anti-CTLA-4 antibody which has recently been  approved in Europe as a monotherapy in the treatment of metastatic melanoma. We  report a single-center study among patients treated within a Temporary  Authorization for Use (TAU) protocol. We also performed a review of the  literature involving expanded access program studies with a focus on factors  associated with overall survival (OS). PATIENTS AND METHODS: This retrospective,   observational study included patients between June 2010 and July 2011 with a  diagnosis of non-resectable stage III or IV melanoma with at least one previous  line of chemotherapy. Treatment consisted of four courses of ipilimumab at a dose  of 3mg/kg every three weeks. RESULTS: 45 patients were included, among whom 23  (51%) had brain metastases. 33 (71%) of the patients completed the induction  phase. The best overall response rate (BORR) was 13% and median overall survival   (OS) was 8 months (95%CI: 7 to 12). OS was not different between patients with  brain metastases at baseline and those without (p = 0.10), regardless of BRAF  V600E status (p = 0.61). OS was poorer in patients who were being treated with  corticoids at baseline (p<0.001) or with LDH at baseline > 500 UI/ml (p = 0.008).  CONCLUSION: A subset of patients most likely to benefit from ipilimumab should be  defined. In our series we found a negative association of baseline  corticosteroids with OS. Unlike high LDH levels, BRAF V600 E status and brain  metastases should not be barriers to the initiation of treatment.
CANIT0000337	25500362	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	45	N/A	A retrospective cohort study	OS was poorer in patients with LDH at baseline > 500 UI/ml (p = 0.008).	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2015 Jan-Feb	 Single-center study under a French Temporary Authorization for Use (TAU) protocol  for ipilimumab in metastatic melanoma: negative impact of baseline  corticosteroids.	 Eur J Dermatol	 UNLABELLED: Ipilimumab is an anti-CTLA-4 antibody which has recently been  approved in Europe as a monotherapy in the treatment of metastatic melanoma. We  report a single-center study among patients treated within a Temporary  Authorization for Use (TAU) protocol. We also performed a review of the  literature involving expanded access program studies with a focus on factors  associated with overall survival (OS). PATIENTS AND METHODS: This retrospective,   observational study included patients between June 2010 and July 2011 with a  diagnosis of non-resectable stage III or IV melanoma with at least one previous  line of chemotherapy. Treatment consisted of four courses of ipilimumab at a dose  of 3mg/kg every three weeks. RESULTS: 45 patients were included, among whom 23  (51%) had brain metastases. 33 (71%) of the patients completed the induction  phase. The best overall response rate (BORR) was 13% and median overall survival   (OS) was 8 months (95%CI: 7 to 12). OS was not different between patients with  brain metastases at baseline and those without (p = 0.10), regardless of BRAF  V600E status (p = 0.61). OS was poorer in patients who were being treated with  corticoids at baseline (p<0.001) or with LDH at baseline > 500 UI/ml (p = 0.008).  CONCLUSION: A subset of patients most likely to benefit from ipilimumab should be  defined. In our series we found a negative association of baseline  corticosteroids with OS. Unlike high LDH levels, BRAF V600 E status and brain  metastases should not be barriers to the initiation of treatment.
CANIT0000338	25524312	Clinical research	Resected high-risk metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG)	N/A	Immune checkpoint therapy plus Tumor vaccine 	Montanide ISA 51 VG (NCIT:C84843); and NY-ESO-1 vaccine (NCIT:C2657); MART-1 vaccinia vaccine (NCIT:C2774); gp100 vaccine (NCIT:C29068); nivolumab (DB09035); 	33	N/A	N/A	Nivolumab with vaccine is well  tolerated as adjuvant therapy and demonstrates immunologic activity with  promising survival in high-risk resected melanoma, justifying further study. PD-L1 tumor status was not  significantly associated with RFS. 	Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2015 Feb 15	 Safety, correlative markers, and clinical results of adjuvant nivolumab in  combination with vaccine in resected high-risk metastatic melanoma.	 Clin Cancer Res	 PURPOSE: The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has  clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine  was investigated as adjuvant therapy in resected stage IIIC and IV melanoma  patients. EXPERIMENTAL DESIGN: HLA-A*0201 positive patients with HMB-45,  NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3  mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and  NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by  nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety  and determination of a maximum tolerated dose (MTD). Secondary objectives  included relapse-free survival (RFS), overall survival (OS), and immunologic  correlative studies. RESULTS: Thirty-three patients were enrolled. Median age was  47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had  stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most  common related adverse events (>40%) were vaccine injection site reaction,  fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse  events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed.  Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was   not reached. Increases in CTLA-4(+)/CD4(+), CD25(+)Treg/CD4(+), and tetramer  specific CD8(+) T-cell populations were observed with treatment (P < 0.05).  Trends for lower baseline myeloid-derived suppressor cell and CD25(+)Treg/CD4(+)   populations were seen in nonrelapsing patients; PD-L1 tumor status was not  significantly associated with RFS. CONCLUSIONS: Nivolumab with vaccine is well  tolerated as adjuvant therapy and demonstrates immunologic activity with  promising survival in high-risk resected melanoma, justifying further study.CI  - (c)2014 American Association for Cancer Research.
CANIT0000339	25531526	Case report	Metastatic melanoma after progression under chemotherapy	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	Case	In all of these patients ipilimumab led to a long-term tumor control of at least 31 months.	All of them developed severe autoimmune toxicity and ipilimumab treatment was discontinued after 1 respectively 2 cycles.	N/A	N/A	N/A	N/A	N/A	2015	 Long-lasting responses under treatment with ipilimumab: an argument against  maintenance therapy 	 Dermatology	 Ipilimumab, a monoclonal CTLA-4 antibody, was the first drug improving overall  survival in patients with metastatic melanoma. However, there are still  unanswered questions concerning therapeutic regimes, e.g. if maintenance therapy   is needed to achieve long-term response. We present three patients with  metastatic melanoma who received ipilimumab after progression under chemotherapy.  In all of these patients ipilimumab led to a long-term tumor control of at least   32 months. Interestingly, all of them developed severe autoimmune toxicity and  ipilimumab treatment was discontinued after 1 respectively 2 cycles. The present   cases demonstrate that a long-term response to ipilimumab can be achieved without  maintenance therapy.CI  - (c) 2014 S. Karger AG, Basel.
CANIT0000340	25538176	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); TXNRD1 (Q16881); 	CTLA-4; TXNRD1	Ipilimumab plus fotemustine	N/A	Immune checkpoint therapy plus Chemotherapy	Fotemustine (DB04106); ipilimumab (DB06186); 	86	N/A	Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study	Median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.7% for patients with brain metastases, respectively.	Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. 	N/A	N/A	Memory T cells (NCIT:C104082); T-Lymphocyte (NCIT:C12476); 	Absolute increase of memory T-cell but not in naive T-cell 	Cell percentage/counts in blood	 2015 Apr	 Three-year follow-up of advanced melanoma patients who received ipilimumab plus  fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II  study.	 Ann Oncol	 BACKGROUND: In the NIBIT-M1 study, we reported a promising activity of ipilimumab  combined with fotemustine in metastatic melanoma (MM) patients with or without  brain metastases. To corroborate these initial findings, we now investigated the   long-term efficacy of this combination. PATIENTS AND METHODS: This analysis  captured the 3-year outcome of MM patients who received ipilimumab combined with   fotemustine as first- or second-line treatment. Median overall survival (OS),  3-year survival rates, immune-related (ir) progression-free survival (irPFS),  brain PFS, and ir duration of response (irDOR) for the entire population and for   patients with brain metastases were assessed. Clinical results were correlated  with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells,  neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status.  RESULTS: Eighty-six MM patients, including 20 with asymptomatic brain metastases   that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the  study. With a median follow-up of 39.9 months, median OS and 3-year survival  rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5%  for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and  27.8% for patients with brain metastases, respectively. Long-term ir adverse  events consisting of G1 rush and pruritus occurred in 21% of patients. The  absolute increase from baseline to week 12 in 'memory' but not in 'naive' T cells  identified patients with a better survival (P = 0.002). The N/L ratio correlated   with a significantly better survival at early time points. BRAF status did not  correlate with clinical outcome. CONCLUSIONS: Long-term analysis of the NIBIT-M1   trial continues to demonstrate efficacy of ipilimumab combined with fotemustine  in MM patients. Fotemustine does not seem to impair the immunologic activity of  ipilimumab. EUDRACT NUMBER: 2010-019356-50. CINICALTRIALSGOV: NCT01654692.CI  - (c) The Author 2014. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000341	25538176	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); TXNRD1 (Q16881); 	CTLA-4; TXNRD1	Ipilimumab plus fotemustine	N/A	Immune checkpoint therapy plus Chemotherapy	Fotemustine (DB04106); ipilimumab (DB06186); 	86	N/A	Italian Network for Tumor Biotherapy (NIBIT)-M2 phase II study	Median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.8% for patients with brain metastases, respectively.	Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. 	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2015 Apr	 Three-year follow-up of advanced melanoma patients who received ipilimumab plus  fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II  study.	 Ann Oncol	 BACKGROUND: In the NIBIT-M1 study, we reported a promising activity of ipilimumab  combined with fotemustine in metastatic melanoma (MM) patients with or without  brain metastases. To corroborate these initial findings, we now investigated the   long-term efficacy of this combination. PATIENTS AND METHODS: This analysis  captured the 3-year outcome of MM patients who received ipilimumab combined with   fotemustine as first- or second-line treatment. Median overall survival (OS),  3-year survival rates, immune-related (ir) progression-free survival (irPFS),  brain PFS, and ir duration of response (irDOR) for the entire population and for   patients with brain metastases were assessed. Clinical results were correlated  with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells,  neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status.  RESULTS: Eighty-six MM patients, including 20 with asymptomatic brain metastases   that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the  study. With a median follow-up of 39.9 months, median OS and 3-year survival  rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5%  for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and  27.8% for patients with brain metastases, respectively. Long-term ir adverse  events consisting of G1 rush and pruritus occurred in 21% of patients. The  absolute increase from baseline to week 12 in 'memory' but not in 'naive' T cells  identified patients with a better survival (P = 0.002). The N/L ratio correlated   with a significantly better survival at early time points. BRAF status did not  correlate with clinical outcome. CONCLUSIONS: Long-term analysis of the NIBIT-M1   trial continues to demonstrate efficacy of ipilimumab combined with fotemustine  in MM patients. Fotemustine does not seem to impair the immunologic activity of  ipilimumab. EUDRACT NUMBER: 2010-019356-50. CINICALTRIALSGOV: NCT01654692.CI  - (c) The Author 2014. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000342	25538176	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); TXNRD1 (Q16881); 	CTLA-4; TXNRD1	Ipilimumab plus fotemustine	N/A	Immune checkpoint therapy plus Chemotherapy	Fotemustine (DB04106); ipilimumab (DB06186); 	86	N/A	Italian Network for Tumor Biotherapy (NIBIT)-M3 phase II study	Median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and 27.8% for patients with brain metastases, respectively.	Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. 	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2015 Apr	 Three-year follow-up of advanced melanoma patients who received ipilimumab plus  fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II  study.	 Ann Oncol	 BACKGROUND: In the NIBIT-M1 study, we reported a promising activity of ipilimumab  combined with fotemustine in metastatic melanoma (MM) patients with or without  brain metastases. To corroborate these initial findings, we now investigated the   long-term efficacy of this combination. PATIENTS AND METHODS: This analysis  captured the 3-year outcome of MM patients who received ipilimumab combined with   fotemustine as first- or second-line treatment. Median overall survival (OS),  3-year survival rates, immune-related (ir) progression-free survival (irPFS),  brain PFS, and ir duration of response (irDOR) for the entire population and for   patients with brain metastases were assessed. Clinical results were correlated  with circulating CD3(+)CD4(+)ICOS(+)CD45RO(+) or CD45RA(+) T cells,  neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status.  RESULTS: Eighty-six MM patients, including 20 with asymptomatic brain metastases   that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the  study. With a median follow-up of 39.9 months, median OS and 3-year survival  rates were 12.9 months [95% confidence interval (CI) 7.1-18.7 months] and 28.5%  for the whole study population, and 12.7 months (95% CI 2.7-22.7 months) and  27.8% for patients with brain metastases, respectively. Long-term ir adverse  events consisting of G1 rush and pruritus occurred in 21% of patients. The  absolute increase from baseline to week 12 in 'memory' but not in 'naive' T cells  identified patients with a better survival (P = 0.002). The N/L ratio correlated   with a significantly better survival at early time points. BRAF status did not  correlate with clinical outcome. CONCLUSIONS: Long-term analysis of the NIBIT-M1   trial continues to demonstrate efficacy of ipilimumab combined with fotemustine  in MM patients. Fotemustine does not seem to impair the immunologic activity of  ipilimumab. EUDRACT NUMBER: 2010-019356-50. CINICALTRIALSGOV: NCT01654692.CI  - (c) The Author 2014. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000343	25538262	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	187	N/A	A retrospective cohort study	Systemic high-dose corticosteroids treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive high-dose corticosteroids, there was no statistically significant difference between treatment arms.	The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5-36 weeks).	N/A	N/A	N/A	N/A	N/A	 2015 Feb 15	 Systemic high-dose corticosteroid treatment does not improve the outcome of  ipilimumab-related hypophysitis: a retrospective cohort study.	 Clin Cancer Res	 PURPOSE: To examine the onset and outcome of ipilimumab-related hypophysitis and   the response to treatment with systemic high-dose corticosteroids (HDS).  EXPERIMENTAL DESIGN: Twenty-five patients who developed ipilimumab-related  hypophysitis were analyzed for the incidence, time to onset, time to resolution,   frequency of resolution, and the effect of systemic HDS on clinical outcome. To  calculate the incidence, the total number (187) of patients with metastatic  melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston,  MA) was retrieved from the DFCI oncology database. Comparisons between  corticosteroid treatment groups were performed using the Fisher exact test. The  distributions of overall survival were based on the method of Kaplan-Meier.  RESULTS: The overall incidence of ipilimumab-related hypophysitis was 13%, with a  higher rate in males (16.1%) than females (8.7%). The median time to onset of  hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5-36  weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency,  secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred   in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment  did not improve the outcome of hypophysitis as measured by resolution frequency  and time to resolution. One-year overall survival in the cohort of patients was  83%, and while it was slightly higher in patients who did not receive HDS, there   was no statistically significant difference between treatment arms. CONCLUSION:  Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be   indicated. Instead, supportive treatment of hypophysitis-related hormone  deficiencies with the corresponding hormone replacement should be given.CI  - (c)2014 American Association for Cancer Research.
CANIT0000344	25576145	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus temozolomide in combination with radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Radiotherapy (NCIT:C15313); temozolomide (DB00853); ipilimumab (DB06186); 	1	N/A	Case	The treatment regime was well tolerated and resulted in unusually long disease stabilization and in a complete response of brain and kidney metastases. Thus, it is speculated that the clinical response was the result of an abscopal effect.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Jul	 [Abscopal effect in the treatment of malignant melanoma].	 Hautarzt	 BACKGROUND: The clearance of non-irradiated tumors after localized radiation  therapy is known as the abscopal effect. CASE REPORT: In the present case report   we initiated a combined therapeutic approach based on sequential administration  of ipilimumab plus temozolomide in combination with radiotherapy. The treatment  regime was well tolerated and resulted in unusually long disease stabilization  and in a complete response of brain and kidney metastases. Thus, it is speculated  that the clinical response was the result of an abscopal effect. CONCLUSION: The   present case report highlights the possible clinical benefit of the abscopal  effect in the treatment of malignant melanoma.
CANIT0000345	25582080	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Basic research	Elevated serum sCD25  predicts resistance to CTLA-4 blockade in patients with melanoma.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD25 (P01589); 	Serum CD25 levels	Gene expression signature in serum	 2015 Feb	 Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2  receptors and negative prognostic impact of soluble CD25.	 Cell Res	 The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab  induces immune-mediated long-term control of metastatic melanoma in a fraction of  patients. Although ipilimumab undoubtedly exerts its therapeutic effects via  immunostimulation, thus far clinically useful, immunologically relevant  biomarkers that predict treatment efficiency have been elusive. Here, we show  that neutralization of IL-2 or blocking the alpha and beta subunits of the IL-2  receptor (CD25 and CD122, respectively) abolished the antitumor effects and the  accompanying improvement of the ratio of intratumoral T effector versus  regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in  preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive  CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant  rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated   in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of  CTLA-4 blockade, the decoy IL-2 receptor alpha (IL-2Ralpha, sCD25) inhibited the   anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients  receiving ipilimumab, baseline serum concentrations of sCD25 represented an  independent indicator of overall survival, with high levels predicting resistance  to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors   in the anticancer activity of CTLA-4 blockade. Importantly, our study provides  the first immunologically relevant biomarker, namely elevated serum sCD25, that  predicts resistance to CTLA-4 blockade in patients with melanoma.
CANIT0000346	25647225	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Case	We report a patient who developed bilateral optic neuropathy with disc edema while taking this medication.	Bilateral optic neuropathy	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2015 Jun	 Ipilimumab-associated bilateral optic neuropathy.	 J Neuroophthalmol	 Ipilimumab is a novel monoclonal antibody targeting the cytotoxic  T-lymphocyte-associated antigen 4 (CTLA-4) receptor that has been shown to  improve survival in metastatic melanoma. Previous case reports have documented  its association with drug-induced uveitis. We report a patient who developed  bilateral optic neuropathy with disc edema while taking this medication.
CANIT0000347	25649350	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	90	N/A	A retrospective cohort study	Ipilimumab was associated with largely excellent functional outcomes among long-term survivors. Chronic endocrine dysfunction and occasional neurologic toxicity (primarily associated with whole-brain radiation) were observed in a small number of patients.	Chronic neurologic toxicities caused substantial morbidity and mortality in 2 patients who received whole-brain radiotherapy >5 years before analysis, and in one patient with chronic, painful peripheral neuropathy. No previously undescribed cardiac, pulmonary, gastrointestinal, hematologic, or neoplastic safety signals were identified.	N/A	N/A	N/A	N/A	N/A	 2015 May	 Survivorship in Immune Therapy: Assessing Chronic Immune Toxicities, Health  Outcomes, and Functional Status among Long-term Ipilimumab Survivors at a Single   Referral Center.	 Cancer Immunol Res	 Ipilimumab, a novel immune checkpoint inhibitor, is associated with long-term  survival in approximately 20% of patients with advanced melanoma and is also  being evaluated in the adjuvant setting. With this growing cohort of survivors,  long-term health outcomes, chronic toxicities, and functional outcomes among  survivors treated with ipilimumab need to be defined. Using retrospective medical  record abstraction, we evaluated disease status, chronic immune- and  non-immune-related health events, pharmacologic management of symptoms, and  functional status in patients with melanoma, with overall survival >/=2 years  following ipilimumab treatment at Vanderbilt University. Ninety patients received  ipilimumab for metastatic disease or as adjuvant therapy between January 2006 and  September 2012, and 33 patients survived >/=2 years, with a median overall  survival of 60.1 months. Of these, 24 patients were alive at the last follow-up  (73%), with 14 patients free of disease (42%). Gastrointestinal and dermatologic   adverse events were frequent but largely transient. By contrast, patients with  hypophysitis universally required ongoing corticosteroids, although largely  remained asymptomatic with appropriate hormone replacement. Surviving patients  generally had excellent performance status (ECOG 0-1 in 23 of 24). Chronic  neurologic toxicities caused substantial morbidity and mortality in 2 patients  who received whole-brain radiotherapy >5 years before analysis, and in one  patient with chronic, painful peripheral neuropathy. No previously undescribed  cardiac, pulmonary, gastrointestinal, hematologic, or neoplastic safety signals  were identified. In conclusion, ipilimumab was associated with largely excellent   functional outcomes among long-term survivors. Chronic endocrine dysfunction and   occasional neurologic toxicity (primarily associated with whole-brain radiation)   were observed in a small number of patients.CI  - (c)2015 American Association for Cancer Research.
CANIT0000348	25658617	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	2	N/A	Case	Peripheral neuropathy	Our first patient represents the severe end of the spectrum of immune-mediated neuropathy. His symptoms were biphasic, progressed over a course of 2 months, and therefore were more compatible with CIDP. The symptoms did not respond to infliximab, high-dose corticosteroids, or IVIG. There was an axonal and demyelinating component with CSF pleocytosis associated with high CSF protein in contrast to albuminocytologic dissociation seen with typical GBS. His symptoms stabilized after treatment with tacrolimus which inhibits T-cell activation. Additionally, the CSF profile normalized after 5 days of treatment indicating a dampened inflammatory process. Case 2 represents the milder end of the spectrum of disease with only sensory involvement and required discontinuation of ipilimumab and treatment with immunosuppression. The time-course relationship with ipilimumab and the coexistent autoimmune hepatitis support the role of underlying immune-mediated mechanism.	N/A	N/A	N/A	N/A	N/A	 2015 Feb-Mar	 Peripheral neuropathy associated with ipilimumab: a report of 2 cases.	 J Immunother	 Ipilimumab, a monoclonal antibody targeting human cytotoxic  T-lymphocyte-associated antigen 4, was approved by the FDA and European Medicines  Agency for the treatment of metastatic melanoma. Immune-related adverse effects  can occur with the use of this agent, but peripheral nervous system problems are   rare. We report 2 cases of ipilimumab-induced polyneuropathy.
CANIT0000349	25658618	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Vogt-Koyanagi-Harada-like syndrome	N/A	N/A	N/A	N/A	N/A	 2015 Feb-Mar	 Vogt-Koyanagi-Harada-like syndrome after CTLA-4 inhibition with ipilimumab for  metastatic melanoma.	 J Immunother	 Cytotoxic T-lymphocyte-associated antigen is a naturally occurring inhibitor of  T-cell costimulation. Monoclonal antibody inhibition of cytotoxic  T-lymphocyte-associated antigen with ipilimumab blocks this negative regulator of  costimulation, promoting T-cell activation and survival, and leads to melanoma  regression. Findings of the Vogt-Koyanagi-Harada (VKH) syndrome, an  uveomeningitic syndrome that features neurological, auditory, ophthalmologic, and  cutaneous involvement because of autoimmune targeting of melanocytic antigen,  have rarely been described in association with melanoma immunotherapy. We  describe a case of VKH-like syndrome in a 45-year-old HLA-A02-positive patient  with metastatic melanoma treated with ipilimumab. Disruption of immune tolerance   by ipilimumab led to melanoma remission while also inciting systemic and  ophthalmic autoimmunity toward melanocytic antigen. These observations provide  insight into the pathophysiology of the VKH syndrome, and the balance between  tumor-associated tolerance and autoimmunity.
CANIT0000350	25677296	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	New-onset uveitis	N/A	N/A	N/A	N/A	N/A	 2015 Feb	 New-onset uveitis during CTLA-4 blockade therapy with ipilimumab in metastatic  melanoma patient.	 Can J Ophthalmol	Unable to provide
CANIT0000351	25694346	Case report	Metastatic malignant melanoma with atypical generalized rash	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	May increase the severity of cutenaous toxicity related to radiotherapy	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Ipilimumab may increase the severity of cutenaous toxicity related to  radiotherapy.	 J Oncol Pharm Pract	 Ipilimumab, monoclonal antibody against cytotoxic T-lymphocyte antigen-4 and,  radiotherapy are commonly used to treat unresectable and metastatic melanoma. As   a result of upregulation of immune system with ipilimumab, many immune-related  adverse effects, such as dermatitis, colitis, hepatitis, and hypophysitis, have  been previously reported in literature. Typically, these effects are treated with  high-dose steroids and mostly heal up. Here, we report a case who was receiving  radiotherapy due to metastatic malignant melanoma with atypical generalized rash,  which was enlarged with concurrent ipilimumab treatment.CI  - (c) The Author(s) 2015.
CANIT0000352	25704439	Clinical research	Advanced, refractory squamous non-small-cell lung cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	117	N/A	A phase II, single-arm	Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment.	20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease.	N/A	N/A	N/A	N/A	N/A	 2015 Mar	 Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for  patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate  063): a phase 2, single-arm trial.	 Lancet Oncol	 BACKGROUND: Patients with squamous non-small-cell lung cancer that is refractory   to multiple treatments have poor outcomes. We assessed the activity of nivolumab,  a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with  advanced, refractory, squamous non-small-cell lung cancer. METHODS: We did this  phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer  centres) in France, Germany, Italy, and USA. Patients who had received two or  more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks  until progression or unacceptable toxic effects. The primary endpoint was the  proportion of patients with a confirmed objective response as assessed by an  independent radiology review committee. We included all treated patients in the  analyses. This study is registered with ClinicalTrials.gov, number NCT01721759.  FINDINGS: Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117  patients. 17 (14.5%, 95% CI 8.7-22.2) of 117 patients had an objective response  as assessed by an independent radiology review committee. Median time to response  was 3.3 months (IQR 2.2-4.8), and median duration of response was not reached  (95% CI 8.31-not applicable); 13 (77%) of 17 of responses were ongoing at the  time of analysis. 30 (26%) of 117 patients had stable disease (median duration  6.0 months, 95% CI 4.7-10.9). 20 (17%) of 117 patients reported grade 3-4  treatment-related adverse events, including: fatigue (five [4%] of 117 patients),  pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two  treatment-associated deaths caused by pneumonia and ischaemic stroke that  occurred in patients with multiple comorbidities in the setting of progressive  disease. INTERPRETATION: Nivolumab has clinically meaningful activity and a  manageable safety profile in previously treated patients with advanced,  refractory, squamous non-small cell lung cancer. These data support the  assessment of nivolumab in randomised, controlled, phase 3 studies of first-line   and second-line treatment. FUNDING: Bristol-Myers Squibb.CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
CANIT0000353	25713437	Clinical research	Advanced melanoma 	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus dacarbazine	Dacarbazine plus placebo	Immune checkpoint therapy plus Chemotherapy	Dacarbazine (DB00851); ipilimumab (DB06186); 	250	252	A phase III clinical trial	The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These   results demonstrate a durable survival benefit with ipilimumab in advanced  melanoma.	In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin.	N/A	N/A	N/A	N/A	N/A	 2015 Apr 1	 Five-year survival rates for treatment-naive patients with advanced melanoma who   received ipilimumab plus dacarbazine in a phase III trial.	 J Clin Oncol	 PURPOSE: There is evidence from nonrandomized studies that a proportion of  ipilimumab-treated patients with advanced melanoma experience long-term survival.  To demonstrate a long-term survival benefit with ipilimumab, we evaluated the  5-year survival rates of patients treated in a randomized, controlled phase III  trial. PATIENTS AND METHODS: A milestone survival analysis was conducted to  capture the 5-year survival rate of treatment-naive patients with advanced  melanoma who received ipilimumab in a phase III trial. Patients were randomly  assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or  placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by  dacarbazine alone every 3 weeks through week 22. Eligible patients could receive   maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety  analysis was conducted on patients who survived at least 5 years and continued to  receive ipilimumab as maintenance therapy. RESULTS: The 5-year survival rate was   18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus  dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo  plus dacarbazine (P = .002). A plateau in the survival curve began at  approximately 3 years. In patients who survived at least 5 years and continued to  receive ipilimumab, grade 3 or 4 immune-related adverse events were observed  exclusively in the skin. CONCLUSION: The additional survival benefit of  ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5   years compared with those who initially received placebo plus dacarbazine. These   results demonstrate a durable survival benefit with ipilimumab in advanced  melanoma.CI  - (c) 2015 by American Society of Clinical Oncology.
CANIT0000354	25725978	Case report	Metastatic lung cancer	Lung carcinoma	EFO:0001071	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus chemotherapy with carboplatin and paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); carboplatin (DB00958); 	1	N/A	Case	After an initial partial response to chemotherapy, the patient achieved complete response persists after 6 years.	Complicated by grade 3 gastro-intestinal toxicity leading to stop the ipilimumab.	N/A	N/A	N/A	N/A	N/A	 2015 Nov	 [Ipilimumab and metastatic lung cancer: Can we change the natural history of the   disease ].	 Rev Mal Respir	 INTRODUCTION: Ipilimumab (anti CTLA-4 antibody) aims to activate antitumor  immunity. This treatment is being evaluated in non-small cell lung cancer. CASE  REPORT: We report a case of a stage IV adenocarcinoma patient randomized in 2008   in the phase II trial CA 184-104 evaluating the combination of ipilimumab to  chemotherapy with carboplatin and paclitaxel. After an initial partial response  to chemotherapy, the patient achieved a complete response with ipilimumab as  maintenance therapy. However, it was complicated by grade 3 gastro-intestinal  toxicity leading to stop the ipilimumab. However, this complete response persists  after 6 years. CONCLUSIONS: Our case illustrates the contribution of  immunotherapy at least in some patients. The mechanisms of action, relationship  between efficacy and toxicity and predictors of efficacy remain to be defined.CI  - Copyright (c) 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.
CANIT0000355	25727227	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	12	N/A	Case	In this series, patients who underwent resection of brain metastases in temporal proximity to receiving ipilimumab had qualitatively improved performance status following surgery in most cases. Surgery facilitated corticosteroid reduction in select patients. Larger analyses are required to better understand possible synergies between craniotomy for melanoma metastases and ipilimumab treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Mar	 Ipilimumab and craniotomy in patients with melanoma and brain metastases: a case   series.	 Neurosurg Focus	 OBJECT In patients with large or symptomatic brain lesions from metastatic  melanoma, the value of resection of metastases to facilitate administration of  systemic ipilimumab therapy has not yet been described. The authors undertook  this study to investigate whether craniotomy creates the opportunity for patients  to receive and benefit from ipilimumab who would otherwise succumb to brain  metastasis prior to the onset of regression. METHODS All patients with metastatic  melanoma who received ipilimumab and underwent craniotomy for metastasis  resection between 2008 and 2014 at the Massachusetts General Hospital were  identified through retrospective chart review. The final analysis included cases   involving patients who underwent craniotomy within 3 months prior to initiation  of therapy or up to 6 months after cessation of ipilimumab administration.  RESULTS Twelve patients met the inclusion criteria based on timing of therapy  (median age 59.2). The median number of metastases at the time of craniotomy was   2. The median number of ipilimumab doses received was 4. Eleven of 12 courses of   ipilimumab were stopped for disease progression, and 1 was stopped for  treatment-induced colitis. Eight of 12 patients had improvement in their  performance status following craniotomy. Of the 6 patients requiring  corticosteroids prior to craniotomy, 3 tolerated corticosteroid dose reduction  after surgery. Ten of 12 patients had died by the time of data collection, with 1  patient lost to follow-up. The median survival after the start of ipilimumab  treatment was 7 months. CONCLUSIONS In this series, patients who underwent  resection of brain metastases in temporal proximity to receiving ipilimumab had  qualitatively improved performance status following surgery in most cases.  Surgery facilitated corticosteroid reduction in select patients. Larger analyses   are required to better understand possible synergies between craniotomy for  melanoma metastases and ipilimumab treatment.
CANIT0000356	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G12D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000357	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000358	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000359	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G14C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000360	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G42C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000361	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61H mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000362	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61K mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000363	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61L mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000364	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000365	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G12D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000366	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000367	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000368	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000369	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G42C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000370	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61H mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000371	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61K mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000372	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61L mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000373	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000374	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G12D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000375	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000376	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000377	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G15C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000378	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G42C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000379	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61H mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000380	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61K mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000381	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61L mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000382	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000383	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G12D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000384	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000385	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000386	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G16C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000387	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G42C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000388	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61H mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000389	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61K mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000390	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61L mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000391	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000392	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G12D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000393	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13D mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000394	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G13R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000395	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G17C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000396	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS G42C mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000397	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61H mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000398	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61K mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000399	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61L mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000400	25736262	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	229	N/A	A retrospective cohort study	This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.	N/A	N/A	N/A	NRAS (P01111); 	NRAS Q61R mutation	Mutational status	 2015 Mar	 Impact of NRAS mutations for patients with advanced melanoma treated with immune   therapies.	 Cancer Immunol Res	 Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies   have become a mainstay in advanced melanoma treatment. We sought to evaluate  whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune  therapy in melanoma. We identified 229 patients with melanoma treated with immune  therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1  (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune  therapy for patients with or without NRAS mutations. Of the 229 patients with  melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild   type. The NRAS-mutant cohort had superior or a trend to superior outcomes  compared with the other cohorts in terms of response to first-line immune therapy  (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P =  0.07), clinical benefit (response + stable disease lasting >/= 24 weeks; 50% vs.   31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P =  0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort  (clinical benefit rate 73% vs. 35%). In an independent group of patient samples,   NRAS-mutant melanoma had higher PD-L1 expression (although not statistically  significant) compared with other genotypes (8/12 vs. 9/20 samples with >/= 1%  expression; 6/12 vs. 6/20 samples with >/= 5% expression), suggesting a potential  mechanism for the clinical results. This retrospective study suggests that NRAS  mutations in advanced melanoma correlate with increased benefit from immune-based  therapies compared with other genetic subtypes. If confirmed by prospective  studies, this may be explained in part by high rates of PD-L1 expression.CI  - (c)2015 American Association for Cancer Research.
CANIT0000401	25754629	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic radiosurgery	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	46	N/A	A retrospective cohort study	The combination of Ipi and SRS appears to be well tolerated. Concurrent delivery of Ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a   temporary increase in tumor size, possibly because of an enhanced immunomodulatory effect.	Grade 3 to 4 toxicities were seen in 20% of patients.	N/A	N/A	N/A	N/A	N/A	 2015 Jun 1	 Stereotactic radiosurgery for melanoma brain metastases in patients receiving  ipilimumab: safety profile and efficacy of combined treatment.	 Int J Radiat Oncol Biol Phys	 PURPOSE: Ipilimumab (Ipi), a monoclonal antibody against cytotoxic T-lymphocyte  antigen-4, has been shown to improve survival in patients with metastatic  melanoma. In this single-institution study, we investigated the safety and  efficacy of stereotactic radiosurgery (SRS) for patients with melanoma brain  metastases (BMs) who also received Ipi. METHODS AND MATERIALS: From 2005 to 2011,  46 patients with melanoma received Ipi and underwent single-fraction SRS for BMs.  A total of 113 BMs (91% intact, 9% postoperative) were treated with a median dose  of 21 Gy (range, 15-24 Gy). Ipi was given at 3 mg/kg (54%) or 10 mg/kg (46%) for   a median of 4 doses (range, 1-21). Adverse events were recorded with the use of  the Common Terminology Criteria for Adverse Events 3.0. Kaplan-Meier methods were  used to estimate survival, and Cox regression was used to investigate  associations. RESULTS: Fifteen patients received SRS during Ipi, 19 received SRS   before Ipi, and 12 received SRS after Ipi. Overall survival (OS) was  significantly associated with the timing of SRS/Ipi (P=.035) and  melanoma-specific graded prognostic assessment (P=.013). Patients treated with  SRS during or before Ipi had better OS and less regional recurrence than did  those treated with SRS after Ipi (1-year OS 65% vs 56% vs 40%, P=.008; 1-year  regional recurrence 69% vs 64% vs 92%, P=.003). SRS during Ipi also yielded a  trend toward less local recurrence than did SRS before or after Ipi (1-year local  recurrence 0% vs 13% vs 11%, P=.21). On magnetic resonance imaging, an increase  in BM diameter to >150% was seen in 50% of patients treated during or before Ipi   but in only 13% of patients treated after Ipi. Grade 3 to 4 toxicities were seen   in 20% of patients. CONCLUSION: Overall, the combination of Ipi and SRS appears  to be well tolerated. Concurrent delivery of Ipi and SRS is associated with  favorable locoregional control and possibly longer survival. It may also cause a   temporary increase in tumor size, possibly because of an enhanced  immunomodulatory effect.CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
CANIT0000402	25761109	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	53	N/A	A multicenter phase II study	Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines.	Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3-4 events (36%). One drug-related death due to pancytopenia was observed.	N/A	N/A	N/A	N/A	N/A	2015	 Phase II DeCOG-study of ipilimumab in pretreated and treatment-naive patients  with metastatic uveal melanoma.	 PLoS One	 PURPOSE: Up to 50% of patients with uveal melanoma (UM) develop metastatic  disease with limited treatment options. The immunomodulating agent ipilimumab has  shown an overall survival (OS) benefit in patients with cutaneous metastatic  melanoma in two phase III trials. As patients with UM were excluded in these  studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II  to assess the efficacy and safety of ipilimumab in patients with metastatic UM.  PATIENTS AND METHODS: We undertook a multicenter phase II study in patients with   different subtypes of metastatic melanoma. Here we present data on patients with   metastatic UM (pretreated and treatment-naive) who received up to four cycles of   ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor  assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to  RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were  graded according to National Cancer Institute Common Toxicity Criteria (CTC)  v.4.0. Primary endpoint was the OS rate at 12 months. RESULTS: Forty five  pretreated (85%) and eight treatment-naive (15%) patients received at least one  dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively.  Median OS was 6.8 months (95% CI 3.7-8.1), median progression-free survival 2.8  months (95% CI 2.5-2.9). The disease control rate at weeks 12 and 24 was 47% and   21%, respectively. Sixteen patients had stable disease (47%), none experienced  partial or complete response. Treatment-related AEs were observed in 35 patients   (66%), including 19 grade 3-4 events (36%). One drug-related death due to  pancytopenia was observed. CONCLUSIONS: Ipilimumab has very limited clinical  activity in patients with metastatic UM. Toxicity was manageable when treated as   per protocol-specific guidelines. TRIAL REGISTRATION: ClinicalTrials.gov  NCT01355120.
CANIT0000403	25795410	Clinical research	Advanced melanoma who progressed after anti-CTLA-4 treatment	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	Chemotherapy	Immune checkpoint therapy	Nivolumab (DB09035); chemotherapy (NCIT:C15632); 	272	133	A randomised, controlled, open-label, phase III trial	Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need.	Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred.	N/A	N/A	N/A	N/A	N/A	 2015 Apr	 Nivolumab versus chemotherapy in patients with advanced melanoma who progressed  after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled,  open-label, phase 3 trial.	 Lancet Oncol	 BACKGROUND: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor  antibody, can result in durable responses in patients with melanoma who have  progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and  safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as   a second-line or later-line treatment in patients with advanced melanoma.  METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited   patients at 90 sites in 14 countries. Eligible patients were 18 years or older,  had unresectable or metastatic melanoma, and progressed after ipilimumab, or  ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive.  Participating investigators randomly assigned (with an interactive voice response  system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg  every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175  mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until  progression or unacceptable toxic effects. We stratified randomisation by BRAF  mutation status, tumour expression of PD-L1, and previous best overall response  to ipilimumab. We used permuted blocks (block size of six) within each stratum.  Primary endpoints were the proportion of patients who had an objective response  and overall survival. Treatment was given open-label, but those doing tumour  assessments were masked to treatment assignment. We assessed objective responses   per-protocol after 120 patients had been treated with nivolumab and had a minimum  follow-up of 24 weeks, and safety in all patients who had had at least one dose  of treatment. The trial is closed and this is the first interim analysis,  reporting the objective response primary endpoint. This study is registered with   ClinicalTrials.gov, number NCT01721746. FINDINGS: Between Dec 21, 2012, and Jan  10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab  and 133 to ICC. Confirmed objective responses were reported in 38 (31.7%, 95% CI   23.5-40.8) of the first 120 patients in the nivolumab group versus five (10.6%,  3.5-23.1) of 47 patients in the ICC group. Grade 3-4 adverse events related to  nivolumab included increased lipase (three [1%] of 268 patients), increased  alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these  included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia   (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%)  nivolumab-treated patients and nine (9%) patients in the ICC group. No  treatment-related deaths occurred. INTERPRETATION: Nivolumab led to a greater  proportion of patients achieving an objective response and fewer toxic effects  than with alternative available chemotherapy regimens for patients with advanced   melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor.  Nivolumab represents a new treatment option with clinically meaningful durable  objective responses in a population of high unmet need. FUNDING: Bristol-Myers  Squibb.CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
CANIT0000404	25800770	Clinical research	Advanced renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	34	N/A	A phase I clinical trial	Patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation. Overall survival is encouraging, and toxicities were generally manageable. Ongoing randomized clinical trials will further assess the impact of nivolumab on overall survival in patients with advanced RCC.	Grade 3 to 4 treatment-related adverse events occurred in 18% of patients; all were reversible.	N/A	N/A	N/A	N/A	N/A	 2015 Jun 20	 Survival, Durable Response, and Long-Term Safety in Patients With Previously  Treated Advanced Renal Cell Carcinoma Receiving Nivolumab.	 J Clin Oncol	 PURPOSE: Blockade of the programmed death-1 inhibitory cell-surface molecule on  immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates   tumor regression in a portion of patients with advanced treatment-refractory  solid tumors. We report clinical activity, survival, and long-term safety in  patients with advanced renal cell carcinoma (RCC) treated with nivolumab in a  phase I study with expansion cohorts. PATIENTS AND METHODS: A total of 34  patients with previously treated advanced RCC, enrolled between 2008 and 2012,  received intravenous nivolumab (1 or 10 mg/kg) in an outpatient setting once  every two weeks for up to 96 weeks and were observed for survival and duration of  response after treatment discontinuation. RESULTS: Ten patients (29%) achieved  objective responses (according to RECIST [version 1.0]), with median response  duration of 12.9 months; nine additional patients (27%) demonstrated stable  disease lasting > 24 weeks. Three of five patients who stopped treatment while in  response continued to respond for >/= 45 weeks. Median overall survival in all  patients (71% with two to five prior systemic therapies) was 22.4 months; 1-, 2-,  and 3-year survival rates were 71%, 48%, and 44%, respectively. Grade 3 to 4  treatment-related adverse events occurred in 18% of patients; all were  reversible. CONCLUSION: Patients with advanced treatment-refractory RCC treated  with nivolumab demonstrated durable responses that in some responders persisted  after drug discontinuation. Overall survival is encouraging, and toxicities were   generally manageable. Ongoing randomized clinical trials will further assess the   impact of nivolumab on overall survival in patients with advanced RCC.CI  - (c) 2015 by American Society of Clinical Oncology.
CANIT0000405	25819643	Clinical research	Unresectable, advanced malignant mesothelioma	Mesothelioma	EFO:0000588	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	29	N/A	An open-label, single-arm, phase II	Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile.	Grade 1-2 treatment-related adverse events occurred in 26 (90%) patients and grade 3-4 adverse events in two (7%) patients. The most common treatment-related adverse events were gastrointestinal, dermatological, and fever.	N/A	N/A	N/A	N/A	N/A	 2015 Apr	 Efficacy and safety of an intensified schedule of tremelimumab for  chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2  study.	 Lancet Respir Med	 BACKGROUND: CTLA4 blockade by tremelimumab 15 mg/kg every 90 days provided  preliminary evidence of activity in patients with pretreated malignant  mesothelioma; however, retrospective exposure-response analysis of data from  patients with melanoma suggested that this schedule could result in underexposure  to tremelimumab. We therefore investigated the efficacy and safety of an  intensified schedule of tremelimumab in patients with advanced malignant  mesothelioma. METHODS: In this open-label, single-arm, phase 2 study,  participants aged 18 years or older with unresectable, advanced malignant  mesothelioma (measurable in accordance with the Response Evaluation Criteria in  Solid Tumors [RECIST]), a life expectancy of 3 months or more, an Eastern  Cooperative Oncology Group performance status of 2 or less, and who had failed a   first-line platinum-based regimen were enrolled at the University Hospital of  Siena, Siena, Italy. Participants received tremelimumab 10 mg/kg once every 4  weeks for six doses, then every 12 weeks until disease progression, unacceptable   toxic effects, or refusal to continue treatment. The primary endpoint was the  proportion of patients achieving an immune-related objective response (complete  or partial), assessed in all patients who received at least one dose of the study  drug. This study is registered with the European Union Clinical Trials Register,   number 2012-002762-12, and ClinicalTrials.gov, number NCT01655888. FINDINGS:  Between July 30, 2012, and July 15, 2013, we enrolled 29 patients with a median  age of 65 years (range 42-78), stage III (n=11) or IV (n=18) disease, and an  Eastern Cooperative Oncology Group performance status of 0-1 (n=23) or 2 (n=6).  Malignant mesothelioma histology was epithelioid (n=21, including one  peritoneal), biphasic (n=6), sarcomatoid (n=1), or undefined (n=1). Patients  received a median of six doses of tremelimumab (range 1-13). After a median  follow-up of 21.3 months (IQR 18.7-25.9), four immune-related-partial responses  were recorded, one at the first tumour assessment (after about 12 weeks) and  three at the second tumour assessment (about 24 weeks), with two responses  occurring after initial progressive disease and one response after initial stable  disease. 15 (52%) of patients achieved disease control, with a median duration of  10.9 months (95% CI 8.2-13.6). According to modified RECIST, one patient (3%)  achieved a partial response and 11 (38%) patients achieved disease control rate.   Grade 1-2 treatment-related adverse events occurred in 26 (90%) patients and  grade 3-4 adverse events in two (7%) patients. The most common treatment-related   adverse events were gastrointestinal, dermatological, and fever. INTERPRETATION:   Our results suggest that the intensified schedule of tremelimumab investigated  seems to have clinical and immunological activity in patients with advanced  malignant mesothelioma, and a good safety profile. The same intensified schedule   is now being investigated in an ongoing randomised, double-blind,  placebo-controlled, phase 2b study. FUNDING: Associazione Italiana per la Ricerca  sul Cancro, Istituto Toscano Tumori, and MedImmune.CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
CANIT0000406	25828465	Case report	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Autoimmune diabetes	N/A	N/A	N/A	N/A	N/A	 2015 Jun	 Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case  report.	 Cancer Immunol Immunother	 The anti programmed cell death-1 (PD-1) antibodies pembrolizumab and nivolumab  have been recently licensed by the Food and Drug Administration for the treatment  of advanced melanoma. Immune checkpoint inhibitors such as these can induce  endocrine adverse events but autoimmune diabetes has not been described to date.   However, there is a strong preclinical rationale that supports this autoimmune  toxicity. We describe for the first time the case of an adult patient who  developed autoimmune diabetes likely as a consequence of PD-1 inhibition with  pembrolizumab. The presence of high serum titres of anti-glutamic acid  decarboxylase antibodies together with a suggestive clinical presentation, age of  the patient and preclinical data strongly support an autoimmune aetiology of the   diabetes. Moreover, the patient was found to have a well-known high-risk human  leucocyte antigen type for the development of type 1 diabetes in children, so the  PD-1 inhibition is very likely to have triggered the autoimmune phenomenon. Our  case suggests that insulin-dependent diabetes might be a rare but important  anti-PD-1 immune-related adverse event.
CANIT0000407	25839442	Case report	Stage 3B resected melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	This case highlights the potential for severe toxicity for long periods after administration of ipilimumab.	Delayed dermatologic hypersensitivity reaction	N/A	N/A	N/A	N/A	N/A	 2015 May	 Delayed dermatologic hypersensitivity reaction secondary to ipilimumab.	 J Immunother	 The treatment of melanoma has long favored the use of immunologic agents.  Ipilimumab is a monoclonal antibody used to enhance the immune response. This  therapy is associated with a variety of adverse reactions including skin  reactions. Although dermatologic toxicities associated with the use of ipilimumab  are common, delayed hypersensitivity reactions related to the drug have yet to be  identified. This report is believed to be the first case of a delayed, severe  dermatologic drug-related reaction secondary to ipilimumab. This case highlights   the potential for severe toxicity for long periods after administration of  ipilimumab.
CANIT0000408	25840693	Clinical research	Complete resection of high-risk stage III melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Placebo	Immune checkpoint therapy	Ipilimumab (DB06186); 	475	476	A randomised, double-blind, phase III	Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies.	The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barr syndrome.	N/A	N/A	N/A	N/A	N/A	 2015 May	 Adjuvant ipilimumab versus placebo after complete resection of high-risk stage  III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.	 Lancet Oncol	 BACKGROUND: Ipilimumab is an approved treatment for patients with advanced  melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with  completely resected stage III melanoma at high risk of recurrence. METHODS: We  did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma  (excluding lymph node metastasis </=1 mm or in-transit metastasis) with adequate   resection of lymph nodes (ie, the primary cutaneous melanoma must have been  completely excised with adequate surgical margins) who had not received previous   systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients  were randomly assigned (1:1), centrally by an interactive voice response system,   to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks   for four doses, then every 3 months for up to 3 years. Using a minimisation  technique, randomisation was stratified by disease stage and geographical region.  The primary endpoint was recurrence-free survival, assessed by an independent  review committee, and analysed by intention to treat. Enrollment is complete but   the study is ongoing for follow-up for analysis of secondary endpoints. This  trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov,   number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951  patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of   whom were included in the intention-to-treat analyses. At a median follow-up of  2.74 years (IQR 2.28-3.22), there were 528 recurrence-free survival events (234  in the ipilimumab group vs 294 in the placebo group). Median recurrence-free  survival was 26.1 months (95% CI 19.3-39.3) in the ipilimumab group versus 17.1  months (95% CI 13.4-21.6) in the placebo group (hazard ratio 0.75; 95% CI  0.64-0.90; p=0.0013); 3-year recurrence-free survival was 46.5% (95% CI  41.5-51.3) in the ipilimumab group versus 34.8% (30.1-39.5) in the placebo group.  The most common grade 3-4 immune-related adverse events in the ipilimumab group  were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50   [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to  discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab   (182 [39%] during the initial treatment period of four doses). Five patients (1%)  died due to drug-related adverse events. Five (1%) participants died because of  drug-related adverse events in the ipilimumab group; three patients died because   of colitis (two with gastrointestinal perforation), one patient because of  myocarditis, and one patient because of multiorgan failure with Guillain-Barre  syndrome. INTERPRETATION: Adjuvant ipilimumab significantly improved  recurrence-free survival for patients with completely resected high-risk stage  III melanoma. The adverse event profile was consistent with that observed in  advanced melanoma, but at higher incidences in particular for endocrinopathies.  The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires   additional assessment based on distant metastasis-free survival and overall  survival endpoints to define its definitive value. FUNDING: Bristol-Myers Squibb.CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
CANIT0000409	25855890	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	2	N/A	Case	N/A	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2015 Jun	 Early recognition of ipilimumab-related autoimmune hypophysitis in patients with   metastatic melanoma: Case studies and recommendations for management.	 Asia Pac J Clin Oncol	 Ipilimumab is a human anti-CTLA-4 monoclonal antibody recently approved for the  treatment of advanced melanoma. Stimulation of T-cell activity unmasks antitumor   activity, but can cause immune-related adverse events. Autoimmune hypophysitis is  of particular importance because its presentation can be subtle but life  threatening. We present two cases where early recognition of ipilimumab-related  autoimmune hypophysitis led to timely intervention and low subsequent morbidity,   without compromise of antitumor effects. We provide recommendations for detection  and management of this potentially life-threatening complication of ipilimumab.CI  - (c) 2015 Wiley Publishing Asia Pty Ltd.
CANIT0000410	25860328	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	110	N/A	A single-centre study	The cost of ipilimumab toxicity is marginal in comparison with the total treatment cost.	Out of the 110 patients, 29 experienced grade 3/4 immune-related adverse events. The total cost of investigating and managing these patients was  140,680, or a median cost of  2860 per patient. Patients experiencing grade 3/4 toxicities had 1-, 2- and 3-year survival rates of 79, 59 and 46%, compared with 24, 17 and 15% in the group that did not experience significant toxicity (P<0.0005). The most common treatment-related toxicity identified was colitis. Two patients died from complications associated with ipilimumab colitis. The cost of ipilimumab toxicity is marginal in comparison with the total treatment cost. Patients treated with ipilimumab who develop significant toxicity have a higher than expected 1-, 2- and 3-year survival.	N/A	N/A	N/A	N/A	N/A	 2015 Jun	 The cost of ipilimumab toxicity: a single-centre analysis.	 Melanoma Res	 There are no published data on the costs associated with investigating and  managing toxicity from ipilimumab treatment in patients with metastatic melanoma.  Patients treated with ipilimumab at The Royal Marsden Hospital between 1  September 2010 and 1 April 2013 were identified. Data on demographics,  investigations and survival outcomes were collected. Patients with grade 3 or  higher immune-related adverse events were identified, and costs of investigating   and managing toxicities in them were calculated on the basis of standard National  Health Service tariffs. Out of the 110 patients, 29 experienced grade 3/4  immune-related adverse events. The total cost of investigating and managing these  patients was pound140,680, or a median cost of pound2860 per patient. Patients  experiencing grade 3/4 toxicities had 1-, 2- and 3-year survival rates of 79, 59   and 46%, compared with 24, 17 and 15% in the group that did not experience  significant toxicity (P<0.0005). The most common treatment-related toxicity  identified was colitis. Two patients died from complications associated with  ipilimumab colitis. The cost of ipilimumab toxicity is marginal in comparison  with the total treatment cost. Patients treated with ipilimumab who develop  significant toxicity have a higher than expected 1-, 2- and 3-year survival.
CANIT0000411	25885696	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	The aim of this article is to support further investigations concerning epigenetic and genetic analysis in order to personalize biological therapy and to reduce immune related adverse events observed after ipilimumab administration.	Ileitis	N/A	N/A	N/A	N/A	N/A	 2015 Mar 1	 Ipilimumab and immune-mediated adverse events: a case report of anti-CTLA4  induced ileitis.	 BMC Cancer	 BACKGROUND: Ipilimumab is a fully human monoclonal antibody directed against  cytotoxic T-lymphocyte antigen-4 , a key negative regulator of T-cell activation   approved by the Food and Drug Administration as of March 2011 for the treatment  of metastatic melanoma. As a result of the up-regulation of the immune system,  several immune-mediated adverse effects have been reported including colitis,  dermatitis, hepatitis and rarely hypophysitis. The most frequent immune-mediated   adverse effects described in literature include gastrointestinal toxicity such as  diarrhea, colitis and case of colitis and ileitis. CASE PRESENTATION: In this  paper we report an interesting case of immune-mediate ileitis without colitis in   a 54 years old woman with metastatic melanoma treated with ipilimumab. We also  discuss about case management and the possible pathological mechanisms  considering also previous reports. CONCLUSIONS: The aim of this article is to  support further investigations concerning epigenetic and genetic analysis in  order to personalize biological therapy and to reduce immune related adverse  events observed after ipilimumab administration.
CANIT0000412	25891174	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	495	N/A	A phase I clinical trial	Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab.	Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2015 May 21	 Pembrolizumab for the treatment of non-small-cell lung cancer.	 N Engl J Med	 BACKGROUND: We assessed the efficacy and safety of programmed cell death 1 (PD-1)  inhibition with pembrolizumab in patients with advanced non-small-cell lung  cancer enrolled in a phase 1 study. We also sought to define and validate an  expression level of the PD-1 ligand 1 (PD-L1) that is associated with the  likelihood of clinical benefit. METHODS: We assigned 495 patients receiving  pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight  every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group  (182 patients) or a validation group (313 patients). We assessed PD-L1 expression  in tumor samples using immunohistochemical analysis, with results reported as the  percentage of neoplastic cells with staining for membranous PD-L1 (proportion  score). Response was assessed every 9 weeks by central review. RESULTS: Common  side effects that were attributed to pembrolizumab were fatigue, pruritus, and  decreased appetite, with no clear difference according to dose or schedule. Among  all the patients, the objective response rate was 19.4%, and the median duration   of response was 12.5 months. The median duration of progression-free survival was  3.7 months, and the median duration of overall survival was 12.0 months. PD-L1  expression in at least 50% of tumor cells was selected as the cutoff from the  training group. Among patients with a proportion score of at least 50% in the  validation group, the response rate was 45.2%. Among all the patients with a  proportion score of at least 50%, median progression-free survival was 6.3  months; median overall survival was not reached. CONCLUSIONS: Pembrolizumab had  an acceptable side-effect profile and showed antitumor activity in patients with   advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor  cells correlated with improved efficacy of pembrolizumab. (Funded by Merck;  KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).
CANIT0000413	25892889	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	7	N/A	Case	N/A	Colitis	N/A	N/A	N/A	N/A	N/A	 2015 Apr 14	 Ipilimumab associated colitis: an IpiColitis case series at MedStar Georgetown  University Hospital.	 World J Gastroenterol	 Although ipilimumab has been shown to improve survival in patients with  metastatic melanoma and cause regression of metastatic renal cell carcinoma, the   associated immune-related toxicities are of concern. The resultant T cell  activation by this monoclonal antibody causes an increased immune response, which  has been associated with many immune-regulated adverse effects. One of the most  concerning effects is the development of colitis. Upwards to 8% of patients have   been reported to develop colitis, with 5% being severe (Grades 3-4). While  initial treatment of such adverse effects is generally comprised of supportive  and symptomatic treatment, more severe cases warrant the use of high dose  steroids. Furthermore, use of anti-TNF agents is usually reserved for those cases  that prove to be refractory to steroids. We describe a systematic case review of   seven patients who developed gastrointestinal symptoms following initiation of  ipilimumab immunotherapy, and present the steps in their evaluation, treatment  and outcomes at our institution.
CANIT0000414	25897158	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	129	N/A	A phase I clinical trial	Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC.	Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis.	N/A	N/A	N/A	N/A	N/A	 2015 Jun 20	 Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1  Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced  Non-Small-Cell Lung Cancer.	 J Clin Oncol	 PURPOSE: Programmed death 1 is an immune checkpoint that suppresses antitumor  immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune  checkpoint inhibitor antibody, was active and generally well tolerated in  patients with advanced solid tumors treated in a phase I trial with expansion  cohorts. We report overall survival (OS), response durability, and long-term  safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in  this trial. PATIENTS AND METHODS: Patients (N = 129) with heavily pretreated  advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2  weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST  (version 1.0) after each cycle. RESULTS: Median OS across doses was 9.9 months;  1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses  and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for  further clinical development. Among 22 patients (17%) with objective responses,  estimated median response duration was 17.0 months. An additional six patients  (5%) had unconventional immune-pattern responses. Response rates were similar in   squamous and nonsquamous NSCLC. Eighteen responding patients discontinued  nivolumab for reasons other than progressive disease; nine (50%) of those had  responses lasting > 9 months after their last dose. Grade 3 to 4  treatment-related adverse events occurred in 14% of patients. Three  treatment-related deaths (2% of patients) occurred, each associated with  pneumonitis. CONCLUSION: Nivolumab monotherapy produced durable responses and  encouraging survival rates in patients with heavily pretreated NSCLC. Randomized   clinical trials with nivolumab in advanced NSCLC are ongoing.CI  - (c) 2015 by American Society of Clinical Oncology.
CANIT0000415	25918390	Clinical research	Advanced cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	29	N/A	N/A	Anti-CTLA-4 therapy may target Tregs in vivo	N/A	N/A	N/A	Monocyte counts (NCIT:C12547); 	Nonclassical monocyte counts	Cell percentage/counts in blood	 2015 May 12	 Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by   nonclassical monocytes in melanoma patients.	 Proc Natl Acad Sci U S A	 Enhancing immune responses with immune-modulatory monoclonal antibodies directed   to inhibitory immune receptors is a promising modality in cancer therapy.  Clinical efficacy has been demonstrated with antibodies blocking inhibitory  immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)  or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4-specific mAb,  showed durable clinical efficacy in metastatic melanoma; its mechanism of action   is, however, only partially understood. This is a study of 29 patients with  advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood  mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients  responding and 14 not responding to ipilimumab by multicolor flow cytometry,  antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and  immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before  (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our  knowledge for the first time, that ipilimumab can engage ex vivo FcgammaRIIIA  (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of  regulatory T cells (Tregs). In contrast, classical CD14(++)CD16(-) monocytes are   unable to do so. Moreover, we show that patients responding to ipilimumab display  significantly higher baseline peripheral frequencies of nonclassical monocytes  compared with nonresponder patients. In the tumor microenvironment, responders  have higher CD68(+)/CD163(+) macrophage ratios at baseline and show decreased  Treg infiltration after treatment. Together, our results suggest that anti-CTLA-4  therapy may target Tregs in vivo. Larger translational studies are, however,  warranted to substantiate this mechanism of action of ipilimumab in patients.
CANIT0000416	25922203	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	As immune checkpoint inhibitors become more widely used to treat melanoma and other malignancies, investigators and clinicians must be attuned to the potential for uncommon neurologic toxicities.	Encephalopathy with a reversible splenial lesion	N/A	N/A	N/A	N/A	N/A	 2015 Jun	 Ipilimumab-induced encephalopathy with a reversible splenial lesion.	 Cancer Immunol Res	 Ipilimumab, an anticytotoxic T-lymphocyte antigen (CTLA)-4 monoclonal antibody,  is a first-line therapy for stage IV melanoma. Although high-grade immune-related  adverse events occur in 25% of patients receiving ipilimumab, serious neurologic   toxicity, primarily consisting of transient sensory and motor neuropathies,  affects less than 1% of patients. We present a case report of a patient with  melanoma who received high-dose ipilimumab at 10 mg/kg as first-line therapy for   metastatic disease. After the third dose, the patient developed mild  encephalopathy with a reversible splenial lesion (MERS) of the corpus callosum by  MRI and neurogenic bladder, two novel immune-related adverse events during  checkpoint inhibition. In addition to headache, delirium, and altered  consciousness commonly seen with MERS, the patient also developed tremor, gait  instability, paresthesias, and neurogenic bladder. The latter two symptoms were  thought to represent sensory and autonomic neuropathies, respectively. The  syndrome gradually resolved following intravenous methylprednisolone at 2 mg/kg  divided twice daily for 5 days and a slow taper of oral prednisone over 8 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000417	25924991	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); paclitaxel (DB01229); 	12	N/A	An open-label, dose-escalation, phase I study	The recommended dose of ipilimumab in phased combination with PTX and CBDCA in Japanese patients with NSCLC was identified as 10 mg/kg. The safety profile was consistent with the previously defined AE profile.	Dose-limiting toxicity (DLT) occurred in 2 patients (ipilimumab 3 mg/kg) and 1 patient (ipilimumab 10 mg/kg). The most common grade 3/4 adverse events (AEs) were decreased hemoglobin, leukopenia, and neutropenia. The most common immune-related AEs affected the skin, gastrointestinal, and nervous system. The safety profile was similar in both cohorts.	N/A	N/A	N/A	N/A	N/A	 2015 Aug	 Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin  in Japanese patients with non-small-cell lung cancer.	 Invest New Drugs	 BACKGROUND: Ipilimumab is an antibody that targets the cytotoxic T-lymphocyte  antigen-4 to potentiate an antitumor response. Adding ipilimumab 10 mg/kg to  paclitaxel (PTX) and carboplatin (CBDCA) in a phased schedule improved  progression-free survival in a phase II non-small-cell lung cancer (NSCLC) study.  METHODS: This dose-escalating, phase I study was designed to identify the  recommended dose of ipilimumab (3 or 10 mg/kg) by evaluating dose-limiting  toxicity (DLT; Cycles 3 and 4) in phased combination with PTX (175 mg/m(2)) and  CBDCA (area under the curve = 6) in Japanese patients with advanced NSCLC.  Treatment was administered intravenously every 3 weeks initially, followed by  some eligible patients receiving maintenance ipilimumab once every 12 weeks.  Additional endpoints included safety, tumor response, pharmacokinetics, and  immunogenicity. RESULTS: Fifteen patients were enrolled and 12 received  ipilimumab (n = 6, 3 mg/kg; n = 6, 10 mg/kg) in combination with PTX and CBDCA.  DLTs occurred in 2 patients (ipilimumab 3 mg/kg) and 1 patient (ipilimumab 10  mg/kg). The most common grade 3/4 adverse events (AEs) were decreased hemoglobin,  leukopenia, and neutropenia. The most common immune-related AEs affected the  skin, gastrointestinal, and nervous system. The safety profile was similar in  both cohorts. Three patients in each cohort achieved a partial response. The  pharmacokinetic (PK) profile of ipilimumab in Japanese patients was similar to  that observed in previous studies in non-Japanese patients. Conclusions The  recommended dose of ipilimumab in phased combination with PTX and CBDCA in  Japanese patients with NSCLC was identified as 10 mg/kg. The safety profile was  consistent with the previously defined AE profile.
CANIT0000418	25956728	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Severe acute orthopnea: ipilimumab-induced bilateral phrenic nerve neuropathy	N/A	N/A	N/A	N/A	N/A	 2015 Aug	 Severe Acute Orthopnea: Ipilimumab-Induced Bilateral Phrenic Nerve Neuropathy.	 Lung	 Ipilimumab is a monoclonal antibody used in the treatment of unresectable or  metastatic melanoma. Several immune-related adverse events including potential  fatal events have been reported following its use. We report a case of a  66-year-old man who presented with severe acute exertional dyspnea and orthopnea   following administration of ipilimumab for metastatic melanoma. Although various   peripheral neuropathy syndromes associated with ipilimumab have been reported,  bilateral phrenic nerve paralysis has not been previously reported. This case  also highlights the clinical features of bilateral phrenic nerve neuropathy.  Pulmonologists have to be aware of these unusual immune-related respiratory  adverse events in patients being treated with monoclonal antibodies.
CANIT0000419	25962110	Case report	 metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	In conclusion, cytomegalovirus reactivation should be included in the differential in patients under immunotherapy with checkpoint inhibitors and has to be considered as a cause for morbidity.	Autoimmune colitis and subsequent cytomegalovirus(CMV)-induced hepatitis	N/A	N/A	N/A	N/A	N/A	 2015 Jun	 Autoimmune Colitis and Subsequent CMV-induced Hepatitis After Treatment With  Ipilimumab.	 J Immunother	 Ipilimumab, a humanized CTLA-4 antibody, improves overall survival in patients  with metastatic melanoma. However, immune-related adverse effects occur in about   65% of ipilimumab-treated patients and have to be adequately managed. A  55-year-old patient developed grade 3 autoimmune colitis 7 weeks after initiation  of ipilimumab treatment and subsequently hepatitis with grade 3 elevation of  transaminases and gamma-glutamyl transferase. Colitis manifested with up to 18  watery and bloody stools per day and severe attacks of abdominal pain. After  exclusion of infectious causes, immunosuppression with corticosteroids was  initiated. Because of recurrent abdominal pain, spontaneous perforation of the  colon had to be excluded. Elevated liver function tests (grade 3 CTCAE) occurred   and differential diagnosis included immune-mediated, toxic, and viral hepatitis.   It is interesting to note that, not an immune-mediated but a  cytomegalovirus-induced hepatitis was diagnosed by serum blood tests and liver  biopsy and was subsequently successfully treated. Careful elaboration of the  patient under immunotherapy was essential as further immunosuppression mandatory   for autoimmune hepatitis would have worsened the viral hepatitis. In conclusion,   cytomegalovirus reactivation should be included in the differential in patients  under immunotherapy with checkpoint inhibitors and has to be considered as a  cause for morbidity.
CANIT0000420	25968455	Clinical research	Metastatic, castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); GM-CSF (P04141); 	CTLA-4; GM-CSF	Ipilimumab plus sargramostim	N/A	Immune checkpoint therapy plus Immune cytokine	Ipilimumab (DB06186); sargramostim (DB00020); 	42	N/A	A phase Ib clinical trial	These results suggest that preexisting expression of immunologic checkpoint marker PD-1 on CD4 Teff cells may help identify patients that may benefit from ipilimumab treatment.	N/A	N/A	N/A	CD4 (P01730); PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	PD-1(+) CD4 Teff cells counts	Gene expression signature on/in immune cell	 2015 Sep	 Preexisting Levels of CD4 T Cells Expressing PD-1 Are Related to Overall Survival  in Prostate Cancer Patients Treated with Ipilimumab.	 Cancer Immunol Res	 Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade can induce tumor  regression and improved survival in cancer patients. This treatment can enhance  adaptive immune responses without an exogenous vaccine, but the immunologic  biomarkers associated with improved clinical outcome in cancer patients are not  fully established. A phase Ib trial in patients with metastatic,  castration-resistant prostate cancer was performed combining ipilimumab with  sargramostim (GM-CSF). In addition to evaluating ipilimumab dose, patients were  followed clinically for response and overall survival, and for immunomodulation  of circulating T cells. PSA declines of >/=50% and radiographic responses were  observed at doses of >/=3 mg/kg/dose. Timing of clinical responses could be  either immediate or delayed. Durable responses were also observed off treatment.   A subset of patients experienced long-term survival with or without objective  clinical responses. The relationship between T-cell phenotype in peripheral blood  and overall survival was examined retrospectively. We found that the treatment  induced an increase in the levels of CD4(+) effector T (Teff) cells, regulatory T  cells, PD-1(+) CD4 Teff cells, and PD-1(+) CD8 T cells. However, these increased   levels were not associated with overall survival. Instead, low pretreatment  baseline levels of PD-1(+) CD4 Teff cells were found to correlate with longer  overall survival. Furthermore, baseline levels of PD-1(+) CD4 Teff cells from  patients with shorter overall survival were higher than from cancer-free male  control subjects. These results suggest that preexisting expression of  immunologic checkpoint marker PD-1 on CD4 Teff cells may help identify patients  that may benefit from ipilimumab treatment.CI  - (c)2015 American Association for Cancer Research.
CANIT0000421	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Adenocarcinoma	EFO:0000228	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000422	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Carcinoid neuroendocrine	EFO:0004243	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000423	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000424	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Kaposi sarcoma	EFO:0000558	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000425	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000426	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Merkel cell skin cancer	EFO:1001471	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000427	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000428	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000429	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Peripheral nerve sheath tumor	EFO:0000760	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000430	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000431	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Sarcoma	EFO:1001968	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000432	25977344	Clinical research	Advanced solid tumors(7 Melanoma, 6 NonCsmall cell lung cancer, 2 Adenocarcinoma, 3 Carcinoid neuroendocrine, 3 Colorectal cancer, 1 Merkel cell carcinoma, 1 Prostate cancer, 1 Kaposi sarcoma, 1 Soft tissue sarcoma, 1 Peripheral nerve sheath tumor, 1 Pancreatic adenocarcinoma, 1 Squamous cell lung cancer)	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	A phase I clinical trial 	Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in  Patients with Advanced Solid Tumors.	 Clin Cancer Res	 PURPOSE: This phase I study evaluated the safety, maximum tolerated dose,  antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in  patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose  escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg  intravenously every 2 weeks until progression or intolerable toxicity. Seven  additional patients received 10 mg/kg every 2 weeks. Thirteen patients  participated in a 3-week intrapatient dose escalation (dose range, 0.005-10  mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No  dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg  every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma  experienced complete responses of 57 and 56+ weeks' duration, respectively. Three  patients with melanoma experienced partial responses. Fifteen patients with  various malignancies experienced stable disease. One patient died of cryptococcal  infection 92 days after pembrolizumab discontinuation, following prolonged  corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab  exhibited pharmacokinetic characteristics typical of humanized monoclonal  antibodies. Maximum serum target engagement was reached with trough levels of  doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based  translational models with a focus on intratumor exposure prediction suggested  robust clinical activity would be observed at doses >/=2 mg/kg every 3 weeks.  CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable  antitumor activity in multiple solid tumors. The lowest dose with full potential   for antitumor activity was 2 mg/kg every 3 weeks.CI  - (c)2015 American Association for Cancer Research.
CANIT0000433	26028255	Clinical research	Progressive metastatic carcinoma	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	41	N/A	A phase II clinical trial	Mismatch-repair status predicted clinical  benefit of immune checkpoint blockade with pembrolizumab.	N/A	N/A	N/A	Mismatch-repair status (NCIT:C20639); 	DNA mismatch repair-deficient	Gene expression signature on/in tumor cell	 2015 Jun 25	 PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.	 N Engl J Med	 BACKGROUND: Somatic mutations have the potential to encode non-self immunogenic  antigens. We hypothesized that tumors with a large number of somatic mutations  due to mismatch-repair defects may be susceptible to immune checkpoint blockade.   METHODS: We conducted a phase 2 study to evaluate the clinical activity of  pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41  patients with progressive metastatic carcinoma with or without mismatch-repair  deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per  kilogram of body weight every 14 days in patients with mismatch repair-deficient   colorectal cancers, patients with mismatch repair-proficient colorectal cancers,   and patients with mismatch repair-deficient cancers that were not colorectal. The  coprimary end points were the immune-related objective response rate and the  20-week immune-related progression-free survival rate. RESULTS: The  immune-related objective response rate and immune-related progression-free  survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients),  respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18  patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal  cancers. The median progression-free survival and overall survival were not  reached in the cohort with mismatch repair-deficient colorectal cancer but were  2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient  colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001],  and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch  repair-deficient noncolorectal cancer had responses similar to those of patients   with mismatch repair-deficient colorectal cancer (immune-related objective  response rate, 71% [5 of 7 patients]; immune-related progression-free survival  rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782  somatic mutations per tumor in mismatch repair-deficient tumors, as compared with  73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation  loads were associated with prolonged progression-free survival (P=0.02).  CONCLUSIONS: This study showed that mismatch-repair status predicted clinical  benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns  Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).
CANIT0000434	26028407	Clinical research	Advanced squamous-cell non-small-cell lung cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Docetaxel	Immune checkpoint therapy	Nivolumab (DB09035); docetaxel (DB01248); 	135	137	A randomized, open-label, international, phase III	Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level.	Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2015 Jul 9	 Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.	 N Engl J Med	 BACKGROUND: Patients with advanced squamous-cell non-small-cell lung cancer  (NSCLC) who have disease progression during or after first-line chemotherapy have  limited treatment options. This randomized, open-label, international, phase 3  study evaluated the efficacy and safety of nivolumab, a fully human IgG4  programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with   docetaxel in this patient population. METHODS: We randomly assigned 272 patients   to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2  weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area  every 3 weeks. The primary end point was overall survival. RESULTS: The median  overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with   nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of  death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95%  CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI,  34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The  response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The  median progression-free survival was 3.5 months with nivolumab versus 2.8 months   with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47  to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither  prognostic nor predictive of benefit. Treatment-related adverse events of grade 3  or 4 were reported in 7% of the patients in the nivolumab group as compared with   55% of those in the docetaxel group. CONCLUSIONS: Among patients with advanced,  previously treated squamous-cell NSCLC, overall survival, response rate, and  progression-free survival were significantly better with nivolumab than with  docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb;  CheckMate 017 ClinicalTrials.gov number, NCT01642004.).
CANIT0000435	26034866	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	11	N/A	N/A	Ipilimumab-associated hepatitis most often presents with a panlobular active hepatitis that resembles autoimmune hepatitis.	Viral and autoimmune serologies were negative in all patients except 1 who had a mildly elevated ANA titer. Nine biopsies showed active hepatitis with 2 distinct histologic patterns: panlobular hepatitis in 6 cases and zone 3 hepatitis in 3. The inflammatory infiltrate was similar in composition in both patterns, composed predominantly of CD8+ T lymphocytes, admixed histiocytes, scattered plasma cells, and eosinophils. Prominent histiocytic sinusoidal infiltrates were present in 7 cases and frequently formed loose histiocytic aggregates. Central vein endothelialitis was present in 8 cases. Patients in this group tended to have markedly elevated ALT, AST, and total bilirubin. Two cases did not fit into the above 2 histologic groups: 1 showed portal inflammation with cholangitis, and the other showed morphologic features indistinguishable from nonalcoholic steatohepatitis. Discontinuation of ipilimumab and administration of immunosuppressives resulted in resolution or marked improvement of LFTs in all patients within 3 months of presentation. Ipilimumab may potentially unmask previously subclinical liver disease, for example, fatty liver disease, and the diagnosis of ipilimumab-induced liver injury may only be recognized with certainty after cessation of the drug leads to normalization of LFTs.	N/A	N/A	N/A	N/A	N/A	 2015 Aug	 Ipilimumab-associated Hepatitis: Clinicopathologic Characterization in a Series  of 11 Cases.	 Am J Surg Pathol	 Ipilimumab is a monoclonal antibody that inhibits the CTLA4 receptor on cytotoxic  T lymphocytes, resulting in immune-mediated tumor cell death. Ipilimumab is most   often used in the treatment of metastatic melanoma, and rarely liver toxicity  necessitating cessation of treatment occurs. The aim of this study was to  characterize the histologic features and clinical course of ipilimumab-associated  hepatitis. Eleven patients with clinical suspicion of ipilimumab-induced  hepatitis, due to the development of abnormal liver function tests (LFTs) while  receiving treatment, and who underwent liver biopsy, were identified over a  6-year period. Ten patients were male and 1 female (median age 58 y), and all  received 1 to 4 doses of ipilimumab. None had known preexisting liver disease.  Two patients were obese, and another had a history of alcohol abuse. Viral and  autoimmune serologies were negative in all patients except 1 who had a mildly  elevated ANA titer. Nine biopsies showed active hepatitis with 2 distinct  histologic patterns: panlobular hepatitis in 6 cases and zone 3 hepatitis in 3.  The inflammatory infiltrate was similar in composition in both patterns, composed  predominantly of CD8+ T lymphocytes, admixed histiocytes, scattered plasma cells,  and eosinophils. Prominent histiocytic sinusoidal infiltrates were present in 7  cases and frequently formed loose histiocytic aggregates. Central vein  endothelialitis was present in 8 cases. Patients in this group tended to have  markedly elevated ALT, AST, and total bilirubin. Two cases did not fit into the  above 2 histologic groups: 1 showed portal inflammation with cholangitis, and the  other showed morphologic features indistinguishable from nonalcoholic  steatohepatitis. Discontinuation of ipilimumab and administration of  immunosuppressives resulted in resolution or marked improvement of LFTs in all  patients within 3 months of presentation. Ipilimumab may potentially unmask  previously subclinical liver disease, for example, fatty liver disease, and the  diagnosis of ipilimumab-induced liver injury may only be recognized with  certainty after cessation of the drug leads to normalization of LFTs. Overall,  ipilimumab-associated hepatitis most often presents with a panlobular active  hepatitis that resembles autoimmune hepatitis. Prominent sinusoidal histiocytic  infiltrates and central vein damage with endothelialitis may be helpful  histologic clues to the diagnosis of ipilimumab-associated hepatitis.
CANIT0000436	26055291	Case report	Melanoma skin metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus electrochemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); electrochemotherapy (NCIT:C15632); 	1	N/A	Case	Complete regression	N/A	N/A	N/A	N/A	N/A	N/A	 2015 May-Jun	 Complete regression of melanoma skin metastases after electrochemotherapy plus  ipilimumab treatment: an unusual clinical presentation.	 Eur J Dermatol	Unable to provide
CANIT0000437	26068559	Case report	Stage III metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Inflammatory orbitopathy	N/A	N/A	N/A	N/A	N/A	 2017 May/Jun	 Inflammatory Orbitopathy Associated With Ipilimumab.	 Ophthalmic Plast Reconstr Surg	 In this case report, the clinical presentation of an inflammatory orbitopathy  seen following treatment with ipilimumab is described. After 3 rounds of  ipilimumab (10 mg/kg) treatment for Stage III metastatic melanoma, the subject of  this case report developed acute eye pain and proptosis. At initial presentation,  she had marked proptosis and diffuse severe ophthalmoparesis. After treatment  with high-dose steroids, over a period of 6 months, the symptoms gradually  resolved fully. Although the condition may mimic thyroid-associated orbitopathy,   imaging and laboratory features suggest that the orbitopathy associated with  ipilimumab is not a secondary effect of thyroid dysfunction but a distinct  inflammatory condition. The authors conclude that immune-related side effects can  occur with biologic agents used to treat malignancies and these side-effects can   involve the eye. This case illustrates the occurrence of an inflammatory  orbitopathy associated with ipilimumab treatment.
CANIT0000438	26100356	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	147	N/A	N/A	Immune-related adverse events were noted on body imaging in 31% of patients with melanoma treated with ipilimumab. Colitis was the most common, followed by sarcoid-like lymphadenopathy and pneumonitis. The results call for an increased awareness of irAEs, given the expanding role of cancer immunotherapy.	Among the 147 patients, 46 (31%) had radiologically identified irAEs. The time interval from the initiation of therapy to the development of irAEs was less than 3 months in 76% (35 of 46) of the patients (range, 0.2-9.1 months). Clinical characteristics did not differ between patients with and without irAEs (P > 0.18). Among the individual types of irAEs, colitis was most common (n = 28; 19%), followed by sarcoid-like lymphadenopathy (n = 8; 5%) and pneumonitis (n = 8; 5%). Hepatitis (n = 3), thyroiditis (n = 2), and pancreatitis (n = 1) were less common. The resolution of irAEs was noted in 32 of 36 patients (89%) with further follow-up scans, with a median time of 2.3 months after the detection of irAE.	N/A	N/A	N/A	N/A	N/A	 2015 Oct	 Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma  Patients Treated with Ipilimumab.	 Cancer Immunol Res	 Ipilimumab is a promising novel immunotherapy agent and is associated with a  variety of immune-related adverse events (irAE). The purpose of this study was to  investigate the manifestations of irAEs on body imaging in patients with advanced  melanoma treated with ipilimumab. One-hundred forty-seven patients with advanced   melanoma (59 women, 88 men; median age, 64.5 years) treated with ipilimumab were   studied. All patients had the baseline and at least one follow-up  chest/abdomen/pelvis CT or PET/CT during therapy, which were reviewed by a  consensus of two radiologists blinded to the clinical data. Findings indicative  of individual types of irAEs were assessed, including thyroiditis, sarcoid-like  lymphadenopathy, pneumonitis, hepatitis, pancreatitis, and colitis. Among the 147  patients, 46 (31%) had radiologically identified irAEs. The time interval from  the initiation of therapy to the development of irAEs was less than 3 months in  76% (35 of 46) of the patients (range, 0.2-9.1 months). Clinical characteristics   did not differ between patients with and without irAEs (P > 0.18). Among the  individual types of irAEs, colitis was most common (n = 28; 19%), followed by  sarcoid-like lymphadenopathy (n = 8; 5%) and pneumonitis (n = 8; 5%). Hepatitis  (n = 3), thyroiditis (n = 2), and pancreatitis (n = 1) were less common. The  resolution of irAEs was noted in 32 of 36 patients (89%) with further follow-up  scans, with a median time of 2.3 months after the detection of irAE. In  conclusion, irAEs were noted on body imaging in 31% of patients with melanoma  treated with ipilimumab. Colitis was the most common, followed by sarcoid-like  lymphadenopathy and pneumonitis. The results call for an increased awareness of  irAEs, given the expanding role of cancer immunotherapy.CI  - (c)2015 American Association for Cancer Research.
CANIT0000439	26113085	Basic research	Human colon cancerCderived HT-29 cell line	Colorectal cancer	EFO:0005842	Intestines	CD137 (Q07011); PD-1 (Q15116); 	CD137; PD-1	Nivolumab plus urelumab	N/A	Immune checkpoint therapy plus Target therapy	Urelumab (DB12077); nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes Engrafted in Rag2-/-IL2Rnull Immunodeficient Mice.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2015 Sep 1	 Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes  Engrafted in Rag2-/-IL2Rgammanull Immunodeficient Mice.	 Cancer Res	 A current pressing need in cancer immunology is the development of preclinical  model systems that are immunocompetent for the study of human tumors. Here, we  report the development of a humanized murine model that can be used to analyze  the pharmacodynamics and antitumor properties of immunostimulatory monoclonal  antibodies (mAb) in settings where the receptors targeted by the mAbs are  expressed. Human lymphocytes transferred into immunodeficient mice underwent  activation and redistribution to murine organs, where they exhibited cell-surface  expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a  lethal CD4(+) T cell-mediated disease (xenograft-versus-host disease), which was   aggravated when murine subjects were administered clinical-grade anti-hCD137  (urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal  HT-29 carcinoma cells and allogeneic human peripheral blood mononuclear cells  (PBMC), or with a patient-derived gastric carcinoma and PBMCs from the same  patient, we found that coadministration of urelumab and nivolumab was sufficient   to significantly slow tumor growth. Correlated with this result were increased  numbers of activated human T lymphocytes producing IFNG and decreased numbers  of human regulatory T lymphocytes in the tumor xenografts, possibly explaining  the efficacy of the therapeutic regimen. Our results offer a proof of concept for  the use of humanized mouse models for surrogate efficacy and histology  investigations of immune checkpoint drugs and their combinations.CI  - (c)2015 American Association for Cancer Research.
CANIT0000440	26153295	Case report	High-grade non-Hodgkin's lymphoma	Non-hodgkins lymphoma	EFO:0005952	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Severe colitis	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Jul 7	 Ipilimumab-associated colitis or refractory Clostridium difficile infection 	 BMJ Case Rep	 We present a case of a patient with a diagnostic dilemma who was referred for  possible faecal microbiota transplantation (FMT) for refractory diarrhoea  secondary to Clostridium difficile infection (CDI). On detailed history, the  patient was exposed to ipilimumab concomitantly while being treated for CDI, and   was instead diagnosed with diarrhoea secondary to superimposed  ipilimumab-associated colitis. Ipilimumab is an anti-CTLA4 monoclonal antibody  approved for use in metastatic melanoma and under trial for other indications.  Ipilimumab is associated with several immune-related adverse effects, of which  diarrhoea and colitis are the most common. While FMT has shown tremendous  efficacy in managing recurrent and refractory CDI, it was not offered in this  case due to negative C. difficile testing showing a high degree of suspicion for   ipilimumab-associated colitis due to recent drug use. Our patient was  successfully managed with fluid resuscitation and steroids, and remains symptom  free at last follow-up at 9 months.CI  - 2015 BMJ Publishing Group Ltd.
CANIT0000441	26174726	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Severe hepatotoxicity	Severe hepatotoxicity	N/A	N/A	N/A	N/A	N/A	 2015 Jul 14	 Resolution of ipilimumab induced severe hepatotoxicity with triple  immunosuppressants therapy.	 BMJ Case Rep	 We describe a case of a patient from Far North Queensland, Australia, with  life-threatening hepatotoxicity caused by ipilimumab induced immune-related  adverse events (irAEs). Our patient presented with non-specific symptoms  including malaise, lethargy and fevers. Her work up revealed acute hepatitis,  which was presumed to be related to ipilimumab treatment for her metastatic  melanoma. Causality for ipilimumab was assessed with the CIOMS scale (Council for  International Organizations of Medical Sciences) and provided a causality level  of 'highly probable' (score +9). She was started on methylprednisolone as per  guidelines for ipilimumab induced irAEs. On the second day of treatment her  transaminases enzymes unexpectedly rose several hundred times. Investigations for  other causes of acute hepatitis including abdominal imaging were negative. She  was started up front on equine antithymocyte globulin, mycophenolate moefetil and  continued on methylprednisolone. She recovered clinically and biochemically in 2   weeks and continues to remain well.CI  - 2015 BMJ Publishing Group Ltd.
CANIT0000442	26198822	Case report	Multiple metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Serological aggravation of autoimmune thyroid disease	N/A	N/A	N/A	N/A	N/A	 2016 Feb	 Serological aggravation of autoimmune thyroid disease in two cases receiving  nivolumab.	 J Dermatol	 Nivolumab, a blockade of programmed cell death 1, is now administrated for  advanced malignant melanomas. Nivolumab-associated adverse events include  organ-specific autoimmune disorders; autoimmune thyroid disease, vitiligo and  insulin-dependent diabetes. However, predisposed persons are currently unknown.  Here, we report serological aggravation of autoimmune thyroid disease in two  cases receiving nivolumab: one with Hashimoto disease and another with probable  subclinical Hashimoto disease. We should verify if nivolumab-related  hypothyroidism and hyperthyroidism are predisposed to occur in euthyroid  individuals with subclinical autoimmune thyroid disease.CI  - (c) 2015 Japanese Dermatological Association.
CANIT0000443	26209970	Case report	Prostatic cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	We report the case of a 64 years old caucasian patient with prostatic cancer who received ipilimumab therapy in a clinical trial. He presented with aphasia, tremor and ataxia, myocloni, hallucinations, anxiety and agitation in turns with somnolence. Cranial nerves, deep tendon reflexes, motor and sensory functions were normal. Electroencephalography showed background slowing but no epileptic discharges. Brain magnetic resonance imaging was normal and showed no signs of hypophysitis. Cerebrospinal fluid findings ruled out infection and neoplastic meningitis. Anti-thyroid antibodies (anti-thyroid-peroxidase antibody and anti-thyroglobulin antibody) were heavily increased. Assuming steroid responsive encephalopathy associated with autoimmune thyroiditis the patient was treated with 1,000 mg methylprednisolone i.v. for 3 days and continued with 1 mg/kg orally. On the 3rd day of treatment the patient's condition started to improve. Within the next few days he gradually returned to his previous state, and electroencephalography eventually showed only slight slowing. Seven months later the patient's condition was stable, and anti-thyroid antibodies were no more detectable.	Steroid responsive encephalopathy associated with autoimmune thyroiditis following ipilimumab therapy	N/A	N/A	N/A	N/A	N/A	 2015 Jul 26	 Steroid responsive encephalopathy associated with autoimmune thyroiditis  following ipilimumab therapy: a case report.	 BMC Res Notes	 BACKGROUND: Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 receptor   antibody used for immunotherapy in cancer. Several immune-related adverse events   are known. Steroid responsive encephalopathy associated with autoimmune  thyroiditis is an autoimmune encephalopathy associated with Hashimoto's Disease  and elevated serum levels of the related antibodies (anti-thyroid-peroxidase  antibody or anti-thyroglobulin antibody). Our case implies that steroid  responsive encephalopathy associated with autoimmune thyroiditis may be another  previously unreported side effect of ipilimumab therapy. CASE PRESENTATION: We  report the case of a 64 years old caucasian patient with prostatic cancer who  received ipilimumab therapy in a clinical trial. He presented with aphasia,  tremor and ataxia, myocloni, hallucinations, anxiety and agitation in turns with   somnolence. Cranial nerves, deep tendon reflexes, motor and sensory functions  were normal. Electroencephalography showed background slowing but no epileptic  discharges. Brain magnetic resonance imaging was normal and showed no signs of  hypophysitis. Cerebrospinal fluid findings ruled out infection and neoplastic  meningitis. Anti-thyroid antibodies (anti-thyroid-peroxidase antibody and  anti-thyroglobulin antibody) were heavily increased. Assuming steroid responsive   encephalopathy associated with autoimmune thyroiditis the patient was treated  with 1,000 mg methylprednisolone i.v. for 3 days and continued with 1 mg/kg  orally. On the 3rd day of treatment the patient's condition started to improve.  Within the next few days he gradually returned to his previous state, and  electroencephalography eventually showed only slight slowing. Seven months later   the patient's condition was stable, and anti-thyroid antibodies were no more  detectable. CONCLUSION: Steroid responsive encephalopathy associated with  autoimmune thyroiditis may be a hitherto unrecognized complication of ipililumab   treatment and should be taken into consideration in patients developing central  nervous symptoms undergoing this treatment.
CANIT0000444	26222619	Clinical research	Sixty-six patients were treated for melanoma, 15 patients for lung cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	83	N/A	A multicentre, retrospective cohort study	Pembrolizumab therapy was associated with cutaneous AEs in 42% of patients. The development of cutaneous AEs, especially of hypopigmentation in patients with melanoma, could point toward better treatment response.	Thirty-five patients (42%) developed cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All 7 patients who developed hypopigmentation were treated for melanoma.	N/A	N/A	N/A	N/A	N/A	 2015 Nov	 Pembrolizumab Cutaneous Adverse Events and Their Association With Disease  Progression.	 JAMA Dermatol	 IMPORTANCE: Immunomodulatory anticancer drugs, such as the anti-programmed  death-1 drug pembrolizumab, have shown promising results in trials, and more  patients will receive such treatments. Little is known about cutaneous adverse  events (AEs) caused by these drugs and their possible correlation with treatment   response. OBJECTIVE: To describe the frequency and spectrum of cutaneous AEs  linked with pembrolizumab and their possible correlation with treatment response.  DESIGN, SETTING, AND PARTICIPANTS: A single-institution, retrospective medical  record review was conducted of patients with cancer who were treated with  pembrolizumab from March 1, 2011, to May 28, 2014. The review comprised 83  consecutive patients who were enrolled in 2 clinical trials, received at least 1   dose of pembrolizumab, and had at least 1 follow-up visit. Patients were grouped   according to the following therapeutic regimen for pembrolizumab: 43 received 10   mg/kg every 3 weeks, 24 received 10 mg/kg every 2 weeks, and 16 received 2 mg/kg   every 3 weeks. Sixty-six patients were treated for melanoma, 15 patients for lung  cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma.  Median follow-up was 15 weeks (range, 2-105 weeks). The analysis was conducted  from March 1 to September 30, 2014. MAIN OUTCOMES AND MEASURES: Occurrence,  severity, and type of cutaneous AEs, as well as disease progression and response   to pembrolizumab treatment. RESULTS: Thirty-five patients (42%) developed  cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were  macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7  [8%]). All 7 patients who developed hypopigmentation were treated for melanoma.  Survival analyses showed that patients who developed cutaneous AEs had  significantly longer progression-free intervals in all 3 groups (pembrolizumab,  10 mg/kg, every 3 weeks, P = .001; pembrolizumab, 10 mg/kg, every 2 weeks, P =  .003; pembrolizumab, 2 mg/kg, every 3 weeks, P = .009) compared with patients who  did not develop cutaneous AEs. CONCLUSIONS AND RELEVANCE: Pembrolizumab therapy  was associated with cutaneous AEs in 42% of patients. The development of  cutaneous AEs, especially of hypopigmentation in patients with melanoma, could  point toward better treatment response.
CANIT0000445	26222619	Clinical research	Sixty-six patients were treated for melanoma, 15 patients for lung cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	83	N/A	A multicentre, retrospective cohort study	Pembrolizumab therapy was associated with cutaneous AEs in 42% of patients. The development of cutaneous AEs, especially of hypopigmentation in patients with melanoma, could point toward better treatment response.	Thirty-five patients (42%) developed cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All 7 patients who developed hypopigmentation were treated for melanoma.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Cutaneous AEs, especially of hypopigmentation	Adverse events	 2015 Nov	 Pembrolizumab Cutaneous Adverse Events and Their Association With Disease  Progression.	 JAMA Dermatol	 IMPORTANCE: Immunomodulatory anticancer drugs, such as the anti-programmed  death-1 drug pembrolizumab, have shown promising results in trials, and more  patients will receive such treatments. Little is known about cutaneous adverse  events (AEs) caused by these drugs and their possible correlation with treatment   response. OBJECTIVE: To describe the frequency and spectrum of cutaneous AEs  linked with pembrolizumab and their possible correlation with treatment response.  DESIGN, SETTING, AND PARTICIPANTS: A single-institution, retrospective medical  record review was conducted of patients with cancer who were treated with  pembrolizumab from March 1, 2011, to May 28, 2014. The review comprised 83  consecutive patients who were enrolled in 2 clinical trials, received at least 1   dose of pembrolizumab, and had at least 1 follow-up visit. Patients were grouped   according to the following therapeutic regimen for pembrolizumab: 43 received 10   mg/kg every 3 weeks, 24 received 10 mg/kg every 2 weeks, and 16 received 2 mg/kg   every 3 weeks. Sixty-six patients were treated for melanoma, 15 patients for lung  cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma.  Median follow-up was 15 weeks (range, 2-105 weeks). The analysis was conducted  from March 1 to September 30, 2014. MAIN OUTCOMES AND MEASURES: Occurrence,  severity, and type of cutaneous AEs, as well as disease progression and response   to pembrolizumab treatment. RESULTS: Thirty-five patients (42%) developed  cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were  macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7  [8%]). All 7 patients who developed hypopigmentation were treated for melanoma.  Survival analyses showed that patients who developed cutaneous AEs had  significantly longer progression-free intervals in all 3 groups (pembrolizumab,  10 mg/kg, every 3 weeks, P = .001; pembrolizumab, 10 mg/kg, every 2 weeks, P =  .003; pembrolizumab, 2 mg/kg, every 3 weeks, P = .009) compared with patients who  did not develop cutaneous AEs. CONCLUSIONS AND RELEVANCE: Pembrolizumab therapy  was associated with cutaneous AEs in 42% of patients. The development of  cutaneous AEs, especially of hypopigmentation in patients with melanoma, could  point toward better treatment response.
CANIT0000446	26222619	Clinical research	Sixty-six patients were treated for melanoma, 15 patients for lung cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma	Merkel cell skin cancer	EFO:1001471	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	83	N/A	A multicentre, retrospective cohort study	Pembrolizumab therapy was associated with cutaneous AEs in 42% of patients. The development of cutaneous AEs, especially of hypopigmentation in patients with melanoma, could point toward better treatment response.	Thirty-five patients (42%) developed cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All 7 patients who developed hypopigmentation were treated for melanoma.	N/A	N/A	N/A	N/A	N/A	 2015 Nov	 Pembrolizumab Cutaneous Adverse Events and Their Association With Disease  Progression.	 JAMA Dermatol	 IMPORTANCE: Immunomodulatory anticancer drugs, such as the anti-programmed  death-1 drug pembrolizumab, have shown promising results in trials, and more  patients will receive such treatments. Little is known about cutaneous adverse  events (AEs) caused by these drugs and their possible correlation with treatment   response. OBJECTIVE: To describe the frequency and spectrum of cutaneous AEs  linked with pembrolizumab and their possible correlation with treatment response.  DESIGN, SETTING, AND PARTICIPANTS: A single-institution, retrospective medical  record review was conducted of patients with cancer who were treated with  pembrolizumab from March 1, 2011, to May 28, 2014. The review comprised 83  consecutive patients who were enrolled in 2 clinical trials, received at least 1   dose of pembrolizumab, and had at least 1 follow-up visit. Patients were grouped   according to the following therapeutic regimen for pembrolizumab: 43 received 10   mg/kg every 3 weeks, 24 received 10 mg/kg every 2 weeks, and 16 received 2 mg/kg   every 3 weeks. Sixty-six patients were treated for melanoma, 15 patients for lung  cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma.  Median follow-up was 15 weeks (range, 2-105 weeks). The analysis was conducted  from March 1 to September 30, 2014. MAIN OUTCOMES AND MEASURES: Occurrence,  severity, and type of cutaneous AEs, as well as disease progression and response   to pembrolizumab treatment. RESULTS: Thirty-five patients (42%) developed  cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were  macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7  [8%]). All 7 patients who developed hypopigmentation were treated for melanoma.  Survival analyses showed that patients who developed cutaneous AEs had  significantly longer progression-free intervals in all 3 groups (pembrolizumab,  10 mg/kg, every 3 weeks, P = .001; pembrolizumab, 10 mg/kg, every 2 weeks, P =  .003; pembrolizumab, 2 mg/kg, every 3 weeks, P = .009) compared with patients who  did not develop cutaneous AEs. CONCLUSIONS AND RELEVANCE: Pembrolizumab therapy  was associated with cutaneous AEs in 42% of patients. The development of  cutaneous AEs, especially of hypopigmentation in patients with melanoma, could  point toward better treatment response.
CANIT0000447	26222619	Clinical research	Sixty-six patients were treated for melanoma, 15 patients for lung cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	83	N/A	A multicentre, retrospective cohort study	Pembrolizumab therapy was associated with cutaneous AEs in 42% of patients. The development of cutaneous AEs, especially of hypopigmentation in patients with melanoma, could point toward better treatment response.	Thirty-five patients (42%) developed cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All 7 patients who developed hypopigmentation were treated for melanoma.	N/A	N/A	N/A	N/A	N/A	 2015 Nov	 Pembrolizumab Cutaneous Adverse Events and Their Association With Disease  Progression.	 JAMA Dermatol	 IMPORTANCE: Immunomodulatory anticancer drugs, such as the anti-programmed  death-1 drug pembrolizumab, have shown promising results in trials, and more  patients will receive such treatments. Little is known about cutaneous adverse  events (AEs) caused by these drugs and their possible correlation with treatment   response. OBJECTIVE: To describe the frequency and spectrum of cutaneous AEs  linked with pembrolizumab and their possible correlation with treatment response.  DESIGN, SETTING, AND PARTICIPANTS: A single-institution, retrospective medical  record review was conducted of patients with cancer who were treated with  pembrolizumab from March 1, 2011, to May 28, 2014. The review comprised 83  consecutive patients who were enrolled in 2 clinical trials, received at least 1   dose of pembrolizumab, and had at least 1 follow-up visit. Patients were grouped   according to the following therapeutic regimen for pembrolizumab: 43 received 10   mg/kg every 3 weeks, 24 received 10 mg/kg every 2 weeks, and 16 received 2 mg/kg   every 3 weeks. Sixty-six patients were treated for melanoma, 15 patients for lung  cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma.  Median follow-up was 15 weeks (range, 2-105 weeks). The analysis was conducted  from March 1 to September 30, 2014. MAIN OUTCOMES AND MEASURES: Occurrence,  severity, and type of cutaneous AEs, as well as disease progression and response   to pembrolizumab treatment. RESULTS: Thirty-five patients (42%) developed  cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were  macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7  [8%]). All 7 patients who developed hypopigmentation were treated for melanoma.  Survival analyses showed that patients who developed cutaneous AEs had  significantly longer progression-free intervals in all 3 groups (pembrolizumab,  10 mg/kg, every 3 weeks, P = .001; pembrolizumab, 10 mg/kg, every 2 weeks, P =  .003; pembrolizumab, 2 mg/kg, every 3 weeks, P = .009) compared with patients who  did not develop cutaneous AEs. CONCLUSIONS AND RELEVANCE: Pembrolizumab therapy  was associated with cutaneous AEs in 42% of patients. The development of  cutaneous AEs, especially of hypopigmentation in patients with melanoma, could  point toward better treatment response.
CANIT0000448	26225580	Clinical research	Previously treated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	193	N/A	N/A	The 2-year OS was significantly lower for patients with lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline.	Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%).	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2015 Oct	 Ipilimumab in the real world: the UK expanded access programme experience in  previously treated advanced melanoma patients.	 Melanoma Res	 Before licensing, ipilimumab was first made available to previously treated  advanced melanoma patients through an expanded access programme (EAP) across  Europe. We interrogated data from UK EAP patients to inform future clinical  practice. Clinicians registered in the UK EAP provided anonymized patient data  using a prespecified variable fields datasheet. Data collected were baseline  patient characteristics, treatment delivered, toxicity, response,  progression-free survival and overall survival (OS). Data were received for 193  previously treated metastatic melanoma patients, whose primary sites were  cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At  baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain   metastases. Of the patients, 53% received all four planned cycles of ipilimumab;   the most common reason for stopping early was disease progression, including  death from melanoma. Toxicity was recorded for 171 patients, 30% of whom  experienced an adverse event of grade 3 or higher, the most common being  diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median   progression-free survival and OS were 2.8 and 6.1 months, respectively; the  1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was  significantly lower for patients with poorer PS (P<0.0001), low albumin  concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate  dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at   baseline. These baseline characteristics are negative predictors of benefit from   ipilimumab and should be taken into consideration before prescription.
CANIT0000449	26225580	Clinical research	Previously treated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	193	N/A	N/A	The 2-year OS was significantly lower for patients with low albumin concentrations (P<0.0001).	Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%).	N/A	N/A	Albumin (P02768); 	Albumin concentrations	Gene expression signature in serum	 2015 Oct	 Ipilimumab in the real world: the UK expanded access programme experience in  previously treated advanced melanoma patients.	 Melanoma Res	 Before licensing, ipilimumab was first made available to previously treated  advanced melanoma patients through an expanded access programme (EAP) across  Europe. We interrogated data from UK EAP patients to inform future clinical  practice. Clinicians registered in the UK EAP provided anonymized patient data  using a prespecified variable fields datasheet. Data collected were baseline  patient characteristics, treatment delivered, toxicity, response,  progression-free survival and overall survival (OS). Data were received for 193  previously treated metastatic melanoma patients, whose primary sites were  cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At  baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain   metastases. Of the patients, 53% received all four planned cycles of ipilimumab;   the most common reason for stopping early was disease progression, including  death from melanoma. Toxicity was recorded for 171 patients, 30% of whom  experienced an adverse event of grade 3 or higher, the most common being  diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median   progression-free survival and OS were 2.8 and 6.1 months, respectively; the  1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was  significantly lower for patients with poorer PS (P<0.0001), low albumin  concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate  dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at   baseline. These baseline characteristics are negative predictors of benefit from   ipilimumab and should be taken into consideration before prescription.
CANIT0000450	26225580	Clinical research	Previously treated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	193	N/A	N/A	The 2-year OS was significantly lower for patients with poorer performance status (PS) (P<0.0001).	Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%).	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2015 Oct	 Ipilimumab in the real world: the UK expanded access programme experience in  previously treated advanced melanoma patients.	 Melanoma Res	 Before licensing, ipilimumab was first made available to previously treated  advanced melanoma patients through an expanded access programme (EAP) across  Europe. We interrogated data from UK EAP patients to inform future clinical  practice. Clinicians registered in the UK EAP provided anonymized patient data  using a prespecified variable fields datasheet. Data collected were baseline  patient characteristics, treatment delivered, toxicity, response,  progression-free survival and overall survival (OS). Data were received for 193  previously treated metastatic melanoma patients, whose primary sites were  cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At  baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain   metastases. Of the patients, 53% received all four planned cycles of ipilimumab;   the most common reason for stopping early was disease progression, including  death from melanoma. Toxicity was recorded for 171 patients, 30% of whom  experienced an adverse event of grade 3 or higher, the most common being  diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median   progression-free survival and OS were 2.8 and 6.1 months, respectively; the  1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was  significantly lower for patients with poorer PS (P<0.0001), low albumin  concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate  dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at   baseline. These baseline characteristics are negative predictors of benefit from   ipilimumab and should be taken into consideration before prescription.
CANIT0000451	26225580	Clinical research	Previously treated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	193	N/A	N/A	The 2-year OS was significantly lower for patients with the presence of brain metastases (P=0.007).	Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%).	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2015 Oct	 Ipilimumab in the real world: the UK expanded access programme experience in  previously treated advanced melanoma patients.	 Melanoma Res	 Before licensing, ipilimumab was first made available to previously treated  advanced melanoma patients through an expanded access programme (EAP) across  Europe. We interrogated data from UK EAP patients to inform future clinical  practice. Clinicians registered in the UK EAP provided anonymized patient data  using a prespecified variable fields datasheet. Data collected were baseline  patient characteristics, treatment delivered, toxicity, response,  progression-free survival and overall survival (OS). Data were received for 193  previously treated metastatic melanoma patients, whose primary sites were  cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At  baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain   metastases. Of the patients, 53% received all four planned cycles of ipilimumab;   the most common reason for stopping early was disease progression, including  death from melanoma. Toxicity was recorded for 171 patients, 30% of whom  experienced an adverse event of grade 3 or higher, the most common being  diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median   progression-free survival and OS were 2.8 and 6.1 months, respectively; the  1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was  significantly lower for patients with poorer PS (P<0.0001), low albumin  concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate  dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at   baseline. These baseline characteristics are negative predictors of benefit from   ipilimumab and should be taken into consideration before prescription.
CANIT0000452	26227432	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	113	N/A	N/A	Both higher baseline levels of lactic dehydrogenase (LDH) (Hazard Ratio [HR] v=1.36, 95% Confidence Interval [CI] 1.16-1.58, P<.001) was associated with worse prognosis.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2015 Sep	 Personalised medicine: Development and external validation of a prognostic model   for metastatic melanoma patients treated with ipilimumab.	 Eur J Cancer	 PURPOSE: The purpose of this study was to set up a prognostic model for the  identification of survival predictors specific for melanoma patients treated with  ipilimumab. EXPERIMENTAL DESIGN: The following prospectively collected data were   utilised: patient and primary tumour characteristics, relapse-free-interval, site  and number of metastases, previous therapies and level of serum biomarkers  (lactic dehydrogenase (LDH), C-reactive protein, beta2-microglobulin, vascular  endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP),  transaminases, leucocyte count, lymphocytes subpopulations). A multivariate  prognostic model was developed using the Cox regression model fitted to the data   of 113 consecutive metastatic patients treated with ipilimumab (3 mg/kg, q3w) at   Veneto Institute of Oncology (IOV). External validation was obtained using the  data of 69 and 34 patients treated at European Oncology Institute (IEO) and  University of Torino (UT), respectively. RESULTS: Median survival was 8.3, 4.9  and 7.1 months from first ipilimumab administration at IOV, IEO and UT,  respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v=1.36, 95%  Confidence Interval [CI] 1.16-1.58, P<.001) and neutrophils (HR=1.76, 95% CI  1.41-2.10, P<.001) were associated with worse prognosis. Model performance was  satisfactory both upon internal validation (Dxy=0.42) and external validation  (Dxy=0.40). Serum LDH and neutrophil count discriminated patients who lived more   (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24 months.  CONCLUSION: Serum LDH and neutrophil count were significant independent  prognostic factors. This externally validated prognostic nomogram, could help  clinicians to identify the patients who would benefit most from ipilimumab and  consequently to improve resource allocation. These easily available biomarkers  deserve further validation.CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
CANIT0000453	26227432	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	113	N/A	N/A	Both higher baseline levels of neutrophils (HR=1.76, 95% CI 1.41-2.10, P<.001) was associated with worse prognosis.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2015 Sep	 Personalised medicine: Development and external validation of a prognostic model   for metastatic melanoma patients treated with ipilimumab.	 Eur J Cancer	 PURPOSE: The purpose of this study was to set up a prognostic model for the  identification of survival predictors specific for melanoma patients treated with  ipilimumab. EXPERIMENTAL DESIGN: The following prospectively collected data were   utilised: patient and primary tumour characteristics, relapse-free-interval, site  and number of metastases, previous therapies and level of serum biomarkers  (lactic dehydrogenase (LDH), C-reactive protein, beta2-microglobulin, vascular  endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP),  transaminases, leucocyte count, lymphocytes subpopulations). A multivariate  prognostic model was developed using the Cox regression model fitted to the data   of 113 consecutive metastatic patients treated with ipilimumab (3 mg/kg, q3w) at   Veneto Institute of Oncology (IOV). External validation was obtained using the  data of 69 and 34 patients treated at European Oncology Institute (IEO) and  University of Torino (UT), respectively. RESULTS: Median survival was 8.3, 4.9  and 7.1 months from first ipilimumab administration at IOV, IEO and UT,  respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v=1.36, 95%  Confidence Interval [CI] 1.16-1.58, P<.001) and neutrophils (HR=1.76, 95% CI  1.41-2.10, P<.001) were associated with worse prognosis. Model performance was  satisfactory both upon internal validation (Dxy=0.42) and external validation  (Dxy=0.40). Serum LDH and neutrophil count discriminated patients who lived more   (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24 months.  CONCLUSION: Serum LDH and neutrophil count were significant independent  prognostic factors. This externally validated prognostic nomogram, could help  clinicians to identify the patients who would benefit most from ipilimumab and  consequently to improve resource allocation. These easily available biomarkers  deserve further validation.CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
CANIT0000454	26282644	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	298	N/A	A retrospective cohort study	Immune-related adverse events are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNF therapy. Practitioners and patients should be prepared to treat immune-related adverse events and should understand that such treatment does not affect OS or TTF.	Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNF therapy.	N/A	N/A	N/A	N/A	N/A	 2015 Oct 1	 Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects  on Survival and Time to Treatment Failure in Patients With Melanoma Treated With   Ipilimumab at Memorial Sloan Kettering Cancer Center.	 J Clin Oncol	 PURPOSE: Ipilimumab is a standard treatment for metastatic melanoma, but  immune-related adverse events (irAEs) are common and can be severe. We reviewed  our large, contemporary experience with ipilimumab treatment outside of clinical   trials to determine the frequency of use of systemic corticosteroid or anti-tumor  necrosis factor alpha (anti-TNFalpha) therapy and the effect of these therapies  on overall survival (OS) and time to treatment failure (TTF). PATIENTS AND  METHODS: We reviewed retrospectively the medical records of patients with  melanoma who had received treatment between April 2011 and July 2013 with  ipilimumab at the standard dose of 3 mg/kg. We collected data on patient  demographics, previous and subsequent treatments, number of ipilimumab doses,  irAEs and how they were treated, and overall survival. RESULTS: Of the 298  patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%)  discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103  patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%)  also required anti-TNFalpha therapy. Defining TTF as either starting a new  treatment or death, estimated median TTF was 5.7 months. Twelve percent of  patients experienced long-term disease control without receiving additional  antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or   the need for systemic corticosteroids. CONCLUSION: IrAEs are common in patients  treated with ipilimumab. In our experience, approximately one-third of  ipilimumab-treated patients required systemic corticosteroids, and almost  one-third of those required further immune suppression with anti-TNFalpha  therapy. Practitioners and patients should be prepared to treat irAEs and should   understand that such treatment does not affect OS or TTF.CI  - (c) 2015 by American Society of Clinical Oncology.
CANIT0000455	26284765	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Pancreatitis	N/A	N/A	N/A	N/A	N/A	 2015 Nov	 Pancreatitis Secondary to Anti-Programmed Death Receptor 1 Immunotherapy  Diagnosed by FDG PET/CT.	 Clin Nucl Med	 A 57-year-old man with metastatic melanoma developed colitis secondary to  ipilimumab, a known immune-related adverse event (irAE). The patient then  received pembrolizumab immunotherapy, an anti-programmed-death-receptor-1 (PD-1)   antibody. Restaging FDG PET/CT study following 3 cycles of therapy demonstrated  diffuse increased FDG uptake throughout the body of the pancreas associated with   fat stranding in the peripancreatic region, suggestive of pembrolizumab-induced  pancreatitis. Although the patient was clinically asymptomatic, diagnosis was  biochemically confirmed with elevated amylase and lipase levels. In the era of  immunotherapy, it will be critical to recognize irAEs early to allow prompt  initiation of appropriate therapy and reduce the risk of long-term sequelae.
CANIT0000456	26287667	Basic research	Hepatocellular carcinoma	Hepatocellular carcinoma	EFO:0000182	Liver	TLR3 (O15455); PTK2B (Q14289); 	TLR3; PTK2B	Poly-ICLC plus sorafenib	N/A	Tumor vaccine plus Target therapy	Poly-ICLC (NCIT:C1198); sorafenib (DB00398); 	Cell lines/ animal models	N/A	Basic research	The combinatorial therapy with poly-ICLC and Sorafenib enhances  tumor control and local immune response hence providing a rationale for future  clinical studies.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2015 Sep 29	 TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and  controls hepatocellular carcinoma progression.	 Oncotarget	 Hepatocellular carcinoma (HCC) is associated with high mortality and the current   therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we  assessed whether combining the TLR3 agonist: lysine-stabilized  polyinosinic-polycytidylic-acid (poly-ICLC) with Sorafenib could enhance tumor  control in HCC. Combinatorial therapy with poly-ICLC and Sorafenib increased  apoptosis and reduced proliferation of HCC cell lines in vitro, in association  with impaired phosphorylation of AKT, MEK and ERK. In vivo, the combinatorial  treatment enhanced control of tumor growth in two mouse models: one transplanted   with Hepa 1-6 cells, and the other with liver tumors induced using the Sleeping  beauty transposon. Tumor cell apoptosis and host immune responses in the tumor  microenvironment were enhanced. Particularly, the activation of local NK cells, T  cells, macrophages and dendritic cells was enhanced. Decreased expression of the   inhibitory signaling molecules PD-1 and PD-L1 was observed in tumor-infiltrating   CD8+ T cells and tumor cells, respectively. Tumor infiltration by  monocytic-myeloid derived suppressor cells (Mo-MDSC) was also reduced indicating   the reversion of the immunosuppressive tumor microenvironment. Our data  demonstrated that the combinatorial therapy with poly-ICLC and Sorafenib enhances  tumor control and local immune response hence providing a rationale for future  clinical studies.
CANIT0000457	26289067	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	59	N/A	N/A	An early increase in eosinophil count during the treatment with ipilimumab was associated with an improved clinical response.	N/A	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Eosinophil counts	Cell percentage/counts in blood	 2015 Dec 15	 Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive  Markers in Melanoma Treatment with Ipilimumab.	 Clin Cancer Res	 PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with  metastatic melanoma. Because only around 20% of patients experience long-term  benefit, reliable markers are needed to predict a clinical response. Therefore,  we sought to determine if some myeloid cells and related inflammatory mediators  could serve as predictive factors for the patients' response to ipilimumab.  EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral   blood of 59 stage IV melanoma patients before the treatment and at different time  points upon the therapy using a clinical laboratory analysis and multicolor flow   cytometry. In addition, the production of related inflammatory factors was  evaluated by ELISA or Bio-Plex assays. RESULTS: An early increase in eosinophil  count during the treatment with ipilimumab was associated with an improved  clinical response. In contrast, elevated amounts of monocytic myeloid-derived  suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders  (n = 36) as compared with basal levels and with responding patients (n = 23).  Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and  granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at  baseline and in responders, suggesting their enhanced immunosuppressive capacity.  Upon the first ipilimumab infusion, nonresponders displayed elevated serum  concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.  CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects  and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors  S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may  benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. (c)2015  AACR.CI  - (c)2015 American Association for Cancer Research.
CANIT0000458	26289067	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	59	N/A	N/A	Elevated amounts of monocytes was found in nonresponders as compared with basal levels and with responding patients.	N/A	N/A	N/A	Monocyte counts (NCIT:C12547); 	Monocytes counts	Cell percentage/counts in blood	 2015 Dec 15	 Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive  Markers in Melanoma Treatment with Ipilimumab.	 Clin Cancer Res	 PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with  metastatic melanoma. Because only around 20% of patients experience long-term  benefit, reliable markers are needed to predict a clinical response. Therefore,  we sought to determine if some myeloid cells and related inflammatory mediators  could serve as predictive factors for the patients' response to ipilimumab.  EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral   blood of 59 stage IV melanoma patients before the treatment and at different time  points upon the therapy using a clinical laboratory analysis and multicolor flow   cytometry. In addition, the production of related inflammatory factors was  evaluated by ELISA or Bio-Plex assays. RESULTS: An early increase in eosinophil  count during the treatment with ipilimumab was associated with an improved  clinical response. In contrast, elevated amounts of monocytic myeloid-derived  suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders  (n = 36) as compared with basal levels and with responding patients (n = 23).  Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and  granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at  baseline and in responders, suggesting their enhanced immunosuppressive capacity.  Upon the first ipilimumab infusion, nonresponders displayed elevated serum  concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.  CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects  and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors  S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may  benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. (c)2015  AACR.CI  - (c)2015 American Association for Cancer Research.
CANIT0000459	26289067	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	59	N/A	N/A	Elevated amounts of monocytic myeloid-derived suppressor cells (moMDSC) was found in nonresponders as compared with basal levels and with responding patients.	N/A	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); 	Monocytic myeloid-derived suppressor cells counts	Cell percentage/counts in blood	 2015 Dec 15	 Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive  Markers in Melanoma Treatment with Ipilimumab.	 Clin Cancer Res	 PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with  metastatic melanoma. Because only around 20% of patients experience long-term  benefit, reliable markers are needed to predict a clinical response. Therefore,  we sought to determine if some myeloid cells and related inflammatory mediators  could serve as predictive factors for the patients' response to ipilimumab.  EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral   blood of 59 stage IV melanoma patients before the treatment and at different time  points upon the therapy using a clinical laboratory analysis and multicolor flow   cytometry. In addition, the production of related inflammatory factors was  evaluated by ELISA or Bio-Plex assays. RESULTS: An early increase in eosinophil  count during the treatment with ipilimumab was associated with an improved  clinical response. In contrast, elevated amounts of monocytic myeloid-derived  suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders  (n = 36) as compared with basal levels and with responding patients (n = 23).  Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and  granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at  baseline and in responders, suggesting their enhanced immunosuppressive capacity.  Upon the first ipilimumab infusion, nonresponders displayed elevated serum  concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.  CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects  and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors  S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may  benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. (c)2015  AACR.CI  - (c)2015 American Association for Cancer Research.
CANIT0000460	26289067	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	59	N/A	N/A	Elevated amounts of neutrophils was found in nonresponders as compared with basal levels and with responding patients.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2015 Dec 15	 Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive  Markers in Melanoma Treatment with Ipilimumab.	 Clin Cancer Res	 PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with  metastatic melanoma. Because only around 20% of patients experience long-term  benefit, reliable markers are needed to predict a clinical response. Therefore,  we sought to determine if some myeloid cells and related inflammatory mediators  could serve as predictive factors for the patients' response to ipilimumab.  EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral   blood of 59 stage IV melanoma patients before the treatment and at different time  points upon the therapy using a clinical laboratory analysis and multicolor flow   cytometry. In addition, the production of related inflammatory factors was  evaluated by ELISA or Bio-Plex assays. RESULTS: An early increase in eosinophil  count during the treatment with ipilimumab was associated with an improved  clinical response. In contrast, elevated amounts of monocytic myeloid-derived  suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders  (n = 36) as compared with basal levels and with responding patients (n = 23).  Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and  granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at  baseline and in responders, suggesting their enhanced immunosuppressive capacity.  Upon the first ipilimumab infusion, nonresponders displayed elevated serum  concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.  CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects  and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors  S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may  benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. (c)2015  AACR.CI  - (c)2015 American Association for Cancer Research.
CANIT0000461	26289067	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	59	N/A	N/A	Granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at baseline and in responders.	N/A	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); PD-L1 (Q9NZQ7); 	PD-L1 expression levels on granulocytic monocytic myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2015 Dec 15	 Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive  Markers in Melanoma Treatment with Ipilimumab.	 Clin Cancer Res	 PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with  metastatic melanoma. Because only around 20% of patients experience long-term  benefit, reliable markers are needed to predict a clinical response. Therefore,  we sought to determine if some myeloid cells and related inflammatory mediators  could serve as predictive factors for the patients' response to ipilimumab.  EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral   blood of 59 stage IV melanoma patients before the treatment and at different time  points upon the therapy using a clinical laboratory analysis and multicolor flow   cytometry. In addition, the production of related inflammatory factors was  evaluated by ELISA or Bio-Plex assays. RESULTS: An early increase in eosinophil  count during the treatment with ipilimumab was associated with an improved  clinical response. In contrast, elevated amounts of monocytic myeloid-derived  suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders  (n = 36) as compared with basal levels and with responding patients (n = 23).  Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and  granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at  baseline and in responders, suggesting their enhanced immunosuppressive capacity.  Upon the first ipilimumab infusion, nonresponders displayed elevated serum  concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.  CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects  and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors  S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may  benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. (c)2015  AACR.CI  - (c)2015 American Association for Cancer Research.
CANIT0000462	26289067	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	59	N/A	N/A	In nonresponders, moMDSCs produced significantly more nitric oxide.	N/A	N/A	N/A	Nitric oxide (NCIT:C695); 	Nitric oxide	Metabolite	 2015 Dec 15	 Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive  Markers in Melanoma Treatment with Ipilimumab.	 Clin Cancer Res	 PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with  metastatic melanoma. Because only around 20% of patients experience long-term  benefit, reliable markers are needed to predict a clinical response. Therefore,  we sought to determine if some myeloid cells and related inflammatory mediators  could serve as predictive factors for the patients' response to ipilimumab.  EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral   blood of 59 stage IV melanoma patients before the treatment and at different time  points upon the therapy using a clinical laboratory analysis and multicolor flow   cytometry. In addition, the production of related inflammatory factors was  evaluated by ELISA or Bio-Plex assays. RESULTS: An early increase in eosinophil  count during the treatment with ipilimumab was associated with an improved  clinical response. In contrast, elevated amounts of monocytic myeloid-derived  suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders  (n = 36) as compared with basal levels and with responding patients (n = 23).  Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and  granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at  baseline and in responders, suggesting their enhanced immunosuppressive capacity.  Upon the first ipilimumab infusion, nonresponders displayed elevated serum  concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.  CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects  and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors  S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may  benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. (c)2015  AACR.CI  - (c)2015 American Association for Cancer Research.
CANIT0000463	26289067	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	59	N/A	N/A	Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of HMGB1 that attract and activate MDSCs.	N/A	N/A	N/A	HMGB1 (P09429); 	Serum HMGB1 levels	Gene expression signature in serum	 2015 Dec 15	 Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive  Markers in Melanoma Treatment with Ipilimumab.	 Clin Cancer Res	 PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with  metastatic melanoma. Because only around 20% of patients experience long-term  benefit, reliable markers are needed to predict a clinical response. Therefore,  we sought to determine if some myeloid cells and related inflammatory mediators  could serve as predictive factors for the patients' response to ipilimumab.  EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral   blood of 59 stage IV melanoma patients before the treatment and at different time  points upon the therapy using a clinical laboratory analysis and multicolor flow   cytometry. In addition, the production of related inflammatory factors was  evaluated by ELISA or Bio-Plex assays. RESULTS: An early increase in eosinophil  count during the treatment with ipilimumab was associated with an improved  clinical response. In contrast, elevated amounts of monocytic myeloid-derived  suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders  (n = 36) as compared with basal levels and with responding patients (n = 23).  Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and  granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at  baseline and in responders, suggesting their enhanced immunosuppressive capacity.  Upon the first ipilimumab infusion, nonresponders displayed elevated serum  concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.  CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects  and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors  S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may  benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. (c)2015  AACR.CI  - (c)2015 American Association for Cancer Research.
CANIT0000464	26289067	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	59	N/A	N/A	Upon the first ipilimumab infusion, nonresponders displayed elevated serum concentrations of S100A8/A9 that attract and activate MDSCs.	N/A	N/A	N/A	S100A8/A9 (P05109); 	Serum S100A8/A9 levels	Gene expression signature in serum	 2015 Dec 15	 Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive  Markers in Melanoma Treatment with Ipilimumab.	 Clin Cancer Res	 PURPOSE: Immunotherapy with ipilimumab improves the survival of patients with  metastatic melanoma. Because only around 20% of patients experience long-term  benefit, reliable markers are needed to predict a clinical response. Therefore,  we sought to determine if some myeloid cells and related inflammatory mediators  could serve as predictive factors for the patients' response to ipilimumab.  EXPERIMENTAL DESIGN: We performed an analysis of myeloid cells in the peripheral   blood of 59 stage IV melanoma patients before the treatment and at different time  points upon the therapy using a clinical laboratory analysis and multicolor flow   cytometry. In addition, the production of related inflammatory factors was  evaluated by ELISA or Bio-Plex assays. RESULTS: An early increase in eosinophil  count during the treatment with ipilimumab was associated with an improved  clinical response. In contrast, elevated amounts of monocytic myeloid-derived  suppressor cells (moMDSC), neutrophils, and monocytes were found in nonresponders  (n = 36) as compared with basal levels and with responding patients (n = 23).  Moreover, in nonresponders, moMDSCs produced significantly more nitric oxide, and  granulocytic MDSCs expressed higher levels of PD-L1 than these parameters at  baseline and in responders, suggesting their enhanced immunosuppressive capacity.  Upon the first ipilimumab infusion, nonresponders displayed elevated serum  concentrations of S100A8/A9 and HMGB1 that attract and activate MDSCs.  CONCLUSIONS: These findings highlight additional mechanisms of ipilimumab effects  and suggest levels of eosinophils, MDSCs, as well as related inflammatory factors  S100A8/A9 and HMGB1 as novel complex predictive markers for patients who may  benefit from the ipilimumab therapy. Clin Cancer Res; 21(24); 5453-9. (c)2015  AACR.CI  - (c)2015 American Association for Cancer Research.
CANIT0000465	26312439	Case report	Nonulcerated melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	This suggests that radiation therapy may also interact rapidly with anti-programmed-death 1 antibodies.	N/A	N/A	N/A	N/A	N/A	N/A	 2015 Dec	 Acute skin reaction suggestive of pembrolizumab-induced radiosensitization.	 Melanoma Res	 The combination of localized radiotherapy and immune checkpoint inhibitors  represents a promising therapeutic strategy for various cancers, including  metastatic melanoma. Radiation therapy may enhance tumor antigen presentation and  cytokine release, which may optimize the systemic antitumor immune response  induced by these immunotherapeutic antibodies, with a potential delayed abscopal   effect. However, clinical experience of using immune checkpoint inhibitors with  concurrent radiotherapy remains scarce. We report here for the first time a case   suggestive of acute skin radiosensitization induced by pembrolizumab, with a  suggestive time relationship between the completion of ionizing radiation, drug  administration, and rapid onset of the skin reaction. This suggests that  radiation therapy may also interact rapidly with anti-programmed-death 1  antibodies. Therefore, caution should be exercised when prescribing this  combination therapy in advanced cancers.
CANIT0000466	26343230	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	58	N/A	N/A	High NLR (>/=4) , high ANC LDH levels (>2), performance status 2, symptomatic brain metastases, and corticosteroids before week 1 were associated with poorer survival on univariate analysis. Using multivariate analysis, a significant association between high NLR (continuous variable) and poorer survival was demonstrated and remained significant after adjustment on potential confounders [hazard ratio (HR) = 121, 95% confidence interval (CI) 107-136]. NLR 4 was an independent prognostic factor (HR = 22, 95% CI 101-478). Intake of corticosteroids before week 1 was not an independent prognostic factor (HR = 128, 95% CI 054-306).High NLR (4) before initiating ipilimumab treatment in patients with metastatic melanoma is an independent prognostic indicator of poor survival.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2016 Jan	 High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment  is associated with reduced overall survival in patients with melanoma.	 Br J Dermatol	 BACKGROUND: There is an unmet need to identify markers predictive of response to   ipilimumab in patients with melanoma because the number of responders to  ipilimumab is low and its cost is very high. An increase in absolute lymphocyte  count (ALC) or low neutrophil/lymphocyte ratio (NLR) just before the third  infusion has been reported to be associated with better overall survival (OS).  OBJECTIVES: Our aim was to determine whether NLR measured before the first  infusion was associated with OS. PATIENTS AND METHODS: Data were collected on a  consecutive series of 58 patients treated with ipilimumab in four hospitals,  including 51 at stage M1c and four at stage M1b. The influences of the NLR and  other factors such as lactate dehydrogenase (LDH), performance status, ALC,  absolute neutrophil count (ANC) and corticosteroids on survival were studied. We   also assessed this association with NLR categorized as a binary variable. The  cut-off value for the NLR was determined with time-dependent receiver operating  characteristic (ROC) analysis. Univariate and multivariate analyses were  performed using Cox regression models. RESULTS: High NLR (>/=) 4, high ANC LDH  levels (>2), performance status >/=2, symptomatic brain metastases, and  corticosteroids before week 1 were associated with poorer survival on univariate   analysis. Using multivariate analysis, a significant association between high NLR  (continuous variable) and poorer survival was demonstrated and remained  significant after adjustment on potential confounders [hazard ratio (HR) = 1.21,   95% confidence interval (CI) 1.07-1.36]. NLR >/=4 was an independent prognostic  factor (HR = 2.2, 95% CI 1.01-4.78). Intake of corticosteroids before week 1 was   not an independent prognostic factor (HR = 1.28, 95% CI 0.54-3.06). CONCLUSIONS:   High NLR (>/=4) before initiating ipilimumab treatment in patients with  metastatic melanoma is an independent prognostic indicator of poor survival.CI  - (c) 2015 British Association of Dermatologists.
CANIT0000467	26343230	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	58	N/A	N/A	High NLR (>/=4) , high ANC LDH levels (>2), performance status 2, symptomatic brain metastases, and corticosteroids before week 1 were associated with poorer survival on univariate analysis. Using multivariate analysis, a significant association between high NLR (continuous variable) and poorer survival was demonstrated and remained significant after adjustment on potential confounders [hazard ratio (HR) = 121, 95% confidence interval (CI) 107-136]. NLR 4 was an independent prognostic factor (HR = 22, 95% CI 101-478). Intake of corticosteroids before week 1 was not an independent prognostic factor (HR = 128, 95% CI 054-306).High NLR (4) before initiating ipilimumab treatment in patients with metastatic melanoma is an independent prognostic indicator of poor survival.	N/A	N/A	N/A	Corticosteroids (NCIT:C211); 	Intake of corticosteroids before week 1	Exposure factors/status	 2016 Jan	 High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment  is associated with reduced overall survival in patients with melanoma.	 Br J Dermatol	 BACKGROUND: There is an unmet need to identify markers predictive of response to   ipilimumab in patients with melanoma because the number of responders to  ipilimumab is low and its cost is very high. An increase in absolute lymphocyte  count (ALC) or low neutrophil/lymphocyte ratio (NLR) just before the third  infusion has been reported to be associated with better overall survival (OS).  OBJECTIVES: Our aim was to determine whether NLR measured before the first  infusion was associated with OS. PATIENTS AND METHODS: Data were collected on a  consecutive series of 58 patients treated with ipilimumab in four hospitals,  including 51 at stage M1c and four at stage M1b. The influences of the NLR and  other factors such as lactate dehydrogenase (LDH), performance status, ALC,  absolute neutrophil count (ANC) and corticosteroids on survival were studied. We   also assessed this association with NLR categorized as a binary variable. The  cut-off value for the NLR was determined with time-dependent receiver operating  characteristic (ROC) analysis. Univariate and multivariate analyses were  performed using Cox regression models. RESULTS: High NLR (>/=) 4, high ANC LDH  levels (>2), performance status >/=2, symptomatic brain metastases, and  corticosteroids before week 1 were associated with poorer survival on univariate   analysis. Using multivariate analysis, a significant association between high NLR  (continuous variable) and poorer survival was demonstrated and remained  significant after adjustment on potential confounders [hazard ratio (HR) = 1.21,   95% confidence interval (CI) 1.07-1.36]. NLR >/=4 was an independent prognostic  factor (HR = 2.2, 95% CI 1.01-4.78). Intake of corticosteroids before week 1 was   not an independent prognostic factor (HR = 1.28, 95% CI 0.54-3.06). CONCLUSIONS:   High NLR (>/=4) before initiating ipilimumab treatment in patients with  metastatic melanoma is an independent prognostic indicator of poor survival.CI  - (c) 2015 British Association of Dermatologists.
CANIT0000468	26343230	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	58	N/A	N/A	High NLR (>/=4) , high ANC LDH levels (>2), performance status 2, symptomatic brain metastases, and corticosteroids before week 1 were associated with poorer survival on univariate analysis. Using multivariate analysis, a significant association between high NLR (continuous variable) and poorer survival was demonstrated and remained significant after adjustment on potential confounders [hazard ratio (HR) = 121, 95% confidence interval (CI) 107-136]. NLR 4 was an independent prognostic factor (HR = 22, 95% CI 101-478). Intake of corticosteroids before week 1 was not an independent prognostic factor (HR = 128, 95% CI 054-306).High NLR (4) before initiating ipilimumab treatment in patients with metastatic melanoma is an independent prognostic indicator of poor survival.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Jan	 High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment  is associated with reduced overall survival in patients with melanoma.	 Br J Dermatol	 BACKGROUND: There is an unmet need to identify markers predictive of response to   ipilimumab in patients with melanoma because the number of responders to  ipilimumab is low and its cost is very high. An increase in absolute lymphocyte  count (ALC) or low neutrophil/lymphocyte ratio (NLR) just before the third  infusion has been reported to be associated with better overall survival (OS).  OBJECTIVES: Our aim was to determine whether NLR measured before the first  infusion was associated with OS. PATIENTS AND METHODS: Data were collected on a  consecutive series of 58 patients treated with ipilimumab in four hospitals,  including 51 at stage M1c and four at stage M1b. The influences of the NLR and  other factors such as lactate dehydrogenase (LDH), performance status, ALC,  absolute neutrophil count (ANC) and corticosteroids on survival were studied. We   also assessed this association with NLR categorized as a binary variable. The  cut-off value for the NLR was determined with time-dependent receiver operating  characteristic (ROC) analysis. Univariate and multivariate analyses were  performed using Cox regression models. RESULTS: High NLR (>/=) 4, high ANC LDH  levels (>2), performance status >/=2, symptomatic brain metastases, and  corticosteroids before week 1 were associated with poorer survival on univariate   analysis. Using multivariate analysis, a significant association between high NLR  (continuous variable) and poorer survival was demonstrated and remained  significant after adjustment on potential confounders [hazard ratio (HR) = 1.21,   95% confidence interval (CI) 1.07-1.36]. NLR >/=4 was an independent prognostic  factor (HR = 2.2, 95% CI 1.01-4.78). Intake of corticosteroids before week 1 was   not an independent prognostic factor (HR = 1.28, 95% CI 0.54-3.06). CONCLUSIONS:   High NLR (>/=4) before initiating ipilimumab treatment in patients with  metastatic melanoma is an independent prognostic indicator of poor survival.CI  - (c) 2015 British Association of Dermatologists.
CANIT0000469	26343230	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	58	N/A	N/A	High NLR (>/=4) , high ANC LDH levels (>2), performance status 2, symptomatic brain metastases, and corticosteroids before week 1 were associated with poorer survival on univariate analysis. Using multivariate analysis, a significant association between high NLR (continuous variable) and poorer survival was demonstrated and remained significant after adjustment on potential confounders [hazard ratio (HR) = 121, 95% confidence interval (CI) 107-136]. NLR 4 was an independent prognostic factor (HR = 22, 95% CI 101-478). Intake of corticosteroids before week 1 was not an independent prognostic factor (HR = 128, 95% CI 054-306).High NLR (4) before initiating ipilimumab treatment in patients with metastatic melanoma is an independent prognostic indicator of poor survival.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2016 Jan	 High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment  is associated with reduced overall survival in patients with melanoma.	 Br J Dermatol	 BACKGROUND: There is an unmet need to identify markers predictive of response to   ipilimumab in patients with melanoma because the number of responders to  ipilimumab is low and its cost is very high. An increase in absolute lymphocyte  count (ALC) or low neutrophil/lymphocyte ratio (NLR) just before the third  infusion has been reported to be associated with better overall survival (OS).  OBJECTIVES: Our aim was to determine whether NLR measured before the first  infusion was associated with OS. PATIENTS AND METHODS: Data were collected on a  consecutive series of 58 patients treated with ipilimumab in four hospitals,  including 51 at stage M1c and four at stage M1b. The influences of the NLR and  other factors such as lactate dehydrogenase (LDH), performance status, ALC,  absolute neutrophil count (ANC) and corticosteroids on survival were studied. We   also assessed this association with NLR categorized as a binary variable. The  cut-off value for the NLR was determined with time-dependent receiver operating  characteristic (ROC) analysis. Univariate and multivariate analyses were  performed using Cox regression models. RESULTS: High NLR (>/=) 4, high ANC LDH  levels (>2), performance status >/=2, symptomatic brain metastases, and  corticosteroids before week 1 were associated with poorer survival on univariate   analysis. Using multivariate analysis, a significant association between high NLR  (continuous variable) and poorer survival was demonstrated and remained  significant after adjustment on potential confounders [hazard ratio (HR) = 1.21,   95% confidence interval (CI) 1.07-1.36]. NLR >/=4 was an independent prognostic  factor (HR = 2.2, 95% CI 1.01-4.78). Intake of corticosteroids before week 1 was   not an independent prognostic factor (HR = 1.28, 95% CI 0.54-3.06). CONCLUSIONS:   High NLR (>/=4) before initiating ipilimumab treatment in patients with  metastatic melanoma is an independent prognostic indicator of poor survival.CI  - (c) 2015 British Association of Dermatologists.
CANIT0000470	26343230	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	58	N/A	N/A	High NLR (>/=4) , high ANC LDH levels (>2), performance status 2, symptomatic brain metastases, and corticosteroids before week 1 were associated with poorer survival on univariate analysis. Using multivariate analysis, a significant association between high NLR (continuous variable) and poorer survival was demonstrated and remained significant after adjustment on potential confounders [hazard ratio (HR) = 121, 95% confidence interval (CI) 107-136]. NLR 4 was an independent prognostic factor (HR = 22, 95% CI 101-478). Intake of corticosteroids before week 1 was not an independent prognostic factor (HR = 128, 95% CI 054-306).High NLR (4) before initiating ipilimumab treatment in patients with metastatic melanoma is an independent prognostic indicator of poor survival.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2016 Jan	 High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment  is associated with reduced overall survival in patients with melanoma.	 Br J Dermatol	 BACKGROUND: There is an unmet need to identify markers predictive of response to   ipilimumab in patients with melanoma because the number of responders to  ipilimumab is low and its cost is very high. An increase in absolute lymphocyte  count (ALC) or low neutrophil/lymphocyte ratio (NLR) just before the third  infusion has been reported to be associated with better overall survival (OS).  OBJECTIVES: Our aim was to determine whether NLR measured before the first  infusion was associated with OS. PATIENTS AND METHODS: Data were collected on a  consecutive series of 58 patients treated with ipilimumab in four hospitals,  including 51 at stage M1c and four at stage M1b. The influences of the NLR and  other factors such as lactate dehydrogenase (LDH), performance status, ALC,  absolute neutrophil count (ANC) and corticosteroids on survival were studied. We   also assessed this association with NLR categorized as a binary variable. The  cut-off value for the NLR was determined with time-dependent receiver operating  characteristic (ROC) analysis. Univariate and multivariate analyses were  performed using Cox regression models. RESULTS: High NLR (>/=) 4, high ANC LDH  levels (>2), performance status >/=2, symptomatic brain metastases, and  corticosteroids before week 1 were associated with poorer survival on univariate   analysis. Using multivariate analysis, a significant association between high NLR  (continuous variable) and poorer survival was demonstrated and remained  significant after adjustment on potential confounders [hazard ratio (HR) = 1.21,   95% confidence interval (CI) 1.07-1.36]. NLR >/=4 was an independent prognostic  factor (HR = 2.2, 95% CI 1.01-4.78). Intake of corticosteroids before week 1 was   not an independent prognostic factor (HR = 1.28, 95% CI 0.54-3.06). CONCLUSIONS:   High NLR (>/=4) before initiating ipilimumab treatment in patients with  metastatic melanoma is an independent prognostic indicator of poor survival.CI  - (c) 2015 British Association of Dermatologists.
CANIT0000471	26343230	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	58	N/A	N/A	High NLR (>/=4) , high ANC LDH levels (>2), performance status 2, symptomatic brain metastases, and corticosteroids before week 1 were associated with poorer survival on univariate analysis. Using multivariate analysis, a significant association between high NLR (continuous variable) and poorer survival was demonstrated and remained significant after adjustment on potential confounders [hazard ratio (HR) = 121, 95% confidence interval (CI) 107-136]. NLR 4 was an independent prognostic factor (HR = 22, 95% CI 101-478). Intake of corticosteroids before week 1 was not an independent prognostic factor (HR = 128, 95% CI 054-306).High NLR (4) before initiating ipilimumab treatment in patients with metastatic melanoma is an independent prognostic indicator of poor survival.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2016 Jan	 High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment  is associated with reduced overall survival in patients with melanoma.	 Br J Dermatol	 BACKGROUND: There is an unmet need to identify markers predictive of response to   ipilimumab in patients with melanoma because the number of responders to  ipilimumab is low and its cost is very high. An increase in absolute lymphocyte  count (ALC) or low neutrophil/lymphocyte ratio (NLR) just before the third  infusion has been reported to be associated with better overall survival (OS).  OBJECTIVES: Our aim was to determine whether NLR measured before the first  infusion was associated with OS. PATIENTS AND METHODS: Data were collected on a  consecutive series of 58 patients treated with ipilimumab in four hospitals,  including 51 at stage M1c and four at stage M1b. The influences of the NLR and  other factors such as lactate dehydrogenase (LDH), performance status, ALC,  absolute neutrophil count (ANC) and corticosteroids on survival were studied. We   also assessed this association with NLR categorized as a binary variable. The  cut-off value for the NLR was determined with time-dependent receiver operating  characteristic (ROC) analysis. Univariate and multivariate analyses were  performed using Cox regression models. RESULTS: High NLR (>/=) 4, high ANC LDH  levels (>2), performance status >/=2, symptomatic brain metastases, and  corticosteroids before week 1 were associated with poorer survival on univariate   analysis. Using multivariate analysis, a significant association between high NLR  (continuous variable) and poorer survival was demonstrated and remained  significant after adjustment on potential confounders [hazard ratio (HR) = 1.21,   95% confidence interval (CI) 1.07-1.36]. NLR >/=4 was an independent prognostic  factor (HR = 2.2, 95% CI 1.01-4.78). Intake of corticosteroids before week 1 was   not an independent prognostic factor (HR = 1.28, 95% CI 0.54-3.06). CONCLUSIONS:   High NLR (>/=4) before initiating ipilimumab treatment in patients with  metastatic melanoma is an independent prognostic indicator of poor survival.CI  - (c) 2015 British Association of Dermatologists.
CANIT0000472	26351349	Clinical research	Platinum-Resistant Ovarian Cancer	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	A phase II clinical trial	The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations.	Grade 3 or 4 treatment-related adverse events occurred in eight (40%) of 20 patients. Two patients had severe adverse events.	N/A	N/A	N/A	N/A	N/A	 2015 Dec 1	 Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With   Platinum-Resistant Ovarian Cancer.	 J Clin Oncol	 PURPOSE: Programmed death-1 (PD-1), a coinhibitory immune signal receptor  expressed in T cells, binds to PD-1 ligand and regulates antitumor immunity.  Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the  safety and antitumor activity of nivolumab in patients with platinum-resistant  ovarian cancer. PATIENTS AND METHODS: Twenty patients with platinum-resistant  ovarian cancer were treated with an intravenous infusion of nivolumab every 2  weeks at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts) from  October 21, 2011. This phase II trial defined the primary end point as the best  overall response. Patients received up to six cycles (four doses per cycle) of  nivolumab treatment or received doses until disease progression occurred. Twenty   nivolumab-treated patients were evaluated at the end of the trial on December 7,   2014. RESULTS: Grade 3 or 4 treatment-related adverse events occurred in eight  (40%) of 20 patients. Two patients had severe adverse events. In the 20 patients   in whom responses could be evaluated, the best overall response was 15%, which  included two patients who had a durable complete response (in the 3-mg/kg  cohort). The disease control rate in all 20 patients was 45%. The median  progression-free survival time was 3.5 months (95% CI, 1.7 to 3.9 months), and  the median overall survival time was 20.0 months (95% CI, 7.0 months to not  reached) at study termination. CONCLUSION: This study, to our knowledge, is the  first to explore the effects of nivolumab against ovarian cancer. The encouraging  safety and clinical efficacy of nivolumab in patients with platinum-resistant  ovarian cancer indicate the merit of additional large-scale investigations (UMIN   Clinical Trials Registry UMIN000005714).CI  - (c) 2015 by American Society of Clinical Oncology.
CANIT0000473	26359337	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	110	N/A	N/A	Expression of cytolytic markers in the immune microenvironment was significantly associated with clinical benefit.	N/A	N/A	N/A	Immune microenvironment (NCIT:C48199); 	Cytolytic gene expression signatures in the immune microenvironment	Gene expression signature on/in immune cell	 2015 Oct 9	 Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.	 Science	 Monoclonal antibodies directed against cytotoxic T lymphocyte-associated  antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for  patients with metastatic melanoma by inhibiting immune checkpoint activity, but  clinical predictors of response to these therapies remain incompletely  characterized. To investigate the roles of tumor-specific neoantigens and  alterations in the tumor microenvironment in the response to ipilimumab, we  analyzed whole exomes from pretreatment melanoma tumor biopsies and matching  germline tissue samples from 110 patients. For 40 of these patients, we also  obtained and analyzed transcriptome data from the pretreatment tumor samples.  Overall mutational load, neoantigen load, and expression of cytolytic markers in   the immune microenvironment were significantly associated with clinical benefit.   However, no recurrent neoantigen peptide sequences predicted responder patient  populations. Thus, detailed integrated molecular characterization of large  patient cohorts may be needed to identify robust determinants of response and  resistance to immune checkpoint inhibitors.CI  - Copyright (c) 2015, American Association for the Advancement of Science.
CANIT0000474	26359337	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	110	N/A	N/A	Neoantigen load was significantly associated with clinical benefit.	N/A	N/A	N/A	Neoantigen load (NCIT:C154155); 	Neoantigen load	Gene expression signature on/in tumor cell	 2015 Oct 9	 Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.	 Science	 Monoclonal antibodies directed against cytotoxic T lymphocyte-associated  antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for  patients with metastatic melanoma by inhibiting immune checkpoint activity, but  clinical predictors of response to these therapies remain incompletely  characterized. To investigate the roles of tumor-specific neoantigens and  alterations in the tumor microenvironment in the response to ipilimumab, we  analyzed whole exomes from pretreatment melanoma tumor biopsies and matching  germline tissue samples from 110 patients. For 40 of these patients, we also  obtained and analyzed transcriptome data from the pretreatment tumor samples.  Overall mutational load, neoantigen load, and expression of cytolytic markers in   the immune microenvironment were significantly associated with clinical benefit.   However, no recurrent neoantigen peptide sequences predicted responder patient  populations. Thus, detailed integrated molecular characterization of large  patient cohorts may be needed to identify robust determinants of response and  resistance to immune checkpoint inhibitors.CI  - Copyright (c) 2015, American Association for the Advancement of Science.
CANIT0000475	26359337	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	110	N/A	N/A	Overall mutational load was significantly associated with clinical benefit.	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2015 Oct 9	 Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.	 Science	 Monoclonal antibodies directed against cytotoxic T lymphocyte-associated  antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for  patients with metastatic melanoma by inhibiting immune checkpoint activity, but  clinical predictors of response to these therapies remain incompletely  characterized. To investigate the roles of tumor-specific neoantigens and  alterations in the tumor microenvironment in the response to ipilimumab, we  analyzed whole exomes from pretreatment melanoma tumor biopsies and matching  germline tissue samples from 110 patients. For 40 of these patients, we also  obtained and analyzed transcriptome data from the pretreatment tumor samples.  Overall mutational load, neoantigen load, and expression of cytolytic markers in   the immune microenvironment were significantly associated with clinical benefit.   However, no recurrent neoantigen peptide sequences predicted responder patient  populations. Thus, detailed integrated molecular characterization of large  patient cohorts may be needed to identify robust determinants of response and  resistance to immune checkpoint inhibitors.CI  - Copyright (c) 2015, American Association for the Advancement of Science.
CANIT0000476	26406148	Clinical research	Advanced renal-cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	Everolimus	Immune checkpoint therapy	Nivolumab (DB09035); everolimus (DB01590); 	410	411	A randomized, open-label, phase III	Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus.	Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).	N/A	N/A	N/A	N/A	N/A	 2015 Nov 5	 Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.	 N Engl J Med	 BACKGROUND: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was  associated with encouraging overall survival in uncontrolled studies involving  previously treated patients with advanced renal-cell carcinoma. This randomized,   open-label, phase 3 study compared nivolumab with everolimus in patients with  renal-cell carcinoma who had received previous treatment. METHODS: A total of 821  patients with advanced clear-cell renal-cell carcinoma for which they had  received previous treatment with one or two regimens of antiangiogenic therapy  were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram  of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally  once daily. The primary end point was overall survival. The secondary end points   included the objective response rate and safety. RESULTS: The median overall  survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable)  with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard  ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to  0.93; P=0.002), which met the prespecified criterion for superiority  (P</=0.0148). The objective response rate was greater with nivolumab than with  everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The  median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with  nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio,  0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse  events occurred in 19% of the patients receiving nivolumab and in 37% of the  patients receiving everolimus; the most common event with nivolumab was fatigue  (in 2% of the patients), and the most common event with everolimus was anemia (in  8%). CONCLUSIONS: Among patients with previously treated advanced renal-cell  carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events  occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb;  CheckMate 025 ClinicalTrials.gov number, NCT01668784.).
CANIT0000477	26412456	Clinical research	Nonsquamous non-small-cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Docetaxel	Immune checkpoint therapy	Nivolumab (DB09035); docetaxel (DB01248); 	292	290	A randomized, open-label, international phase III study	Among patients  with advanced nonsquamous NSCLC that had progressed during or after  platinum-based chemotherapy, overall survival was longer with nivolumab than with  docetaxel.Better outcome with PD-L1 expression 1%	Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2015 Oct 22	 Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.	 N Engl J Med	 BACKGROUND: Nivolumab, a fully human IgG4 programmed death 1 (PD-1)  immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may  restore antitumor immunity. METHODS: In this randomized, open-label,  international phase 3 study, we assigned patients with nonsquamous non-small-cell  lung cancer (NSCLC) that had progressed during or after platinum-based doublet  chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight  every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface  area every 3 weeks. The primary end point was overall survival. RESULTS: Overall   survival was longer with nivolumab than with docetaxel. The median overall  survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292  patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290  patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to  0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56)  with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional  follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with  nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19%  with nivolumab versus 12% with docetaxel (P=0.02). Although progression-free  survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2  months, respectively), the rate of progression-free survival at 1 year was higher  with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was  associated with even greater efficacy than docetaxel across all end points in  subgroups defined according to prespecified levels of tumor-membrane expression  (>/=1%, >/=5%, and >/=10%) of the PD-1 ligand. Treatment-related adverse events  of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as  compared with 54% of those in the docetaxel group. CONCLUSIONS: Among patients  with advanced nonsquamous NSCLC that had progressed during or after  platinum-based chemotherapy, overall survival was longer with nivolumab than with  docetaxel. (Funded by Bristol-Myers Squibb; CheckMate 057 ClinicalTrials.gov  number, NCT01673867.).
CANIT0000478	26421864	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Osteonecrosis of the jaw	N/A	N/A	N/A	N/A	N/A	 2015 Dec	 Osteonecrosis of the jaw a new complication related to Ipilimumab.	 Oral Oncol	Unable to provide
CANIT0000479	26426340	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	101	N/A	A multicentre, retrospective cohort study	There is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.	N/A	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	2015	 Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated  with Anti-CTLA-4 Antibodies: Association with Overall Survival 	 PLoS One	 Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against  cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show  a statistically significant benefit in overall survival in advanced melanoma  patients. Currently, there is no proven association between the BRAFV600 mutation  and the disease control rate in response to ipilimumab. This analysis was carried  out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome  of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center  analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated  with anti-CTLA-4 antibodies from December 2006 until August 2012. The median  overall survival, defined from the treatment start date with the anti-CTLA-4.  Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant  patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months  (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The  median OS of NRAS mutated patients (n = 24) was 12.1 months and although was  prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03   months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference  didn't reach statistical significance (p = 0.56). 69 patients were able to  complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with  selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following   either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles   of treatment. Based on our results, there is no difference in the median OS in  patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status  alone is not sufficient to predict the outcome of patients treated with  anti-CTLA-4 Abs.
CANIT0000480	26426340	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	101	N/A	A multicentre, retrospective cohort study	There is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.	N/A	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	2015	 Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated  with Anti-CTLA-4 Antibodies: Association with Overall Survival 	 PLoS One	 Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against  cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show  a statistically significant benefit in overall survival in advanced melanoma  patients. Currently, there is no proven association between the BRAFV600 mutation  and the disease control rate in response to ipilimumab. This analysis was carried  out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome  of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center  analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated  with anti-CTLA-4 antibodies from December 2006 until August 2012. The median  overall survival, defined from the treatment start date with the anti-CTLA-4.  Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant  patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months  (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The  median OS of NRAS mutated patients (n = 24) was 12.1 months and although was  prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03   months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference  didn't reach statistical significance (p = 0.56). 69 patients were able to  complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with  selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following   either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles   of treatment. Based on our results, there is no difference in the median OS in  patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status  alone is not sufficient to predict the outcome of patients treated with  anti-CTLA-4 Abs.
CANIT0000481	26446948	Clinical research	Resected and Unresectable Metastatic Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	148	N/A	A retrospective cohort study	Cutaneous immune-related adverse events are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses.	IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III elevation in amylase/lipase, and 2 (1.35%) had grade III colitis.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Cutaneous immune-related adverse events	Adverse events	 2016 Feb 15	 Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of  Immune-Related Adverse Events and Association with Outcomes.	 Clin Cancer Res	 PURPOSE: Retrospective analysis of irAEs in melanoma patients treated with  nivolumab. EXPERIMENTAL DESIGN: Data were pooled from 148 patients (33 resected,   115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone   every 2 weeks for 12 weeks. Patients with stable disease or regression received  an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2  additional years. Frequency, grade, and characteristics of immune-related adverse  events (irAE) were analyzed. A 12-week landmark survival analysis using a  multivariate time-dependent Cox proportional hazard model assessed difference in   overall survival (OS) in the presence or absence of irAEs. RESULTS: IrAEs of any   grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were  infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III  elevation in amylase/lipase, and 2 (1.35%) had grade III colitis. A statistically  significant OS difference was noted among patients with any grade of irAE versus   those without (P </= 0.001), and OS benefit was noted in patients who reported  three or more irAE events (P </= 0.001). Subset analyses showed statistically  significant OS differences with rash [P = 0.001; HR, 0.423; 95% confidence  interval (CI), 0.243-0.735] and vitiligo (P = 0.012; HR, 0.184; 95% CI,  0.036-0.94). Rash and vitiligo also correlated with statistically significant OS   differences in patients with metastatic disease (P = 0.004 and P = 0.028,  respectively). No significant survival differences were seen with other irAEs  (endocrinopathies, colitis, or pneumonitis). CONCLUSIONS: Cutaneous irAEs are  associated with improved survival in melanoma patients treated with nivolumab,  and clinical benefit should be validated in larger prospective analyses.CI  - (c)2015 American Association for Cancer Research.
CANIT0000482	26472184	Basic research	Human melanoma cells (A375)	Melanoma	EFO:0000756	Skin	HMGB1 (P09429); 	HMGB1; 	LTX-315	N/A	Tumor vaccine	LTX-315 (DB12748); 	Cell lines	N/A	Basic research	The oncolytic effect of LTX-315 involving perturbation of both the cell membrane and the mitochondria with subsequent release of DAMPs may highlight the ability of LTX-315 to induce complete regression and long-term protective immune responses as previously reported in experimental animal models.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2015 Oct 27	 The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria  distortion in human melanoma cells.	 Oncotarget	 Host defense peptides (HDPs) are naturally occurring molecules found in most  species, in which they play a significant role in the first line defense against   intruding pathogens, and several HDPs have been shown to possess anticancer  activity. Structure-activity relationship studies on the HDP bovine lactoferricin  revealed a de novo design of a nonamer peptide LTX-315, with oncolytic  properties. In the present study, we investigated the oncolytic activity of  LTX-315 in human melanoma cells (A375). LTX-315 induced a rapid plasma membrane  disruption and cell death within 2 hours. At a low concentration,  fluorescence-labeled LTX-315 was internalized and accumulated in cytoplasmic  vacuoles in close proximity to the mitochondria. The mitochondrial membrane  potential was shown to depolarize as a consequence of LTX-315 treatment and at  ultrastructural level, the mitochondria morphology was significantly altered.  Release of danger signals (DAMPs) such as ATP, Cytochrome C and HMGB1 into the  cell supernatant of cultured cells was evident minutes after peptide treatment.  The oncolytic effect of LTX-315 involving perturbation of both the cell membrane   and the mitochondria with subsequent release of DAMPs may highlight the ability  of LTX-315 to induce complete regression and long-term protective immune  responses as previously reported in experimental animal models.
CANIT0000483	26491202	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis	N/A	N/A	N/A	N/A	N/A	 2016 Jan	 Acetylcholine receptor binding antibody-associated myasthenia gravis and  rhabdomyolysis induced by nivolumab in a patient with melanoma.	 Jpn J Clin Oncol	 We reported an 81-year-old woman with metastatic melanoma, in whom myasthenia  gravis and rhabdomyolysis developed after nivolumab monotherapy. The first  symptom of myasthenia gravis was dyspnea. Ultrasonography detected hypokinesis of  the bilateral diaphragm suggesting myasthenia gravis, although there was no  abnormal finding of the lungs in computed tomography images. Acetylcholine  receptor binding antibodies were low-titer positive in the preserved serum before  administration of nivolumab, strongly suggesting that the myasthenia gravis was a  nivolumab-related immune adverse event. Despite the remarkable clinical benefits   of immune checkpoint inhibitors for patients with advanced melanoma, it is  important to recognize unexpected immune-related adverse events.CI  - (c) The Author 2015. Published by Oxford University Press. All rights reserved.  For Permissions, please email: journals.permissions@oup.com.
CANIT0000484	26493961	Basic research	B16f10 and B16-OVA melanoma cell line	Melanoma	EFO:0000756	Skin	CD137 (Q07011); 	CD137; 	Anti-CD137 (1D8) antibody	N/A	Immune checkpoint therapy	Anti-CD137 (1D8)antibody (NCIT:C155745); 	Cell lines/ animal models	N/A	Basic research	We show that cross-priming of tumor  antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to  enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory  mAbs.Enhance clinical antitumor effects in patient with BATF3-Dependent Dendritic Cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	BATF3 (Q9NR55); Dendritic cells (NCIT:C12583); 	BATF3-Dependent Dendritic Cells	Gene expression signature on/in immune cell	 2016 Jan	 Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal  Antibodies Requires BATF3-Dependent Dendritic Cells.	 Cancer Discov	 UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses  can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-)  mice, which are defective for cross-presentation of cell-associated antigens, we   show that BATF3-dependent dendritic cells (DC) are essential for the response to   therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an  endogenous CTL-mediated immune response toward tumor-associated antigens,  including neoantigens. As a result, the immunomodulatory mAbs could not amplify  any therapeutically functional immune response in these mice. Moreover,  administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated  cross-priming and synergized with anti-CD137- and anti-PD-1-mediated  immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas,  whereas this function was lost in Batf3(-/-) mice. These experiments show that  cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to  the efficacy of immunostimulatory mAbs and represents a very attractive point of   intervention to enhance their clinical antitumor effects. SIGNIFICANCE:  Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical  responses in different types of cancer. We show that cross-priming of tumor  antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to  enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory  mAbs.CI  - (c)2015 American Association for Cancer Research.
CANIT0000485	26493961	Basic research	B16f10 and B16-OVA melanoma cell line	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	RMP1-14	N/A	Immune checkpoint therapy	RMP1-14 (NCIT:C128037); 	Cell lines/ animal models	N/A	Basic research	We show that cross-priming of tumor  antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to  enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory  mAbs.Enhance clinical antitumor effects in patient with BATF3-Dependent Dendritic Cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	BATF3 (Q9NR55); Dendritic cells (NCIT:C12583); 	BATF3-Dependent Dendritic Cells	Gene expression signature on/in immune cell	 2016 Jan	 Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal  Antibodies Requires BATF3-Dependent Dendritic Cells.	 Cancer Discov	 UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses  can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-)  mice, which are defective for cross-presentation of cell-associated antigens, we   show that BATF3-dependent dendritic cells (DC) are essential for the response to   therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an  endogenous CTL-mediated immune response toward tumor-associated antigens,  including neoantigens. As a result, the immunomodulatory mAbs could not amplify  any therapeutically functional immune response in these mice. Moreover,  administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated  cross-priming and synergized with anti-CD137- and anti-PD-1-mediated  immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas,  whereas this function was lost in Batf3(-/-) mice. These experiments show that  cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to  the efficacy of immunostimulatory mAbs and represents a very attractive point of   intervention to enhance their clinical antitumor effects. SIGNIFICANCE:  Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical  responses in different types of cancer. We show that cross-priming of tumor  antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to  enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory  mAbs.CI  - (c)2015 American Association for Cancer Research.
CANIT0000486	26493961	Basic research	MC-38-OVA cell Line	Colorectal cancer	EFO:0005842	Intestines	CD137 (Q07011); 	CD137; 	Anti-CD137 (1D8) antibody	N/A	Immune checkpoint therapy	Anti-CD137 (1D8)antibody (NCIT:C155745); 	Cell lines/ animal models	N/A	Basic research	We show that cross-priming of tumor  antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to  enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory  mAbs.Enhance clinical antitumor effects in patient with BATF3-Dependent Dendritic Cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	BATF3 (Q9NR55); Dendritic cells (NCIT:C12583); 	BATF3-Dependent Dendritic Cells	Gene expression signature on/in immune cell	 2016 Jan	 Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal  Antibodies Requires BATF3-Dependent Dendritic Cells.	 Cancer Discov	 UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses  can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-)  mice, which are defective for cross-presentation of cell-associated antigens, we   show that BATF3-dependent dendritic cells (DC) are essential for the response to   therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an  endogenous CTL-mediated immune response toward tumor-associated antigens,  including neoantigens. As a result, the immunomodulatory mAbs could not amplify  any therapeutically functional immune response in these mice. Moreover,  administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated  cross-priming and synergized with anti-CD137- and anti-PD-1-mediated  immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas,  whereas this function was lost in Batf3(-/-) mice. These experiments show that  cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to  the efficacy of immunostimulatory mAbs and represents a very attractive point of   intervention to enhance their clinical antitumor effects. SIGNIFICANCE:  Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical  responses in different types of cancer. We show that cross-priming of tumor  antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to  enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory  mAbs.CI  - (c)2015 American Association for Cancer Research.
CANIT0000487	26493961	Basic research	MC-38-OVA cell Line	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	RMP1-14	N/A	Immune checkpoint therapy	RMP1-14 (NCIT:C128037); 	Cell lines/ animal models	N/A	Basic research	We show that cross-priming of tumor  antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to  enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory  mAbs.Enhance clinical antitumor effects in patient with BATF3-Dependent Dendritic Cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	BATF3 (Q9NR55); Dendritic cells (NCIT:C12583); 	BATF3-Dependent Dendritic Cells	Gene expression signature on/in immune cell	 2016 Jan	 Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti-PD-1 Monoclonal  Antibodies Requires BATF3-Dependent Dendritic Cells.	 Cancer Discov	 UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses  can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-)  mice, which are defective for cross-presentation of cell-associated antigens, we   show that BATF3-dependent dendritic cells (DC) are essential for the response to   therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an  endogenous CTL-mediated immune response toward tumor-associated antigens,  including neoantigens. As a result, the immunomodulatory mAbs could not amplify  any therapeutically functional immune response in these mice. Moreover,  administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated  cross-priming and synergized with anti-CD137- and anti-PD-1-mediated  immunostimulation in tumor therapy against B16-ovalbumin-derived melanomas,  whereas this function was lost in Batf3(-/-) mice. These experiments show that  cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to  the efficacy of immunostimulatory mAbs and represents a very attractive point of   intervention to enhance their clinical antitumor effects. SIGNIFICANCE:  Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical  responses in different types of cancer. We show that cross-priming of tumor  antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to  enhance the antitumor efficacy of anti-PD-1 and anti-CD137 immunostimulatory  mAbs.CI  - (c)2015 American Association for Cancer Research.
CANIT0000488	26504067	Clinical research	Advanced, refractory melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	196	N/A	N/A	Normal baseline serum C-reactive protein (CRP) level correlated with improved treatment response and OS.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2015 Nov	 Long-term Survival with Ipilimumab: Experience from a National Expanded Access  Program for Patients with Melanoma.	 Anticancer Res	 AIM: Evaluation of efficacy and safety of ipilimumab in patients with advanced,  refractory melanoma enrolled into a national ipilimumab Expanded Access Program.   PATIENTS AND METHODS: Adult patients with advanced/metastatic refractory melanoma  were eligible for study inclusion. Ipilimumab was administered up to a total of  four doses. RESULTS: One hundred and ninety-six patients were analyzed. Full  ipilimumab induction was administered to 66.8% of patients. Median overall  survival (OS) in the entire cohort was 7.5 months. Median OS for patients after  four doses of ipilimumab was significantly longer than for patients with fewer  doses (12.3 months vs. 2.0 months respectively; p<0.001). Median OS for patients   with objective tumor response was 42.3 months. Normal baseline serum lactate  dehydrogenase (LDH) and C-reactive protein (CRP) levels, and the number of  affected organs correlated with improved OS. CONCLUSION: The number of affected  organs and combination of baseline LDH and CRP levels could potentially serve as   predictors for both treatment response and OS.CI  - Copyright(c) 2015 International Institute of Anticancer Research (Dr. John G.  Delinassios), All rights reserved.
CANIT0000489	26504067	Clinical research	Advanced, refractory melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	196	N/A	N/A	Normal baseline serum lactate dehydrogenase (LDH) correlated with improved treatment response and OS.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2015 Nov	 Long-term Survival with Ipilimumab: Experience from a National Expanded Access  Program for Patients with Melanoma.	 Anticancer Res	 AIM: Evaluation of efficacy and safety of ipilimumab in patients with advanced,  refractory melanoma enrolled into a national ipilimumab Expanded Access Program.   PATIENTS AND METHODS: Adult patients with advanced/metastatic refractory melanoma  were eligible for study inclusion. Ipilimumab was administered up to a total of  four doses. RESULTS: One hundred and ninety-six patients were analyzed. Full  ipilimumab induction was administered to 66.8% of patients. Median overall  survival (OS) in the entire cohort was 7.5 months. Median OS for patients after  four doses of ipilimumab was significantly longer than for patients with fewer  doses (12.3 months vs. 2.0 months respectively; p<0.001). Median OS for patients   with objective tumor response was 42.3 months. Normal baseline serum lactate  dehydrogenase (LDH) and C-reactive protein (CRP) levels, and the number of  affected organs correlated with improved OS. CONCLUSION: The number of affected  organs and combination of baseline LDH and CRP levels could potentially serve as   predictors for both treatment response and OS.CI  - Copyright(c) 2015 International Institute of Anticancer Research (Dr. John G.  Delinassios), All rights reserved.
CANIT0000490	26504067	Clinical research	Advanced, refractory melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	196	N/A	N/A	The number of affected organs correlated with improved treatment response and OS.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Number of affected organs	Disease status	 2015 Nov	 Long-term Survival with Ipilimumab: Experience from a National Expanded Access  Program for Patients with Melanoma.	 Anticancer Res	 AIM: Evaluation of efficacy and safety of ipilimumab in patients with advanced,  refractory melanoma enrolled into a national ipilimumab Expanded Access Program.   PATIENTS AND METHODS: Adult patients with advanced/metastatic refractory melanoma  were eligible for study inclusion. Ipilimumab was administered up to a total of  four doses. RESULTS: One hundred and ninety-six patients were analyzed. Full  ipilimumab induction was administered to 66.8% of patients. Median overall  survival (OS) in the entire cohort was 7.5 months. Median OS for patients after  four doses of ipilimumab was significantly longer than for patients with fewer  doses (12.3 months vs. 2.0 months respectively; p<0.001). Median OS for patients   with objective tumor response was 42.3 months. Normal baseline serum lactate  dehydrogenase (LDH) and C-reactive protein (CRP) levels, and the number of  affected organs correlated with improved OS. CONCLUSION: The number of affected  organs and combination of baseline LDH and CRP levels could potentially serve as   predictors for both treatment response and OS.CI  - Copyright(c) 2015 International Institute of Anticancer Research (Dr. John G.  Delinassios), All rights reserved.
CANIT0000491	26534966	Clinical research	Pediatric Patients with Advanced Solid Tumors melanoma, sarcoma, Renal/bladder carcinoma, Neuroblastoma	Bladder cancer	EFO:0000292	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	33	N/A	A phase I clinical trial 	Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance.	Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2016 Mar 15	 Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid  Tumors.	 Clin Cancer Res	 PURPOSE: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for   treatment of metastatic melanoma but not studied in children until this phase I  protocol. EXPERIMENTAL DESIGN: This study examined safety, pharmacokinetics, and   immunogenicity, and immune correlates of ipilimumab administered to subjects  </=21 years old with recurrent or progressive solid tumors. Dose escalation  cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3  design. Response was assessed after 6 weeks and 12 weeks, and then every 3  months. Treatment was continued until disease progression or unacceptable  toxicity. RESULTS: Thirty-three patients received 72 doses of ipilimumab.  Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory  solid tumors (n = 4). Immune-related adverse events included pancreatitis,  pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting  toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a  half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T   cells, but no change in regulatory T-cell populations. Six subjects had confirmed  stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma,  and synovial sarcoma). CONCLUSIONS: Ipilimumab was safely administered to  pediatric patients using management algorithms for immune-related toxicities. The  spectrum of immune-related adverse events is similar to those described in  adults; however, many of the pediatric toxicities were evident after a single  dose. Although no objective tumor regressions were observed with ipilimumab as a   single agent, subjects with immune-related toxicities had an increased overall  survival compared with those who showed no evidence of breaking tolerance.CI  - (c)2015 American Association for Cancer Research.
CANIT0000492	26534966	Clinical research	Pediatric Patients with Advanced Solid Tumors melanoma, sarcoma, Renal/bladder carcinoma, Neuroblastoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	33	N/A	A phase I clinical trial 	Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance.	Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2016 Mar 15	 Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid  Tumors.	 Clin Cancer Res	 PURPOSE: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for   treatment of metastatic melanoma but not studied in children until this phase I  protocol. EXPERIMENTAL DESIGN: This study examined safety, pharmacokinetics, and   immunogenicity, and immune correlates of ipilimumab administered to subjects  </=21 years old with recurrent or progressive solid tumors. Dose escalation  cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3  design. Response was assessed after 6 weeks and 12 weeks, and then every 3  months. Treatment was continued until disease progression or unacceptable  toxicity. RESULTS: Thirty-three patients received 72 doses of ipilimumab.  Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory  solid tumors (n = 4). Immune-related adverse events included pancreatitis,  pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting  toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a  half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T   cells, but no change in regulatory T-cell populations. Six subjects had confirmed  stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma,  and synovial sarcoma). CONCLUSIONS: Ipilimumab was safely administered to  pediatric patients using management algorithms for immune-related toxicities. The  spectrum of immune-related adverse events is similar to those described in  adults; however, many of the pediatric toxicities were evident after a single  dose. Although no objective tumor regressions were observed with ipilimumab as a   single agent, subjects with immune-related toxicities had an increased overall  survival compared with those who showed no evidence of breaking tolerance.CI  - (c)2015 American Association for Cancer Research.
CANIT0000493	26534966	Clinical research	Pediatric Patients with Advanced Solid Tumors melanoma, sarcoma, Renal/bladder carcinoma, Neuroblastoma	Neuroblastoma	EFO:0000621	Nervous system	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	33	N/A	A phase I clinical trial 	Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance.	Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2016 Mar 15	 Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid  Tumors.	 Clin Cancer Res	 PURPOSE: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for   treatment of metastatic melanoma but not studied in children until this phase I  protocol. EXPERIMENTAL DESIGN: This study examined safety, pharmacokinetics, and   immunogenicity, and immune correlates of ipilimumab administered to subjects  </=21 years old with recurrent or progressive solid tumors. Dose escalation  cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3  design. Response was assessed after 6 weeks and 12 weeks, and then every 3  months. Treatment was continued until disease progression or unacceptable  toxicity. RESULTS: Thirty-three patients received 72 doses of ipilimumab.  Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory  solid tumors (n = 4). Immune-related adverse events included pancreatitis,  pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting  toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a  half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T   cells, but no change in regulatory T-cell populations. Six subjects had confirmed  stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma,  and synovial sarcoma). CONCLUSIONS: Ipilimumab was safely administered to  pediatric patients using management algorithms for immune-related toxicities. The  spectrum of immune-related adverse events is similar to those described in  adults; however, many of the pediatric toxicities were evident after a single  dose. Although no objective tumor regressions were observed with ipilimumab as a   single agent, subjects with immune-related toxicities had an increased overall  survival compared with those who showed no evidence of breaking tolerance.CI  - (c)2015 American Association for Cancer Research.
CANIT0000494	26534966	Clinical research	Pediatric Patients with Advanced Solid Tumors melanoma, sarcoma, Renal/bladder carcinoma, Neuroblastoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	33	N/A	A phase I clinical trial 	Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance.	Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2016 Mar 15	 Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid  Tumors.	 Clin Cancer Res	 PURPOSE: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for   treatment of metastatic melanoma but not studied in children until this phase I  protocol. EXPERIMENTAL DESIGN: This study examined safety, pharmacokinetics, and   immunogenicity, and immune correlates of ipilimumab administered to subjects  </=21 years old with recurrent or progressive solid tumors. Dose escalation  cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3  design. Response was assessed after 6 weeks and 12 weeks, and then every 3  months. Treatment was continued until disease progression or unacceptable  toxicity. RESULTS: Thirty-three patients received 72 doses of ipilimumab.  Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory  solid tumors (n = 4). Immune-related adverse events included pancreatitis,  pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting  toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a  half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T   cells, but no change in regulatory T-cell populations. Six subjects had confirmed  stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma,  and synovial sarcoma). CONCLUSIONS: Ipilimumab was safely administered to  pediatric patients using management algorithms for immune-related toxicities. The  spectrum of immune-related adverse events is similar to those described in  adults; however, many of the pediatric toxicities were evident after a single  dose. Although no objective tumor regressions were observed with ipilimumab as a   single agent, subjects with immune-related toxicities had an increased overall  survival compared with those who showed no evidence of breaking tolerance.CI  - (c)2015 American Association for Cancer Research.
CANIT0000495	26534966	Clinical research	Pediatric Patients with Advanced Solid Tumors melanoma, sarcoma, Renal/bladder carcinoma, Neuroblastoma	Sarcoma	EFO:0000691	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	33	N/A	A phase I clinical trial 	Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance.	Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2016 Mar 15	 Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid  Tumors.	 Clin Cancer Res	 PURPOSE: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for   treatment of metastatic melanoma but not studied in children until this phase I  protocol. EXPERIMENTAL DESIGN: This study examined safety, pharmacokinetics, and   immunogenicity, and immune correlates of ipilimumab administered to subjects  </=21 years old with recurrent or progressive solid tumors. Dose escalation  cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3  design. Response was assessed after 6 weeks and 12 weeks, and then every 3  months. Treatment was continued until disease progression or unacceptable  toxicity. RESULTS: Thirty-three patients received 72 doses of ipilimumab.  Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory  solid tumors (n = 4). Immune-related adverse events included pancreatitis,  pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting  toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a  half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T   cells, but no change in regulatory T-cell populations. Six subjects had confirmed  stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma,  and synovial sarcoma). CONCLUSIONS: Ipilimumab was safely administered to  pediatric patients using management algorithms for immune-related toxicities. The  spectrum of immune-related adverse events is similar to those described in  adults; however, many of the pediatric toxicities were evident after a single  dose. Although no objective tumor regressions were observed with ipilimumab as a   single agent, subjects with immune-related toxicities had an increased overall  survival compared with those who showed no evidence of breaking tolerance.CI  - (c)2015 American Association for Cancer Research.
CANIT0000496	26541511	Clinical research	Pretreated patients with different subtypes of metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	103	N/A	An open-label, multicenter, single-arm phase II	Ipilimumab is a treatment option for pretreated patients with advanced cutaneous melanoma seen in daily routine. Toxicity was manageable when treated as per protocol-specific guidelines.	Treatment-related AEs were observed in 71 patients (69 %), including 20 grade 3-4 events (19 %). No new and unexpected safety findings were noted.	N/A	N/A	N/A	N/A	N/A	 2015 Nov 6	 Open-label, multicenter, single-arm phase II DeCOG-study of ipilimumab in  pretreated patients with different subtypes of metastatic melanoma.	 J Transl Med	 BACKGROUND: Ipilimumab is an approved immunotherapy that has shown an overall  survival benefit in patients with cutaneous metastatic melanoma in two phase III   trials. As results of registrational trials might not answer all questions  regarding safety and efficacy of ipilimumab in patients with advanced melanoma  seen in daily clinical practice, the Dermatologic Cooperative Oncology Group  conducted a phase II study to assess the efficacy and safety of ipilimumab in  patients with different subtypes of metastatic melanoma. PATIENTS AND METHODS: We  undertook a multicenter phase II study in melanoma patients irrespective of  location of the primary melanoma. Here we present data on patients with  pretreated metastatic cutaneous, mucosal and occult melanoma who received up to  four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals.   Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according  to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were  graded according to National Cancer Institute Common Toxicity Criteria (CTC)  v.4.0. Primary endpoint was the OS rate at 12 months. RESULTS: 103 pretreated  patients received at least one dose of ipilimumab, including 83 cutaneous, seven   mucosal and 13 occult melanomas. 1-year OS rates for cutaneous, mucosal and  occult melanoma were 38 %, 14 % and 27 %, respectively. Median OS was 6.8 months   (95 % CI 5.3-9.9) for cutaneous, 9.6 months (95 % CI 1.6-11.1) for mucosal, and  9.9 months (lower 95 % CI 2.3, upper 95 % CI non-existent) for occult melanoma.  Overall response rates for cutaneous, mucosal and occult melanoma were 16 %, 17 %  and 11 %, respectively. Eleven patients had partial response (16 %) and ten  patients experienced stable disease (14 %), none achieved a complete response.  Treatment-related AEs were observed in 71 patients (69 %), including 20 grade 3-4  events (19 %). No new and unexpected safety findings were noted. CONCLUSIONS:  Ipilimumab is a treatment option for pretreated patients with advanced cutaneous   melanoma seen in daily routine. Toxicity was manageable when treated as per  protocol-specific guidelines. TRIAL REGISTRATION: Clinical Trials.gov  NCT01355120.
CANIT0000497	26551782	Case report	Refractory Hodgkin's lymphoma after allogeneic stem cell transplantation	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Remarkable and fast response	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Mar	 Nivolumab in a patient with refractory Hodgkin's lymphoma after allogeneic stem  cell transplantation.	 Bone Marrow Transplant	Unable to provide
CANIT0000498	26566869	Basic research	Human osteosarcoma U2OS cells 	Osteosarcoma	EFO:0000637	Bone	UNREGULATED NECROSIS (N/A); 	UNREGULATED NECROSIS; 	LTX-315	N/A	Tumor vaccine	LTX-315 (DB12748); 	Cell lines	N/A	Basic research	LTX-315 triggers unregulated necrosis, which may contribute to its pro-inflammatory and pro-immune effects.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	2015	 The oncolytic peptide LTX-315 triggers necrotic cell death.	 Cell Cycle	 The oncolytic peptide LTX-315 has been designed for killing human cancer cells  and turned out to stimulate anti-cancer immune responses when locally injected  into tumors established in immunocompetent mice. Here, we investigated the  question whether LTX-315 induces apoptosis or necrosis. Transmission electron  microscopy or morphometric analysis of chromatin-stained tumor cells revealed  that LTX-315 failed to induce apoptotic nuclear condensation and rather induced a  necrotic phenotype. Accordingly, LTX-315 failed to stimulate the activation of  caspase-3, and inhibition of caspases by means of Z-VAD-fmk was unable to reduce   cell killing by LTX-315. In addition, 2 prominent inhibitors of regulated  necrosis (necroptosis), namely, necrostatin-1 and cycosporin A, failed to reduce   LTX-315-induced cell death. In conclusion, it appears that LTX-315 triggers  unregulated necrosis, which may contribute to its pro-inflammatory and pro-immune  effects.
CANIT0000499	26602778	Case report	Metastatic melanoma patient with elevated PD-1 expression on B cells	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Idiopathic thrombocytopenic purpura	N/A	N/A	N/A	N/A	N/A	 2016 Mar	 Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma  patient with elevated PD-1 expression on B cells.	 Ann Oncol	Unable to provide
CANIT0000500	26615135	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Parathyroid hormone-related peptide-linked hypercalcemia	N/A	N/A	N/A	N/A	N/A	 2015 Dec	 Parathyroid Hormone-Related Peptide-Linked Hypercalcemia in a Melanoma Patient  Treated With Ipilimumab: Hormone Source and Clinical and Metabolic Correlates.	 Semin Oncol	 A patient diagnosed with metastatic melanoma developed the paraneoplastic  syndrome of humoral hypercalcemia of malignancy and cachexia after receiving  ipilumumab. The cause of the hypercalcemia was thought to be secondary to  parathyroid hormone-related peptide (PTHrP) as plasma levels were found to be  elevated. The patient underwent two tumor biopsies: at diagnosis (when calcium  levels were normal) and upon development of hypercalcemia and cachexia. PTHrP  expression was higher in melanoma cells when hypercalcemia had occurred than  prior to its onset. Metabolic characterization of melanoma cells revealed that,  with development of hypercalcemia, there was high expression of monocarboxylate  transporter 1 (MCT1), which is the main importer of lactate and ketone bodies  into cells. MCT1 is associated with high mitochondrial metabolism.  Beta-galactosidase (beta-GAL), a marker of senescence, had reduced expression in   melanoma cells upon development of hypercalcemia compared to pre-hypercalcemia.  In conclusion, PTHrP expression in melanoma is associated with cachexia,  increased cancer cell lactate and ketone body import, high mitochondrial  metabolism, and reduced senescence. Further studies are required to determine if   PTHrP regulates cachexia, lactate and ketone body import, mitochondrial  metabolism, and senescence in cancer cells.CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
CANIT0000501	26647899	Case report	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Feasible treatment option	N/A	N/A	N/A	N/A	N/A	N/A	2015	 [Therapeutic Effect and Tolerance of Ipilimumam in Metastatic Malignant Melanoma   in Children - a Case Report].	 Klin Onkol	 BACKGROUND: Malignant melanoma is a rare malignancy in the pediatric population.   Etiology is usually unknown. Clinical symptoms are nonspecific, clinical behavior  and biology features may differ from those in an adult population. The most  important prognostic factor is spread of disease. Surgical resection is treatment  of choice for localized melanoma. Advanced and metastatic melanoma is still an  incurable disease. CASE: We are presenting an eight-year- old boy with metastatic  malignant melanoma of unknown origin based on TP53 mutation (Li Fraumeni  syndrome). He underwent surgery and adjuvant chemotherapy (temozolomide as single  agent). Complete remission was achieved at the end of treatment. Two years after   the end of therapy (and 31 months from diagnosis) he developed metastatic  progression to the lungs. He has received immunotherapy with ipilimumab,  according to our knowledge as the first child under the age of 12 in Europe. He  completed three courses of ipilimumab, with irAE (immune related adverse event)  grade III during the first course of anti CTLA 4. Therefore, further doses of  ipilimumab were given with corticoids and antihistamines as premedication. Also,   asymptomatic thyreoiditis grade II has been confirmed. The best documented  treatment response is stable disease. Performance status was excellent. Three  years since the first progression, he developed further massive progression to  the lungs. Second line immunotherapy with anti-PD 1 monoclonal antibody  (pembrolizumab) is currently going on. So far, the overall survival of the  patient is 74 months. CONCLUSION: The presented case study supports the  administration of immunotherapy in children younger than 12 years. Therapeutic  effect has led to significant overall survival with tolerable toxicity. The  problem remains significantly limited number of pediatric clinical trials using  immunotherapy.
CANIT0000502	26649979	Basic research	Murine models of lymphoma	Lymphoma	EFO:0000574	Blood and lymph nodes	HEPARANASE (Q9Y251); 	HEPARANASE; 	Heparan sulfate mimetic PG545	N/A	Immune checkpoint therapy	Heparan sulfate mimetic PG545 (NCIT:C95202); 	Cell lines/ animal models	N/A	Basic research	These results reveal that PG545 activates NK cells and that this activation is critical for the antitumor effect of PG545. Moreover, our findings may have important implications for improving NK cell-based antitumor therapies.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2016 Jan	 Heparan sulfate mimetic PG545-mediated antilymphoma effects require  TLR9-dependent NK cell activation.	 J Clin Invest	 Heparan sulfate (HS) is an essential component of the extracellular matrix (ECM),  which serves as a barrier to tumor invasion and metastasis. Heparanase promotes  tumor growth by cleaving HS chains of proteoglycan and releasing HS-bound  angiogenic growth factors and facilitates tumor invasion and metastasis by  degrading the ECM. HS mimetics, such as PG545, have been developed as antitumor  agents and are designed to suppress angiogenesis and metastasis by inhibiting  heparanase and competing for the HS-binding domain of angiogenic growth factors.   However, how PG545 exerts its antitumor effect remains incompletely defined.  Here, using murine models of lymphoma, we determined that the antitumor effects  of PG545 are critically dependent on NK cell activation and that NK cell  activation by PG545 requires TLR9. We demonstrate that PG545 does not activate  TLR9 directly but instead enhances TLR9 activation through the elevation of the  TLR9 ligand CpG in DCs. Specifically, PG545 treatment resulted in CpG  accumulation in the lysosomal compartment of DCs, leading to enhanced production   of IL-12, which is essential for PG545-mediated NK cell activation. Overall,  these results reveal that PG545 activates NK cells and that this activation is  critical for the antitumor effect of PG545. Moreover, our findings may have  important implications for improving NK cell-based antitumor therapies.
CANIT0000503	26655111	Case report	Relapsed Hodgkin's lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Posterior reversible encephalopathy syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Posterior reversible encephalopathy syndrome following pembrolizumab therapy for   relapsed Hodgkin's lymphoma.	 J Oncol Pharm Pract	 Posterior reversible encephalopathy syndrome (PRES) is characterized by a group  of central nervous system related symptoms. Diagnosis is usually made by computed  tomography or magnetic resonance imaging. Common causes can be arterial  hypertension, sepsis, autoimmune disorders, and medications. We report PRES in a   relapsed Hodgkin's Lymphoma patient after a dose of pembrolizumab.
CANIT0000504	26673995	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	The patient encountered several adverse events during the treatment. Some of them are quite common (e.g. skin affections), others (e.g. endocrinopathies) are less frequent.	N/A	N/A	N/A	N/A	N/A	2015	 [Possible Pitfalls of Ipilimumab Therapy in Malignant Melanoma - a Case Report].	 Klin Onkol	 BACKGROUND: Metastatic melanoma is a malignancy with one of the highest mortality  rates. However, with the introduction of new drugs during the last decade, the  prognosis of patients began to improve. Ipilimumab is one of the first so called   modern drugs in melanoma treatment. The therapy is often complicated by adverse  effects which are referred as immunerelated adverse events due to its mechanism  of action. CASE: We present a case of 68-year- old women with metastatic melanoma  who underwent treatment with ipilimumab. The patient encountered several adverse   events during the treatment. Some of them are quite common (e.g. skin  affections), others (e.g. endocrinopathies) are less frequent. CONCLUSION: This  case study highlights the need for close observation not only during the actual  treatment with ipilimumab, but also several weeks or months after the last dose.   This case study also demonstrates further need of education of doctors who do not  usually come in to contact with such patients.
CANIT0000505	26692064	Case report	Stage IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Bilateral uveitis and papillitis	N/A	N/A	N/A	N/A	N/A	 2016 Apr 12	 A case of bilateral uveitis and papillitis in a patient treated with  pembrolizumab.	 Eur J Ophthalmol	 PURPOSE: Drug-induced uveitis is a well-known effect of ocular inflammation that   has been reported with many medications. Pembrolizumab is a newer generation of  the anti-programmed cell death-1 monoclonal antibodies that was recently approved  by the Food and Drug Administration for the treatment of advanced melanoma.  Immune-mediated adverse events involving different organs have been reported in  recent literature in association with this drug. We present the first reported  case of uveitis in association with pembrolizumab therapy. CASE REPORT: An  82-year-old man with stage IV melanoma was started on pembrolizumab infusion  treatment every 3 weeks. Two months after initiating therapy, he presented with  bilateral severe anterior uveitis and papillitis with fast and complete recovery   after withholding further pembrolizumab infusions and treatment with topical  steroid. Uveitis recurred after restarting pembrolizumab therapy. CONCLUSIONS: In  current clinical practice, many new drugs are being approved, requiring better  characterization of the prevalence, onset, and nature of adverse events in order   to aid development of effective management strategies. Ophthalmologists should  keep in mind that drugs are always a possible cause of ocular inflammation in  patients presenting with uveitis.
CANIT0000506	26712903	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus stereotactic radiation	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); stereotactic ablative radiotherapy (NCIT:C157991); 	26	N/A	A retrospective cohort study	In our series, stereotactic radiation to melanoma brain metastases(BMs) is well tolerated in patients who received nivolumab. BM control and OS appear prolonged compared with standard current treatment. Prospective evaluation is warranted.	One patient experienced grade 2 headaches following SRS with symptomatic relief with steroid treatment. No other treatment-related neurologic toxicities or scalp reactions were reported. Eight (11%) local BM failures with a 20% increase in volume were noted. Of these lesions, hemorrhage was noted in 4, and edema was noted in 7.	N/A	N/A	N/A	N/A	N/A	 2016 Mar	 Clinical outcomes of melanoma brain metastases treated with stereotactic  radiation and anti-PD-1 therapy.	 Ann Oncol	 BACKGROUND: The anti-programmed death-1 (anti-PD-1) therapy nivolumab has  significant clinical activity in patients with metastatic melanoma. However,  little is known about the safety and outcomes in patients receiving anti-PD-1  therapy and stereotactic radiation for the treatment of brain metastases (BMs).  PATIENTS AND METHODS: Data were analyzed retrospectively from two prospective  nivolumab protocols enrolling 160 patients with advanced resected and  unresectable melanoma at a single institution. Patients were included if BMs were  diagnosed and treated with stereotactic radiation within 6 months of receiving  nivolumab. The primary end point of this study was neurotoxicity; secondary end  points included BM control and survival. RESULTS: Twenty-six patients with a  total of 73 BMs treated over 30 sessions were identified. Radiation was  administered before, during and after nivolumab in 33 lesions (45%), 5 lesions  (7%), and 35 lesions (48%), respectively. All BMs were treated with stereotactic   radiosurgery (SRS) in a single session except 12 BMs treated with fractionated  stereotactic radiation therapy, nine of which were in the postoperative setting.   One patient experienced grade 2 headaches following SRS with symptomatic relief  with steroid treatment. No other treatment-related neurologic toxicities or scalp  reactions were reported. Eight (11%) local BM failures with a >/=20% increase in   volume were noted. Of these lesions, hemorrhage was noted in 4, and edema was  noted in 7. Kaplan-Meier estimates for local BM control following radiation at 6   and 12 months were 91% and 85%, respectively. Median overall survival (OS) from  the date of stereotactic radiation and nivolumab initiation was 11.8 and 12.0  months, respectively, in patients receiving nivolumab for unresected disease  (median OS was not reached in patients treated in the resected setting).  CONCLUSIONS: In our series, stereotactic radiation to melanoma BMs is well  tolerated in patients who received nivolumab. BM control and OS appear prolonged   compared with standard current treatment. Prospective evaluation is warranted.CI  - (c) The Author 2015. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000507	26771550	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Nivolumab can cause or worsen dry eye disease to the point of corneal perforation.	Dry eye progressing to corneal perforation	N/A	N/A	N/A	N/A	N/A	 2016 Mar	 Cyclosporine for Dry Eye Associated With Nivolumab: A Case Progressing to Corneal  Perforation.	 Cornea	 PURPOSE: To present the clinical outcome of 2 cases of severe dry eye associated   with Nivolumab, with 1 case progressing to corneal perforation. DESIGN: Case  report. CASE 1: : A 58-year-old man with metastatic melanoma was referred for the  management of severe bilateral dry eyes after undergoing his sixth cycle of  Nivolumab. The right eye progressed to corneal perforation 4 weeks after  referral, after which Nivolumab was discontinued. When metastatic disease  recurred, Nivolumab was continued with an ocular surface stabilized with an  intensive regimen that included topical cyclosporine. CASE 2: : A 46-year-old  woman with metastatic melanoma was referred for severe dry eye symptoms around  the timing of her third cycle of Nivolumab. Improvement of symptoms and surface  staining was achieved with a regimen that included aggressive lubrication and  topical cyclosporine. On follow-up after completing Nivolumab therapy, metastatic  melanoma has remained regressed. CONCLUSIONS: Nivolumab can cause or worsen dry  eye disease to the point of corneal perforation. Given that its antitumor effect   is immune-mediated, therapies targeting ocular surface inflammation can be  effective for stabilizing dry eye disease in patients who continue treatment with  Nivolumab.
CANIT0000508	26783344	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	39	N/A	N/A	Ipilimumab and tremelimumab may  induce a severe and extensive form of inflammatory bowel disease. Rapid  escalation to infliximab should be advocated in patients who do not respond to  steroids. Patients treated with anti-CTLA-4 should be advised to avoid NSAIDs.	Thirty-nine patients with anti-CTLA-4 enterocolitis were included (ipilimumab n = 37; tremelimumab n = 2). The most frequent symptom was diarrhoea. Ten patients had extra-intestinal manifestations. Most colonoscopies showed ulcerations involving the rectum and sigmoid, 66% of patients had extensive colitis, 55% had patchy distribution and 20% had ileal inflammation. Endoscopic colonic biopsies showed acute colitis in most patients, while half of the patients had chronic duodenitis. Thirty-five patients received steroids that led to complete clinical remission in 13 patients (37%). Twelve patients required infliximab, of whom 10 (83%) responded. Six patients underwent colectomy (perforation n = 5; toxic megacolon n = 1); one of them died postoperatively. Four patients had a persistent enterocolitis at follow-up colonoscopy. Patients with enterocolitis were more frequently prescribed NSAIDs compared with patients without enterocolitis (31 vs 5%, p = 0.003).	N/A	N/A	N/A	N/A	N/A	 2016 Apr	 Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an  Inflammatory Bowel Disease.	 J Crohns Colitis	 BACKGROUND: Therapeutic monoclonal anti-cytotoxic T-lymphocyte-associated antigen  4 (CTLA-4) antibodies are associated with immune-mediated enterocolitis. The aim   of this study was to provide a detailed description of this entity. METHODS: We  included patients with endoscopic signs of inflammation after anti-CTLA-4  infusions for cancer treatment. Other causes of enterocolitis were excluded.  Clinical, biological and endoscopic data were recorded. A single pathologist  reviewed endoscopic biopsies and colectomy specimens from 27 patients. Patients  with and without enterocolitis after ipilimumab-treated melanoma were compared,  to identify clinical factors associated with enterocolitis. RESULTS: Thirty-nine   patients with anti-CTLA-4 enterocolitis were included (ipilimumab n = 37;  tremelimumab n = 2). The most frequent symptom was diarrhoea. Ten patients had  extra-intestinal manifestations. Most colonoscopies showed ulcerations involving   the rectum and sigmoid, 66% of patients had extensive colitis, 55% had patchy  distribution and 20% had ileal inflammation. Endoscopic colonic biopsies showed  acute colitis in most patients, while half of the patients had chronic  duodenitis. Thirty-five patients received steroids that led to complete clinical   remission in 13 patients (37%). Twelve patients required infliximab, of whom 10  (83%) responded. Six patients underwent colectomy (perforation n = 5; toxic  megacolon n = 1); one of them died postoperatively. Four patients had a  persistent enterocolitis at follow-up colonoscopy. Patients with enterocolitis  were more frequently prescribed NSAIDs compared with patients without  enterocolitis (31 vs 5%, p = 0.003). CONCLUSIONS: Ipilimumab and tremelimumab may  induce a severe and extensive form of inflammatory bowel disease. Rapid  escalation to infliximab should be advocated in patients who do not respond to  steroids. Patients treated with anti-CTLA-4 should be advised to avoid NSAIDs.CI  - Copyright (c) 2016 European Crohn's and Colitis Organisation (ECCO). Published by  Oxford University Press. All rights reserved. For permissions, please email:  journals.permissions@oup.com.
CANIT0000509	26783344	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	39	N/A	N/A	Ipilimumab and tremelimumab may  induce a severe and extensive form of inflammatory bowel disease. Rapid  escalation to infliximab should be advocated in patients who do not respond to  steroids. Patients treated with anti-CTLA-4 should be advised to avoid NSAIDs.	Thirty-nine patients with anti-CTLA-4 enterocolitis were included (ipilimumab n = 37; tremelimumab n = 2). The most frequent symptom was diarrhoea. Ten patients had extra-intestinal manifestations. Most colonoscopies showed ulcerations involving the rectum and sigmoid, 66% of patients had extensive colitis, 55% had patchy distribution and 20% had ileal inflammation. Endoscopic colonic biopsies showed acute colitis in most patients, while half of the patients had chronic duodenitis. Thirty-five patients received steroids that led to complete clinical remission in 13 patients (37%). Twelve patients required infliximab, of whom 10 (83%) responded. Six patients underwent colectomy (perforation n = 5; toxic megacolon n = 1); one of them died postoperatively. Four patients had a persistent enterocolitis at follow-up colonoscopy. Patients with enterocolitis were more frequently prescribed NSAIDs compared with patients without enterocolitis (31 vs 5%, p = 0.003).	N/A	N/A	N/A	N/A	N/A	 2016 Apr	 Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an  Inflammatory Bowel Disease.	 J Crohns Colitis	 BACKGROUND: Therapeutic monoclonal anti-cytotoxic T-lymphocyte-associated antigen  4 (CTLA-4) antibodies are associated with immune-mediated enterocolitis. The aim   of this study was to provide a detailed description of this entity. METHODS: We  included patients with endoscopic signs of inflammation after anti-CTLA-4  infusions for cancer treatment. Other causes of enterocolitis were excluded.  Clinical, biological and endoscopic data were recorded. A single pathologist  reviewed endoscopic biopsies and colectomy specimens from 27 patients. Patients  with and without enterocolitis after ipilimumab-treated melanoma were compared,  to identify clinical factors associated with enterocolitis. RESULTS: Thirty-nine   patients with anti-CTLA-4 enterocolitis were included (ipilimumab n = 37;  tremelimumab n = 2). The most frequent symptom was diarrhoea. Ten patients had  extra-intestinal manifestations. Most colonoscopies showed ulcerations involving   the rectum and sigmoid, 66% of patients had extensive colitis, 55% had patchy  distribution and 20% had ileal inflammation. Endoscopic colonic biopsies showed  acute colitis in most patients, while half of the patients had chronic  duodenitis. Thirty-five patients received steroids that led to complete clinical   remission in 13 patients (37%). Twelve patients required infliximab, of whom 10  (83%) responded. Six patients underwent colectomy (perforation n = 5; toxic  megacolon n = 1); one of them died postoperatively. Four patients had a  persistent enterocolitis at follow-up colonoscopy. Patients with enterocolitis  were more frequently prescribed NSAIDs compared with patients without  enterocolitis (31 vs 5%, p = 0.003). CONCLUSIONS: Ipilimumab and tremelimumab may  induce a severe and extensive form of inflammatory bowel disease. Rapid  escalation to infliximab should be advocated in patients who do not respond to  steroids. Patients treated with anti-CTLA-4 should be advised to avoid NSAIDs.CI  - Copyright (c) 2016 European Crohn's and Colitis Organisation (ECCO). Published by  Oxford University Press. All rights reserved. For permissions, please email:  journals.permissions@oup.com.
CANIT0000510	26787752	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	209	N/A	N/A	A baseline signature of high absolute eosinophil counts (AEC) is associated with favorable outcome following ipilimumab.	N/A	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Eosinophil counts	Cell percentage/counts in blood	 2016 Jun 15	 Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced  Melanoma Patients Treated with Ipilimumab.	 Clin Cancer Res	 PURPOSE: To identify baseline peripheral blood biomarkers associated with  clinical outcome following ipilimumab treatment in advanced melanoma patients.  EXPERIMENTAL DESIGN: Frequencies of myeloid-derived suppressor cells (MDSC) and  regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood  counts, and clinical characteristics were assessed in 209 patients. Endpoints  were overall survival (OS) and best overall response. Statistical calculations  were done by Kaplan-Meier and Cox regression analysis, including calibration and   discrimination by C-statistics. RESULTS: Low baseline LDH, absolute monocyte  counts (AMC), Lin(-)CD14(+)HLA-DR(-/low)-MDSC frequencies, and high absolute  eosinophil counts (AEC), relative lymphocyte counts (RLC), and  CD4(+)CD25(+)FoxP3(+)-Treg frequencies were significantly associated with better   survival, and were considered in a combination model. Patients (43.5%) presenting  with the best biomarker signature had a 30% response rate and median survival of   16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3%   response rate and median survival of 4 months. The occurrence of adverse events  correlated with neither baseline biomarker signatures nor the clinical benefit of  ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC,  and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated  with OS (P < 0.001 for all pairwise comparisons) in the main study and  additionally in an independent validation cohort. CONCLUSIONS: A baseline  signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is  associated with favorable outcome following ipilimumab. Prospective investigation  of the predictive impact of these markers following ipilimumab and other  treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12);  2908-18. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000511	26787752	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	209	N/A	N/A	A baseline signature of high regulatory T cells (Treg) is associated with favorable outcome following ipilimumab.	N/A	N/A	N/A	Treg cells (CL:0000815); T-Lymphocyte (NCIT:C12476); 	Regulatory T-cell 	Cell percentage/counts in blood	 2016 Jun 15	 Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced  Melanoma Patients Treated with Ipilimumab.	 Clin Cancer Res	 PURPOSE: To identify baseline peripheral blood biomarkers associated with  clinical outcome following ipilimumab treatment in advanced melanoma patients.  EXPERIMENTAL DESIGN: Frequencies of myeloid-derived suppressor cells (MDSC) and  regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood  counts, and clinical characteristics were assessed in 209 patients. Endpoints  were overall survival (OS) and best overall response. Statistical calculations  were done by Kaplan-Meier and Cox regression analysis, including calibration and   discrimination by C-statistics. RESULTS: Low baseline LDH, absolute monocyte  counts (AMC), Lin(-)CD14(+)HLA-DR(-/low)-MDSC frequencies, and high absolute  eosinophil counts (AEC), relative lymphocyte counts (RLC), and  CD4(+)CD25(+)FoxP3(+)-Treg frequencies were significantly associated with better   survival, and were considered in a combination model. Patients (43.5%) presenting  with the best biomarker signature had a 30% response rate and median survival of   16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3%   response rate and median survival of 4 months. The occurrence of adverse events  correlated with neither baseline biomarker signatures nor the clinical benefit of  ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC,  and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated  with OS (P < 0.001 for all pairwise comparisons) in the main study and  additionally in an independent validation cohort. CONCLUSIONS: A baseline  signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is  associated with favorable outcome following ipilimumab. Prospective investigation  of the predictive impact of these markers following ipilimumab and other  treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12);  2908-18. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000512	26787752	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	209	N/A	N/A	A baseline signature of high relative lymphocyte counts (RLC) is associated with favorable outcome following ipilimumab.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Relative lymphocyte counts	Cell percentage/counts in blood	 2016 Jun 15	 Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced  Melanoma Patients Treated with Ipilimumab.	 Clin Cancer Res	 PURPOSE: To identify baseline peripheral blood biomarkers associated with  clinical outcome following ipilimumab treatment in advanced melanoma patients.  EXPERIMENTAL DESIGN: Frequencies of myeloid-derived suppressor cells (MDSC) and  regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood  counts, and clinical characteristics were assessed in 209 patients. Endpoints  were overall survival (OS) and best overall response. Statistical calculations  were done by Kaplan-Meier and Cox regression analysis, including calibration and   discrimination by C-statistics. RESULTS: Low baseline LDH, absolute monocyte  counts (AMC), Lin(-)CD14(+)HLA-DR(-/low)-MDSC frequencies, and high absolute  eosinophil counts (AEC), relative lymphocyte counts (RLC), and  CD4(+)CD25(+)FoxP3(+)-Treg frequencies were significantly associated with better   survival, and were considered in a combination model. Patients (43.5%) presenting  with the best biomarker signature had a 30% response rate and median survival of   16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3%   response rate and median survival of 4 months. The occurrence of adverse events  correlated with neither baseline biomarker signatures nor the clinical benefit of  ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC,  and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated  with OS (P < 0.001 for all pairwise comparisons) in the main study and  additionally in an independent validation cohort. CONCLUSIONS: A baseline  signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is  associated with favorable outcome following ipilimumab. Prospective investigation  of the predictive impact of these markers following ipilimumab and other  treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12);  2908-18. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000513	26787752	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	209	N/A	N/A	A baseline signature of low absolute monocyte counts (AMC) is associated with favorable outcome following ipilimumab.	N/A	N/A	N/A	Monocyte counts (NCIT:C12547); 	Absolute monocyte counts	Cell percentage/counts in blood	 2016 Jun 15	 Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced  Melanoma Patients Treated with Ipilimumab.	 Clin Cancer Res	 PURPOSE: To identify baseline peripheral blood biomarkers associated with  clinical outcome following ipilimumab treatment in advanced melanoma patients.  EXPERIMENTAL DESIGN: Frequencies of myeloid-derived suppressor cells (MDSC) and  regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood  counts, and clinical characteristics were assessed in 209 patients. Endpoints  were overall survival (OS) and best overall response. Statistical calculations  were done by Kaplan-Meier and Cox regression analysis, including calibration and   discrimination by C-statistics. RESULTS: Low baseline LDH, absolute monocyte  counts (AMC), Lin(-)CD14(+)HLA-DR(-/low)-MDSC frequencies, and high absolute  eosinophil counts (AEC), relative lymphocyte counts (RLC), and  CD4(+)CD25(+)FoxP3(+)-Treg frequencies were significantly associated with better   survival, and were considered in a combination model. Patients (43.5%) presenting  with the best biomarker signature had a 30% response rate and median survival of   16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3%   response rate and median survival of 4 months. The occurrence of adverse events  correlated with neither baseline biomarker signatures nor the clinical benefit of  ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC,  and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated  with OS (P < 0.001 for all pairwise comparisons) in the main study and  additionally in an independent validation cohort. CONCLUSIONS: A baseline  signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is  associated with favorable outcome following ipilimumab. Prospective investigation  of the predictive impact of these markers following ipilimumab and other  treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12);  2908-18. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000514	26787752	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	209	N/A	N/A	A baseline signature of low myeloid-derived suppressor cells (MDSC) is associated with favorable outcome following ipilimumab.	N/A	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); 	Monocytic myeloid-derived suppressor cells counts	Cell percentage/counts in blood	 2016 Jun 15	 Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced  Melanoma Patients Treated with Ipilimumab.	 Clin Cancer Res	 PURPOSE: To identify baseline peripheral blood biomarkers associated with  clinical outcome following ipilimumab treatment in advanced melanoma patients.  EXPERIMENTAL DESIGN: Frequencies of myeloid-derived suppressor cells (MDSC) and  regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood  counts, and clinical characteristics were assessed in 209 patients. Endpoints  were overall survival (OS) and best overall response. Statistical calculations  were done by Kaplan-Meier and Cox regression analysis, including calibration and   discrimination by C-statistics. RESULTS: Low baseline LDH, absolute monocyte  counts (AMC), Lin(-)CD14(+)HLA-DR(-/low)-MDSC frequencies, and high absolute  eosinophil counts (AEC), relative lymphocyte counts (RLC), and  CD4(+)CD25(+)FoxP3(+)-Treg frequencies were significantly associated with better   survival, and were considered in a combination model. Patients (43.5%) presenting  with the best biomarker signature had a 30% response rate and median survival of   16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3%   response rate and median survival of 4 months. The occurrence of adverse events  correlated with neither baseline biomarker signatures nor the clinical benefit of  ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC,  and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated  with OS (P < 0.001 for all pairwise comparisons) in the main study and  additionally in an independent validation cohort. CONCLUSIONS: A baseline  signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is  associated with favorable outcome following ipilimumab. Prospective investigation  of the predictive impact of these markers following ipilimumab and other  treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12);  2908-18. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000515	26787752	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	209	N/A	N/A	A baseline signature of low serum lactate dehydrogenase (LDH) is associated with favorable outcome following ipilimumab.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Jun 15	 Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced  Melanoma Patients Treated with Ipilimumab.	 Clin Cancer Res	 PURPOSE: To identify baseline peripheral blood biomarkers associated with  clinical outcome following ipilimumab treatment in advanced melanoma patients.  EXPERIMENTAL DESIGN: Frequencies of myeloid-derived suppressor cells (MDSC) and  regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood  counts, and clinical characteristics were assessed in 209 patients. Endpoints  were overall survival (OS) and best overall response. Statistical calculations  were done by Kaplan-Meier and Cox regression analysis, including calibration and   discrimination by C-statistics. RESULTS: Low baseline LDH, absolute monocyte  counts (AMC), Lin(-)CD14(+)HLA-DR(-/low)-MDSC frequencies, and high absolute  eosinophil counts (AEC), relative lymphocyte counts (RLC), and  CD4(+)CD25(+)FoxP3(+)-Treg frequencies were significantly associated with better   survival, and were considered in a combination model. Patients (43.5%) presenting  with the best biomarker signature had a 30% response rate and median survival of   16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3%   response rate and median survival of 4 months. The occurrence of adverse events  correlated with neither baseline biomarker signatures nor the clinical benefit of  ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC,  and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated  with OS (P < 0.001 for all pairwise comparisons) in the main study and  additionally in an independent validation cohort. CONCLUSIONS: A baseline  signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is  associated with favorable outcome following ipilimumab. Prospective investigation  of the predictive impact of these markers following ipilimumab and other  treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12);  2908-18. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000516	26787823	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	53	N/A	N/A	PD-1 blockade increases the frequency of T cells, B cells, and myeloid-derived suppressor cells in tumors, with the CD8(+) effector memory T-cell subset being the major T-cell phenotype expanded in patients with a response to therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2016 Mar	 PD-1 Blockade Expands Intratumoral Memory T Cells.	 Cancer Immunol Res	 Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are  mediated by T cells, which we characterized in 102 tumor biopsies obtained from  53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were  dissociated, and single-cell infiltrates were analyzed by multicolor flow  cytometry using two computational approaches to resolve the leukocyte phenotypes   at the single-cell level. There was a statistically significant increase in the  frequency of T cells in patients who responded to therapy. The frequency of  intratumoral B cells and monocytic myeloid-derived suppressor cells significantly  increased in patients' biopsies taken on treatment. The percentage of cells with   a regulatory T-cell phenotype, monocytes, and natural killer cells did not change  while on PD-1 blockade therapy. CD8(+) memory T cells were the most prominent  phenotype that expanded intratumorally on therapy. However, the frequency of  CD4(+) effector memory T cells significantly decreased on treatment, whereas  CD4(+) effector T cells significantly increased in nonresponding tumors on  therapy. In peripheral blood, an unusual population of blood cells expressing  CD56 was detected in two patients with regressing melanoma. In conclusion, PD-1  blockade increases the frequency of T cells, B cells, and myeloid-derived  suppressor cells in tumors, with the CD8(+) effector memory T-cell subset being  the major T-cell phenotype expanded in patients with a response to therapy.CI  - (c)2016 American Association for Cancer Research.
CANIT0000517	26790556	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	A 77-year-old man with metastatic melanoma developed fever, cough and dyspnoea soon after the start of ipilimumab treatment leading to the diagnosis of a bronchiolitis obliterans organising pneumonia (BOOP). The patient was treated with clarithromycin allowing a good clinical and radiological evolution.	N/A	N/A	N/A	N/A	N/A	 2015 Dec	 Unusual pulmonary toxicity of ipilimumab treated by macrolides.	 Acta Clin Belg	 INTRODUCTION: Ipilimumab is a human monoclonal antibody that blocks  cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) and promotes antitumour  immunity. It has recently been approved for the treatment of metastatic melanoma   patients. Ipilimumab is now widely used and the spectrum of side effects because   of autoimmunity is expanding. To our knowledge, this is the first report of an  ipilimumab-induced pulmonary immune-related adverse event (irAE) that was  successfully treated by macrolides without corticosteroids. CASE REPORT: A  77-year-old man with metastatic melanoma developed fever, cough and dyspnoea soon  after the start of ipilimumab treatment leading to the diagnosis of a  bronchiolitis obliterans organising pneumonia (BOOP). The patient was treated  with clarithromycin allowing a good clinical and radiological evolution.  CONCLUSION: Macrolides seem to have a therapeutic anti-inflammatory potential in   the case of mild to moderate pulmonary ipilimumab-induced irAEs. However, more  data are needed to confirm macrolides use in this indication in clinical practice  and corticosteroids remain the gold standard treatment in case of severe  ipilimumab-associated irAEs.
CANIT0000518	26794281	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	66	N/A	N/A	LDH could be a useful marker at baseline and during treatment to predict early response or progression in patients with advanced melanoma who receive anti-PD-1 therapy.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Feb 2	 Serum lactate dehydrogenase as an early marker for outcome in patients treated  with anti-PD-1 therapy in metastatic melanoma.	 Br J Cancer	 BACKGROUND: Treatment with programmed death receptor-1 (PD-1) antibodies is  associated with high response rates in patients with advanced melanoma. Reliable   markers for early response and outcome are still sparse. METHODS: We evaluated 66  consecutive patients with advanced/metastatic melanoma treated with nivolumab or   pembrolizumab between 2013 and 2014. The main objectives of this study were to  investigate whether, first, serum lactate dehydrogenase (LDH) at baseline (normal  vs above the upper limit of normal) correlates with overall survival (OS), and,  second, whether the change of LDH during treatment predicts response before the  first scan and OS in patients with an elevated baseline LDH. RESULTS: After a  median follow-up of 9 months, patients with an elevated baseline LDH (N=34) had a  significantly shorter OS compared with patients with normal LDH (N=32; 6-month  OS: 60.8% vs 81.6% and 12-month OS: 44.2% vs 71.5% (log-rank P=0.0292). In those   34 patients with elevated baseline LDH, the relative change during treatment was   significantly associated with an objective response on the first scan: the 11  (32%) patients with partial remission had a mean reduction of -27.3% from  elevated baseline LDH. In contrast, patients with progressive disease (N=15) had   a mean increase of +39%. Patients with a relative increase over 10% from elevated  baseline LDH had a significantly shorter OS compared with patients with 10%  change (4.3 vs 15.7 months, log-rank P<0.00623). CONCLUSIONS: LDH could be a  useful marker at baseline and during treatment to predict early response or  progression in patients with advanced melanoma who receive anti-PD-1 therapy.
CANIT0000519	26794281	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	66	N/A	N/A	LDH could be a useful marker at baseline and during treatment to predict early response or progression in patients with advanced melanoma who receive anti-PD-1 therapy.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Feb 2	 Serum lactate dehydrogenase as an early marker for outcome in patients treated  with anti-PD-1 therapy in metastatic melanoma.	 Br J Cancer	 BACKGROUND: Treatment with programmed death receptor-1 (PD-1) antibodies is  associated with high response rates in patients with advanced melanoma. Reliable   markers for early response and outcome are still sparse. METHODS: We evaluated 66  consecutive patients with advanced/metastatic melanoma treated with nivolumab or   pembrolizumab between 2013 and 2014. The main objectives of this study were to  investigate whether, first, serum lactate dehydrogenase (LDH) at baseline (normal  vs above the upper limit of normal) correlates with overall survival (OS), and,  second, whether the change of LDH during treatment predicts response before the  first scan and OS in patients with an elevated baseline LDH. RESULTS: After a  median follow-up of 9 months, patients with an elevated baseline LDH (N=34) had a  significantly shorter OS compared with patients with normal LDH (N=32; 6-month  OS: 60.8% vs 81.6% and 12-month OS: 44.2% vs 71.5% (log-rank P=0.0292). In those   34 patients with elevated baseline LDH, the relative change during treatment was   significantly associated with an objective response on the first scan: the 11  (32%) patients with partial remission had a mean reduction of -27.3% from  elevated baseline LDH. In contrast, patients with progressive disease (N=15) had   a mean increase of +39%. Patients with a relative increase over 10% from elevated  baseline LDH had a significantly shorter OS compared with patients with 10%  change (4.3 vs 15.7 months, log-rank P<0.00623). CONCLUSIONS: LDH could be a  useful marker at baseline and during treatment to predict early response or  progression in patients with advanced melanoma who receive anti-PD-1 therapy.
CANIT0000520	26795275	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	N/A	N/A	Autoimmune hemolytic anemia	N/A	N/A	N/A	N/A	N/A	 2016 Apr	 Autoimmune hemolytic anemia induced by anti-PD-1 therapy in metastatic melanoma.	 Melanoma Res	 We report the occurrence of autoimmune hemolytic anemia in a patient receiving  the anti-PD-1 monoclonal antibody, nivolumab, for metastatic melanoma in the  presence of known red cell alloantibodies, despite having received prior  ipilimumab without evidence of hemolysis. The patient had a history of multiple  red cell alloantibodies and a positive direct antiglobulin test, identified at  the time of a prior transfusion, which occurred before treatment with ipilimumab.  The patient developed symptomatic warm autoimmune hemolytic anemia after four  cycles of treatment with nivolumab. Clinical improvement was noted following  cessation of the drug and treatment with corticosteroids. Given that there was no  prior history of hemolysis, even during treatment with ipilimumab, we hypothesize  that anti-PD-1 therapy disrupted peripheral tolerance, unmasking an underlying  autoimmune predisposition.
CANIT0000521	26802161	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	720	N/A	N/A	Patients with absolute neutrophil counts (ANC)  7500 had a significantly increased risk of death and of progression.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2016 Apr	 Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic  relevance in metastatic melanoma patients receiving ipilimumab.	 Ann Oncol	 BACKGROUND: Clinical responses to ipilimumab are variable in terms of onset,  magnitude and duration. Upfront identification of patients who are more likely or  unlikely to benefit from treatment is a major need. PATIENTS AND METHODS:  Prospectively collected data from 720 advanced melanoma patients treated with  ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The   derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline  peripheral blood cell counts, and receiver operating characteristic curve was  used to evaluate the best cutoff for this marker. Patients were stratified  according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and  their combination. The prognostic values of ANC and dNLR for survival were  assessed using multivariate Cox proportional hazard models. A subgroup analysis  including LDH in the models was also carried out. RESULTS: The median follow-up  was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were  significantly associated with the outcome of ipilimumab-treated melanoma  patients, in terms of disease progression and death (P < 0.0001 for all).  Furthermore, for each elevated variable, prognosis worsened. Patients with both  ANC >/= 7500 and dNLR >/= 3 had a significantly and independently increased risk   of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of  progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower   ANC and dNLR. Patients with one of the two factors elevated displayed an  intermediate risk of progression and death. The 1- and 2-year survival rates were  2% and 0%, respectively, for patients with ANC >/= 7500 and dNLR >/= 3, and 43%  and 24%, respectively, for patients with both lower ANC and dNLR. CONCLUSIONS:  Although these findings need to be confirmed and validated, we suggest that a  neutrophil-based index may help risk-group stratification and assist  disease-management strategies. Furthermore, the potential predictive value of  this index for response to ipilimumab should be investigated in randomized  clinical trials.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000522	26802161	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	720	N/A	N/A	Patients with derived neutrophil-to-lymphocyte ratio (dNLR)  3 had a significantly increased risk of death and of progression.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2016 Apr	 Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic  relevance in metastatic melanoma patients receiving ipilimumab.	 Ann Oncol	 BACKGROUND: Clinical responses to ipilimumab are variable in terms of onset,  magnitude and duration. Upfront identification of patients who are more likely or  unlikely to benefit from treatment is a major need. PATIENTS AND METHODS:  Prospectively collected data from 720 advanced melanoma patients treated with  ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The   derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline  peripheral blood cell counts, and receiver operating characteristic curve was  used to evaluate the best cutoff for this marker. Patients were stratified  according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and  their combination. The prognostic values of ANC and dNLR for survival were  assessed using multivariate Cox proportional hazard models. A subgroup analysis  including LDH in the models was also carried out. RESULTS: The median follow-up  was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were  significantly associated with the outcome of ipilimumab-treated melanoma  patients, in terms of disease progression and death (P < 0.0001 for all).  Furthermore, for each elevated variable, prognosis worsened. Patients with both  ANC >/= 7500 and dNLR >/= 3 had a significantly and independently increased risk   of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of  progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower   ANC and dNLR. Patients with one of the two factors elevated displayed an  intermediate risk of progression and death. The 1- and 2-year survival rates were  2% and 0%, respectively, for patients with ANC >/= 7500 and dNLR >/= 3, and 43%  and 24%, respectively, for patients with both lower ANC and dNLR. CONCLUSIONS:  Although these findings need to be confirmed and validated, we suggest that a  neutrophil-based index may help risk-group stratification and assist  disease-management strategies. Furthermore, the potential predictive value of  this index for response to ipilimumab should be investigated in randomized  clinical trials.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000523	26811403	Case report	Metastatic mucosal melanoma	Mucosal melanoma	MONDO:0000544	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Effectivity	Immune therapy-related colitis and new onset vitiligo	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Response of metastatic mucosal melanoma to immunotherapy: It can get worse before  it gets better.	 J Oncol Pharm Pract	 Immune therapy with checkpoint inhibitors has revolutionized the management of  metastatic melanoma. Ipilimumab, nivolumab, and pembrolizumab are all  FDA-approved immune checkpoint inhibitors to treat metastatic melanoma. Responses  to immune checkpoint inhibitors are usually delayed. An interim progression on  restaging computed tomography scans pseudo-progression may be observed before  response to treatment occur. In this case, we report a significant interim  progression of metastatic mucosal melanoma before meaningful responses to  immunotherapy occurred. The patient developed significant immune therapy-related   colitis and new onset vitiligo. Further restaging computed tomography scans  showed sustained tumor response despite stopping the immune therapy.
CANIT0000524	26811403	Case report	Metastatic mucosal melanoma	Mucosal melanoma	MONDO:0000544	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Effectivity	Immune therapy-related colitis and new onset vitiligo	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Response of metastatic mucosal melanoma to immunotherapy: It can get worse before  it gets better.	 J Oncol Pharm Pract	 Immune therapy with checkpoint inhibitors has revolutionized the management of  metastatic melanoma. Ipilimumab, nivolumab, and pembrolizumab are all  FDA-approved immune checkpoint inhibitors to treat metastatic melanoma. Responses  to immune checkpoint inhibitors are usually delayed. An interim progression on  restaging computed tomography scans pseudo-progression may be observed before  response to treatment occur. In this case, we report a significant interim  progression of metastatic mucosal melanoma before meaningful responses to  immunotherapy occurred. The patient developed significant immune therapy-related   colitis and new onset vitiligo. Further restaging computed tomography scans  showed sustained tumor response despite stopping the immune therapy.
CANIT0000525	26828905	Case report	Relapsed/refractory Hodgkin lymphoma after allogeneic stem cell transplantation	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Major clinical response	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Major clinical response to nivolumab in relapsed/refractory Hodgkin lymphoma  after allogeneic stem cell transplantation.	 Bone Marrow Transplant	Unable to provide
CANIT0000526	26832745	Basic research	B16F10 melanoma, EMT6 mammary, and CT26 colon carcinoma cell lines, B16F10 mouse melanoma models	Colorectal cancer	EFO:0005842	Intestines	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	Cell lines/ animal models	N/A	Basic research	These data support further evaluation of NKTR-214 in  humans for a variety of tumor types, adding to the repertoire of potent and  potentially curative cancer immunotherapies.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2016 Feb 1	 NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased  Tumor Exposure, and Marked Efficacy in Mouse Tumor Models.	 Clin Cancer Res	 PURPOSE: Aldesleukin, recombinant human IL2, is an effective immunotherapy for  metastatic melanoma and renal cancer, with durable responses in approximately 10%  of patients; however, severe side effects limit maximal dosing and thus the  number of patients able to receive treatment and potential cure. NKTR-214 is a  prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin.  The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In  vivo, the PEG chains slowly release to generate active IL2 conjugates.  EXPERIMENTAL DESIGN: We evaluated the bioactivity and receptor binding of  NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor  pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination  with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in  non-human primates. RESULTS: In a murine melanoma tumor model, the ratio of  tumor-killing CD8(+) T cells to Foxp3(+) regulatory T cells was greater than 400   for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation  of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG  molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to  conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single  agent and provided durable immunity that was resistant to tumor rechallenge in  combination with anti-CTLA-4 antibody. NKTR-214 was well tolerated in non-human  primates. CONCLUSIONS: These data support further evaluation of NKTR-214 in  humans for a variety of tumor types, adding to the repertoire of potent and  potentially curative cancer immunotherapies.CI  - (c)2016 American Association for Cancer Research.
CANIT0000527	26832745	Basic research	B16F10 melanoma, EMT6 mammary, and CT26 colon carcinoma cell lines, B16F10 mouse melanoma models	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	Cell lines/ animal models	N/A	Basic research	These data support further evaluation of NKTR-214 in  humans for a variety of tumor types, adding to the repertoire of potent and  potentially curative cancer immunotherapies.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2016 Feb 1	 NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased  Tumor Exposure, and Marked Efficacy in Mouse Tumor Models.	 Clin Cancer Res	 PURPOSE: Aldesleukin, recombinant human IL2, is an effective immunotherapy for  metastatic melanoma and renal cancer, with durable responses in approximately 10%  of patients; however, severe side effects limit maximal dosing and thus the  number of patients able to receive treatment and potential cure. NKTR-214 is a  prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin.  The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In  vivo, the PEG chains slowly release to generate active IL2 conjugates.  EXPERIMENTAL DESIGN: We evaluated the bioactivity and receptor binding of  NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor  pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination  with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in  non-human primates. RESULTS: In a murine melanoma tumor model, the ratio of  tumor-killing CD8(+) T cells to Foxp3(+) regulatory T cells was greater than 400   for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation  of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG  molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to  conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single  agent and provided durable immunity that was resistant to tumor rechallenge in  combination with anti-CTLA-4 antibody. NKTR-214 was well tolerated in non-human  primates. CONCLUSIONS: These data support further evaluation of NKTR-214 in  humans for a variety of tumor types, adding to the repertoire of potent and  potentially curative cancer immunotherapies.CI  - (c)2016 American Association for Cancer Research.
CANIT0000528	26837003	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	34	N/A	N/A	A paucity of genetic pathways involved in B vitamin biosynthesis is associated with an increased risk of colitis.	Colitis	N/A	N/A	B vitamin biosynthesis (NCIT:C45812); 	Gene expression signatures involved in B vitamin biosynthesis	Gene expression signature on/in tumor cell	 2016 Feb 2	 Intestinal microbiome analyses identify melanoma patients at risk for  checkpoint-blockade-induced colitis.	 Nat Commun	 The composition of the intestinal microbiota influences the development of  inflammatory disorders. However, associating inflammatory diseases with specific   microbial members of the microbiota is challenging, because clinically detectable  inflammation and its treatment can alter the microbiota's composition.  Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that  blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is  associated with new-onset, immune-mediated colitis. Here we conduct a prospective  study of patients with metastatic melanoma undergoing ipilimumab treatment and  correlate the pre-inflammation faecal microbiota and microbiome composition with   subsequent colitis development. We demonstrate that increased representation of  bacteria belonging to the Bacteroidetes phylum is correlated with resistance to  the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of  genetic pathways involved in polyamine transport and B vitamin biosynthesis is  associated with an increased risk of colitis. Identification of these biomarkers   may enable interventions to reduce the risk of inflammatory complications  following cancer immunotherapy.
CANIT0000529	26837003	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	34	N/A	N/A	A paucity of genetic pathways involved in polyamine transport is associated with an increased risk of colitis.	Colitis	N/A	N/A	Polyamine transport (NCIT:C19824); 	Gene expression signatures involved in polyamine transport	Gene expression signature on/in tumor cell	 2016 Feb 2	 Intestinal microbiome analyses identify melanoma patients at risk for  checkpoint-blockade-induced colitis.	 Nat Commun	 The composition of the intestinal microbiota influences the development of  inflammatory disorders. However, associating inflammatory diseases with specific   microbial members of the microbiota is challenging, because clinically detectable  inflammation and its treatment can alter the microbiota's composition.  Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that  blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is  associated with new-onset, immune-mediated colitis. Here we conduct a prospective  study of patients with metastatic melanoma undergoing ipilimumab treatment and  correlate the pre-inflammation faecal microbiota and microbiome composition with   subsequent colitis development. We demonstrate that increased representation of  bacteria belonging to the Bacteroidetes phylum is correlated with resistance to  the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of  genetic pathways involved in polyamine transport and B vitamin biosynthesis is  associated with an increased risk of colitis. Identification of these biomarkers   may enable interventions to reduce the risk of inflammatory complications  following cancer immunotherapy.
CANIT0000530	26837003	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	34	N/A	N/A	Increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis.	Colitis	N/A	N/A	Bacteroidetes phylum (NCIT:C76203); 	Bacteroidetes phylum	Microbiota	 2016 Feb 2	 Intestinal microbiome analyses identify melanoma patients at risk for  checkpoint-blockade-induced colitis.	 Nat Commun	 The composition of the intestinal microbiota influences the development of  inflammatory disorders. However, associating inflammatory diseases with specific   microbial members of the microbiota is challenging, because clinically detectable  inflammation and its treatment can alter the microbiota's composition.  Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that  blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is  associated with new-onset, immune-mediated colitis. Here we conduct a prospective  study of patients with metastatic melanoma undergoing ipilimumab treatment and  correlate the pre-inflammation faecal microbiota and microbiome composition with   subsequent colitis development. We demonstrate that increased representation of  bacteria belonging to the Bacteroidetes phylum is correlated with resistance to  the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of  genetic pathways involved in polyamine transport and B vitamin biosynthesis is  associated with an increased risk of colitis. Identification of these biomarkers   may enable interventions to reduce the risk of inflammatory complications  following cancer immunotherapy.
CANIT0000531	26837059	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Upregulation of granzyme B and interferon-gamma mRNA in responding lesions by  treatment with nivolumab for metastatic melanoma: a case report.	 J Eur Acad Dermatol Venereol	Unable to provide
CANIT0000532	26846115	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	Case	N/A	Gastrointestinal toxicities	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Ipilimumab-Induced Gastrointestinal Toxicities: A Management Algorithm.	 Dig Dis Sci	 Ipilimumab is a cytotoxic T-lymphocyte-associated antigen-4-blocking monoclonal  antibody, which has shown a significant survival benefit in metastatic melanoma  patients. Despite being a promising therapy for a disease with an otherwise  rather dismal prognosis, it is associated with several immune-related adverse  effects (IRAE) mainly targeted toward the digestive tract, skin, liver, and  hypothalamic-pituitary axis. Ipilimumab-induced gastrointestinal toxicity (IGT)  include diarrhea (~44 %), colitis (~18 %), bowel perforation (<1 %), and  pancreatitis (<1.5 %). Early recognition of IRAE and treatment initiation are  critical to decrease the risk of further complications. Management included  steroids as initial therapy, followed by infliximab (anti-tumor necrosis factor  alpha antibody) and/or surgical option for complications like bowel perforation.   We present a series of three patients with metastatic melanoma, who received  treatment with ipilimumab, and presented with varying gastrointestinal clinical  manifestations and complications. Through this case series, our attempt is to  make practicing gastroenterologists cognizant about the wide spectrum of  gastrointestinal toxicity of this rather new clinical entity, as well as to  discuss management algorithm for IGT.
CANIT0000533	26861469	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	168	N/A	A phase II dose-ranging trial	Results of these intensive ECG analyses indicate that nivolumab has no clinically meaningful effect on QTc interval when administered at doses up to 10.0 mg/kg.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Mar	 Evaluation of the potential for QTc prolongation in patients with solid tumors  receiving nivolumab.	 Cancer Chemother Pharmacol	 PURPOSE: The fully human monoclonal antibody nivolumab binds to the programmed  death-1 (PD-1) receptor, blocking interactions between PD-1 and its ligands on  tumor cells and preventing T cell exhaustion in patients with cancer. The  potential for corrected QT interval (QTc) prolongation was assessed in a subset  of patients enrolled in a phase 2 dose-ranging study of nivolumab. METHODS:  Triplicate 12-lead electrocardiograms (ECGs) obtained predose and post-dose were   assessed by an independent ECG core laboratory. QTc derived from Fridericia's  formula (QTcF) was evaluated by central tendency, categorical, and  concentration-response analyses. RESULTS: No patients had QTcF intervals or  changes from baseline in QTcF (DeltaQTcF) exceeding prespecified thresholds  indicating borderline or prolonged QTcF (>480 ms) or DeltaQTcF (>60 ms). Among  146 patients randomized to nivolumab 0.3, 2.0, or 10.0 mg/kg every 3 weeks, the  maximum increases in mean (+/- SD) QTcF at any time point were 4.9 (+/- 13.4),  1.2 (+/- 10.1), and 2.0 (+/- 8.9) ms, respectively. There was no relationship  between QTcF and nivolumab serum concentration and no association between  predicted maximum QTcF and mean maximum nivolumab concentration in any dosage  group. CONCLUSION: Results of these intensive ECG analyses indicate that  nivolumab has no clinically meaningful effect on QTc interval when administered  at doses up to 10.0 mg/kg.
CANIT0000534	26865455	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	Pneumonitis	Both patients presented with ground-glass and reticular opacities and consolidations in a peripheral distribution on CT, demonstrating a radiographic pattern of cryptogenic organizing pneumonia. Consolidations were extensive and rapidly developed within 8 weeks of therapy in both cases. Both patients were treated with corticosteroids with subsequent improvement of respiratory symptoms and radiographic findings. One patient experienced recurrent pneumonitis after completing corticosteroid taper, or a pneumonitis flare, in the absence of nivolumab retreatment, with subsequent improvement upon corticosteroid readministration.	N/A	N/A	N/A	N/A	N/A	 2016 Apr	 Anti-PD-1 Inhibitor-Related Pneumonitis in Non-Small Cell Lung Cancer.	 Cancer Immunol Res	 The recent approval of two PD-1 inhibitors for the treatment of non-small cell  lung cancer (NSCLC) has rapidly led to the widespread use of these agents in  oncology practices. Pneumonitis has been recognized as a potentially  life-threatening adverse event among NSCLC patients treated with PD-1 inhibitors;  however, the detailed clinical and radiographic manifestations of this entity  remain to be described. We report on two cases of anti-PD-1 pneumonitis in  advanced NSCLC patients treated with nivolumab after its FDA approval. Both  patients presented with ground-glass and reticular opacities and consolidations  in a peripheral distribution on CT, demonstrating a radiographic pattern of  cryptogenic organizing pneumonia. Consolidations were extensive and rapidly  developed within 8 weeks of therapy in both cases. Both patients were treated  with corticosteroids with subsequent improvement of respiratory symptoms and  radiographic findings. One patient experienced recurrent pneumonitis after  completing corticosteroid taper, or a pneumonitis flare, in the absence of  nivolumab retreatment, with subsequent improvement upon corticosteroid  readministration. With the increasing use of immune checkpoint inhibitors in a  growing number of tumor types, awareness of the radiographic and clinical  manifestations of PD-1 inhibitor-related pneumonitis will be critical for the  prompt diagnosis and management of this potentially serious adverse event.CI  - (c)2016 American Association for Cancer Research.
CANIT0000535	26867901	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	86	N/A	A retrospective cohort study	A third radiologic pattern of ipilimumab-associated colitis was observed in this study: isolated recto-sigmoid colitis without diverticulosis. All patterns of ipilimumab-associated colitis include recto-sigmoid involvement.	Isolated recto-sigmoid colitis	N/A	N/A	N/A	N/A	N/A	 2016 Feb	 Isolated recto-sigmoid colitis: a new imaging pattern of ipilimumab-associated  colitis.	 Abdom Radiol (NY)	 PURPOSE: The purpose of this study is to describe typical CT findings and  distinct imaging patterns of ipilimumab-associated colitis in immunotherapeutic  treatment of melanoma. MATERIALS AND METHODS: This HIPAA-compliant retrospective   study included 86 patients with melanoma imaged with CT or PET/CT of the abdomen   and pelvis during or shortly after administration of ipilimumab. Twelve of 86  patients (14%) developed symptoms of colitis and underwent CT imaging of the  abdomen and pelvis while symptomatic. Two radiologists reviewed CT images to  evaluate for the presence of CT findings of colitis including mesenteric vessel  engorgement, pericolonic inflammatory change, hyperenhancement of colonic mucosa,  colonic wall thickening, fluid-filled colonic distension, pneumoperitoneum,  pneumatosis, and diverticulosis in the inflamed segment of colon. One nuclear  medicine radiologist reviewed PET images for abnormally increased FDG uptake in  the colon. The diagnosis of ipilimumab-associated colitis was made based on  clinical presentation, imaging findings, and laboratory data. RESULTS: Common CT   findings of ipilimumab-associated colitis included colonic mucosal  hyperenhancement (10/12 [83%]), mesenteric vessel engorgement (9/12 [75.0%]),  colonic wall thickening (9/12 [75%]), and pericolonic fat stranding (2/12 [16%]).  No patient developed pneumatosis or pneumoperitoneum. Diffuse colitis was present  in 4/12 (33%) patients. Segmental colitis with associated diverticulosis (was  present in 2/12 (17%) patients). A third pattern, isolated recto-sigmoid colitis   without diverticulosis, was observed in 6/12 (50%) patients. All patients with  colitis demonstrated recto-sigmoid involvement. CONCLUSIONS: A third radiologic  pattern of ipilimumab-associated colitis was observed in this study: isolated  recto-sigmoid colitis without diverticulosis. All patterns of  ipilimumab-associated colitis include recto-sigmoid involvement.
CANIT0000536	26880821	Case report	Perianal nodular melanoma	Nodular melanoma	EFO:0008515	Skin	CTLA-4 (P16410); BRAF (P15056); 	CTLA-4; BRAF	Vemurafenib followed by ipilimumab	N/A	Target therapy followed by Immune checkpoint therapy	Ipilimumab (DB06186); vemurafenib (DB08881); dacarbazine (DB00851); 	Cell lines	N/A	Case	The patient underwent wide local excision but was unresponsive to dacarbazine. Targeted therapy with vemurafenib had shown clinical improvement for a 5-month duration until he showed signs of disease progression. Just after the shift of adjuvant therapy to ipilimumab, he was diagnosed with multiple cerebral metastases that eventually led to his demise 6 months after initiation of vemurafenib, having had a 12-month survival period from the time of initial melanoma diagnosis.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2016 Feb 15	 Perianal melanoma with a BRAF gene mutation in a young Portuguese Roma native.	 BMJ Case Rep	 A case of a young man diagnosed with perianal nodular melanoma with a gene  mutation, accompanied by regional and pulmonary metastases on initial  presentation, and later on with hepatic and bone involvement, is presented. The  patient underwent wide local excision but was unresponsive to dacarbazine.  Targeted therapy with vemurafenib had shown clinical improvement for a 5-month  duration until he showed signs of disease progression. Just after the shift of  adjuvant therapy to ipilimumab, he was diagnosed with multiple cerebral  metastases that eventually led to his demise 6 months after initiation of  vemurafenib, having had a 12-month survival period from the time of initial  melanoma diagnosis.CI  - 2016 BMJ Publishing Group Ltd.
CANIT0000537	26880821	Case report	Perianal nodular melanoma	Nodular melanoma	EFO:0008515	Skin	CTLA-4 (P16410); 	CTLA-4; 	Dacarbazine followed by ipilimumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Ipilimumab (DB06186); dacarbazine (DB00851); ipilimumab (DB06186); 	Cell lines	N/A	Case	The patient underwent wide local excision but was unresponsive to dacarbazine. Targeted therapy with vemurafenib had shown clinical improvement for a 5-month duration until he showed signs of disease progression. Just after the shift of adjuvant therapy to ipilimumab, he was diagnosed with multiple cerebral metastases that eventually led to his demise 6 months after initiation of vemurafenib, having had a 12-month survival period from the time of initial melanoma diagnosis.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2016 Feb 15	 Perianal melanoma with a BRAF gene mutation in a young Portuguese Roma native.	 BMJ Case Rep	 A case of a young man diagnosed with perianal nodular melanoma with a gene  mutation, accompanied by regional and pulmonary metastases on initial  presentation, and later on with hepatic and bone involvement, is presented. The  patient underwent wide local excision but was unresponsive to dacarbazine.  Targeted therapy with vemurafenib had shown clinical improvement for a 5-month  duration until he showed signs of disease progression. Just after the shift of  adjuvant therapy to ipilimumab, he was diagnosed with multiple cerebral  metastases that eventually led to his demise 6 months after initiation of  vemurafenib, having had a 12-month survival period from the time of initial  melanoma diagnosis.CI  - 2016 BMJ Publishing Group Ltd.
CANIT0000538	26883763	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Late-onset panhypopituitarism	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Late-onset panhypopituitarism in a 72-year-old male patient treated with  ipilimumab for metastatic melanoma: a case report.	 J Endocrinol Invest	Unable to provide
CANIT0000539	26926680	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus TriMixDC-MEL	N/A	Immune checkpoint therapy plus Tumor vaccine 	TriMixDC-MEL (NCIT:C2594); ipilimumab (DB06186); 	39	N/A	A phase II clinical trial	The combination of TriMixDC-MEL and ipilimumab is tolerable and results in an encouraging rate of highly durable tumor responses in patients with pretreated advanced melanoma.	The most common treatment-related adverse events (all grades) consisted of local DC injection site skin reactions (100%), transient post-DC infusion chills (38%) and flu-like symptoms (84%), dermatitis (64%), hepatitis (13%), hypophysitis (15%), and diarrhea/colitis (15%). Grade 3 or 4 immune-related adverse events occurred in 36% of patients. There was no grade 5 adverse event.	N/A	N/A	N/A	N/A	N/A	 2016 Apr 20	 Phase II Study of Autologous Monocyte-Derived mRNA Electroporated Dendritic Cells  (TriMixDC-MEL) Plus Ipilimumab in Patients With Pretreated Advanced Melanoma.	 J Clin Oncol	 PURPOSE: Autologous monocyte-derived dendritic cells (DCs) electroporated with  synthetic mRNA (TriMixDC-MEL) are immunogenic and have antitumor activity as a  monotherapy in patients with pretreated advanced melanoma. Ipilimumab, an  immunoglobulin G1 monoclonal antibody directed against the cytotoxic  T-lymphocyte-associated protein 4 receptor that counteracts physiologic  suppression of T-cell function, improves the overall survival of patients with  advanced melanoma. This phase II study investigated the combination of  TriMixDC-MEL and ipilimumab in patients with pretreated advanced melanoma.  PATIENTS AND METHODS: Thirty-nine patients were treated with TriMixDC-MEL (4 x  10(6) cells administered intradermally and 20 x 10(6) cells administered  intravenously) plus ipilimumab (10 mg/kg every 3 weeks for a total of four  administrations, followed by maintenance therapy every 12 weeks in patients who  remained progression free). Six-month disease control rate according to the  immune-related response criteria served as the primary end point. RESULTS: The  6-month disease control rate was 51% (95% CI, 36% to 67%), and the overall tumor   response rate was 38% (including eight complete and seven partial responses).  Seven complete responses and one partial tumor response are ongoing after a  median follow-up time of 36 months (range, 22 to 43 months). The most common  treatment-related adverse events (all grades) consisted of local DC injection  site skin reactions (100%), transient post-DC infusion chills (38%) and flu-like   symptoms (84%), dermatitis (64%), hepatitis (13%), hypophysitis (15%), and  diarrhea/colitis (15%). Grade 3 or 4 immune-related adverse events occurred in  36% of patients. There was no grade 5 adverse event. CONCLUSION: The combination   of TriMixDC-MEL and ipilimumab is tolerable and results in an encouraging rate of  highly durable tumor responses in patients with pretreated advanced melanoma.CI  - (c) 2016 by American Society of Clinical Oncology.
CANIT0000540	26928461	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	N/A	N/A	Autoimmune bullous skin disorders	N/A	N/A	N/A	N/A	N/A	 2016 May	 Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting  PD-1 and PD-L1.	 Cancer Immunol Res	 Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as  cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1  (PD-1) may confer durable disease control in several malignancies. In some  patients, immune checkpoint mAbs cause cutaneous immune-related adverse events.  Although the most commonly reported cutaneous toxicities are mild, a subset may  persist despite therapy and can lead to severe or life-threatening toxicity.  Autoimmune blistering disorders are not commonly associated with immune  checkpoint mAb therapy. We report a case series of patients who developed bullous  pemphigoid (BP), an autoimmune process classically attributed to pathologic  autoantibody formation and complement deposition. Three patients were identified.  Two patients developed BP while receiving the anti-PD-1 mAb nivolumab, and one  while receiving the anti-PD-L1 mAb durvalumab. The clinicopathologic features of   each patient and rash, and corresponding radiologic findings at the development  of the rash and after its treatment, are described. Patients receiving an  anti-PD-1/PD-L1 mAb may develop immune-related BP. This may be related to both  T-cell- and B-cell-mediated responses. Referral to a dermatologist for accurate  diagnosis and management is recommended. Cancer Immunol Res; 4(5); 383-9. (c)2016  AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000541	26928461	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	3	N/A	N/A	N/A	Autoimmune bullous skin disorders	N/A	N/A	N/A	N/A	N/A	 2016 May	 Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting  PD-1 and PD-L1.	 Cancer Immunol Res	 Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as  cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1  (PD-1) may confer durable disease control in several malignancies. In some  patients, immune checkpoint mAbs cause cutaneous immune-related adverse events.  Although the most commonly reported cutaneous toxicities are mild, a subset may  persist despite therapy and can lead to severe or life-threatening toxicity.  Autoimmune blistering disorders are not commonly associated with immune  checkpoint mAb therapy. We report a case series of patients who developed bullous  pemphigoid (BP), an autoimmune process classically attributed to pathologic  autoantibody formation and complement deposition. Three patients were identified.  Two patients developed BP while receiving the anti-PD-1 mAb nivolumab, and one  while receiving the anti-PD-L1 mAb durvalumab. The clinicopathologic features of   each patient and rash, and corresponding radiologic findings at the development  of the rash and after its treatment, are described. Patients receiving an  anti-PD-1/PD-L1 mAb may develop immune-related BP. This may be related to both  T-cell- and B-cell-mediated responses. Referral to a dermatologist for accurate  diagnosis and management is recommended. Cancer Immunol Res; 4(5); 383-9. (c)2016  AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000542	26928461	Clinical research	Metastatic melanoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	N/A	N/A	Autoimmune bullous skin disorders	N/A	N/A	N/A	N/A	N/A	 2016 May	 Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting  PD-1 and PD-L1.	 Cancer Immunol Res	 Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as  cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1  (PD-1) may confer durable disease control in several malignancies. In some  patients, immune checkpoint mAbs cause cutaneous immune-related adverse events.  Although the most commonly reported cutaneous toxicities are mild, a subset may  persist despite therapy and can lead to severe or life-threatening toxicity.  Autoimmune blistering disorders are not commonly associated with immune  checkpoint mAb therapy. We report a case series of patients who developed bullous  pemphigoid (BP), an autoimmune process classically attributed to pathologic  autoantibody formation and complement deposition. Three patients were identified.  Two patients developed BP while receiving the anti-PD-1 mAb nivolumab, and one  while receiving the anti-PD-L1 mAb durvalumab. The clinicopathologic features of   each patient and rash, and corresponding radiologic findings at the development  of the rash and after its treatment, are described. Patients receiving an  anti-PD-1/PD-L1 mAb may develop immune-related BP. This may be related to both  T-cell- and B-cell-mediated responses. Referral to a dermatologist for accurate  diagnosis and management is recommended. Cancer Immunol Res; 4(5); 383-9. (c)2016  AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000543	26928461	Clinical research	Metastatic melanoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	3	N/A	N/A	N/A	Autoimmune bullous skin disorders	N/A	N/A	N/A	N/A	N/A	 2016 May	 Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting  PD-1 and PD-L1.	 Cancer Immunol Res	 Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as  cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1  (PD-1) may confer durable disease control in several malignancies. In some  patients, immune checkpoint mAbs cause cutaneous immune-related adverse events.  Although the most commonly reported cutaneous toxicities are mild, a subset may  persist despite therapy and can lead to severe or life-threatening toxicity.  Autoimmune blistering disorders are not commonly associated with immune  checkpoint mAb therapy. We report a case series of patients who developed bullous  pemphigoid (BP), an autoimmune process classically attributed to pathologic  autoantibody formation and complement deposition. Three patients were identified.  Two patients developed BP while receiving the anti-PD-1 mAb nivolumab, and one  while receiving the anti-PD-L1 mAb durvalumab. The clinicopathologic features of   each patient and rash, and corresponding radiologic findings at the development  of the rash and after its treatment, are described. Patients receiving an  anti-PD-1/PD-L1 mAb may develop immune-related BP. This may be related to both  T-cell- and B-cell-mediated responses. Referral to a dermatologist for accurate  diagnosis and management is recommended. Cancer Immunol Res; 4(5); 383-9. (c)2016  AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000544	26940583	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Severe hyponatremia and immune nephritis	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Severe Hyponatremia and Immune Nephritis Following an Initial Infusion of  Nivolumab.	 Target Oncol	 Anti-programmed cell death-1 (PD-1) antibodies pembrolizumab and nivolumab are  becoming increasingly important in the treatment of melanoma and non-small cell  lung cancer. These agents are known to induce many immune-related adverse events,  but rapid-onset nephritis and immune-related hyponatremia have not been described  to date. We describe the case of an adult patient who developed severe  hyponatremia and rapid-onset nephritis following the first infusion of nivolumab   for metastatic melanoma.
CANIT0000545	26946531	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Late-onset pericardial tamponade, bilateral pleural effusions and recurrent immune monoarthritis	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Late-onset pericardial tamponade, bilateral pleural effusions and recurrent  immune monoarthritis induced by ipilimumab use for metastatic melanoma.	 J Oncol Pharm Pract	 While an important agent in the contemporary anti-melanoma armamentarium,  ipilimumab is associated with serious immune reactions including late  immune-mediated side effects. Recently, a case of late-onset acute pericarditis  with tamponade was reported at 12 weeks after the last dose of ipilimumab. While   polyarthralgia rheumatica has been previously documented with ipilimumab, we were  not able to find any reports of recurrent monoarthritis with the use of this  agent. Therefore, we present herein a unique case featuring a patient with  late-onset autoimmune pleuropericarditis leading to cardiac tamponade at 24 weeks  post-ipilimumab and recurrent late immune knee arthritis at 8 and 32 weeks,  respectively. Furthermore, this late-onset toxicity seen with ipilimumab might  also be expected with the PD1 inhibitors currently in clinical use. Timely  diagnosis and prompt steroid use are crucial to ensure favorable clinical  outcomes in these patients.
CANIT0000546	26951310	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	655	N/A	An international, multicenter, open-label, phase Ib study	Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 May 1	 Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With  Advanced Melanoma Treated With Pembrolizumab.	 J Clin Oncol	 PURPOSE: We evaluated atypical response patterns and the relationship between  overall survival and best overall response measured per immune-related response  criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1  (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in  the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827).  PATIENTS AND METHODS: Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks  or every 3 weeks. Atypical responses were identified by using centrally assessed   irRC data in patients with >/= 28 weeks of imaging. Pseudoprogression was defined  as >/= 25% increase in tumor burden at week 12 (early) or any assessment after  week 12 (delayed) that was not confirmed as progressive disease at next  assessment. Response was assessed centrally per irRC and RECIST v1.1. RESULTS: Of  the 655 patients with melanoma enrolled, 327 had >/= 28 weeks of imaging  follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%]  with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of  the 592 patients who survived >/= 12 weeks, 84 (14%) experienced progressive  disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall  survival rates were 77.6% in patients with nonprogressive disease per both  criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1  but nonprogressive disease per irRC (n = 84), and 17.3% in patients with  progressive disease per both criteria (n = 177). CONCLUSION: Atypical responses  were observed in patients with melanoma treated with pembrolizumab. Based on  survival analysis, conventional RECIST might underestimate the benefit of  pembrolizumab in approximately 15% of patients; modified criteria that permit  treatment beyond initial progression per RECIST v1.1 might prevent premature  cessation of treatment.CI  - (c) 2016 by American Society of Clinical Oncology.
CANIT0000547	26952546	Clinical research	Locally advanced and metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	315	N/A	A multicentre, single-arm, two-cohort, phase II trial	Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response.	Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumour-infiltrating immune cells	Gene expression signature on/in immune cell	 2016 May 7	 Atezolizumab in patients with locally advanced and metastatic urothelial  carcinoma who have progressed following treatment with platinum-based  chemotherapy: a single-arm, multicentre, phase 2 trial.	 Lancet	 BACKGROUND: Patients with metastatic urothelial carcinoma have few treatment  options after failure of platinum-based chemotherapy. In this trial, we assessed   treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal  antibody that binds selectively to programmed death ligand 1 (PD-L1), in this  patient population. METHODS: For this multicentre, single-arm, two-cohort, phase   2 trial, patients (aged >/=18 years) with inoperable locally advanced or  metastatic urothelial carcinoma whose disease had progressed after previous  platinum-based chemotherapy were enrolled from 70 major academic medical centres   and community oncology practices in Europe and North America. Key inclusion  criteria for enrolment were Eastern Cooperative Oncology Group performance status  of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid  Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function,  and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded   tumour specimens with sufficient viable tumour content were needed from all  patients before enrolment. Patients received treatment with intravenous  atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on  tumour-infiltrating immune cells (ICs) was assessed prospectively by  immunohistochemistry. The co-primary endpoints were the independent review  facility-assessed objective response rate according to RECIST v1.1 and the  investigator-assessed objective response rate according to immune-modified  RECIST, analysed by intention to treat. A hierarchical testing procedure was used  to assess whether the objective response rate was significantly higher than the  historical control rate of 10% at an alpha level of 0.05. This study is  registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between May 13,  2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled  into the study. Of these patients, 310 received atezolizumab treatment (five  enrolled patients later did not meet eligibility criteria and were not dosed with  study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in  the tumour microenvironment was defined by the percentage of PD-L1-positive  immune cells: IC0 (<1%), IC1 (>/=1% but <5%), and IC2/3 (>/=5%). The primary  analysis (data cutoff May 5, 2015) showed that compared with a historical control  overall response rate of 10%, treatment with atezolizumab resulted in a  significantly improved RECIST v1.1 objective response rate for each prespecified   immune cell group (IC2/3: 27% [95% CI 19-37], p<0.0001; IC1/2/3: 18% [13-24],  p=0.0004) and in all patients (15% [11-20], p=0.0058). With longer follow-up  (data cutoff Sept 14, 2015), by independent review, objective response rates were  26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15%   (11-19) overall in all 310 patients. With a median follow-up of 11.7 months (95%   CI 11.4-12.2), ongoing responses were recorded in 38 (84%) of 45 responders.  Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation   load to be independently predictive for response to atezolizumab. Grade 3-4  treatment-related adverse events, of which fatigue was the most common (five  patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4  immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with   pneumonitis, increased aspartate aminotransferase, increased alanine  aminotransferase, rash, and dyspnoea being the most common. No treatment-related   deaths occurred during the study. INTERPRETATION: Atezolizumab showed durable  activity and good tolerability in this patient population. Increased levels of  PD-L1 expression on immune cells were associated with increased response. This  report is the first to show the association of TCGA subtypes with response to  immune checkpoint inhibition and to show the importance of mutation load as a  biomarker of response to this class of agents in advanced urothelial carcinoma.  FUNDING: F Hoffmann-La Roche Ltd.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000548	26952546	Clinical research	Locally advanced and metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	315	N/A	A multicentre, single-arm, two-cohort, phase III trial	Atezolizumab showed durable activity and good tolerability in this patient population. Response to atezolizumab occurred in all TCGA subtypes but was significantly higher in the luminal cluster II subtype than in other subtypes.	Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study.	N/A	N/A	TCGA subtypes (NCIT:C98269); 	TCGA subtypes	Disease status	 2016 May 7	 Atezolizumab in patients with locally advanced and metastatic urothelial  carcinoma who have progressed following treatment with platinum-based  chemotherapy: a single-arm, multicentre, phase 2 trial.	 Lancet	 BACKGROUND: Patients with metastatic urothelial carcinoma have few treatment  options after failure of platinum-based chemotherapy. In this trial, we assessed   treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal  antibody that binds selectively to programmed death ligand 1 (PD-L1), in this  patient population. METHODS: For this multicentre, single-arm, two-cohort, phase   2 trial, patients (aged >/=18 years) with inoperable locally advanced or  metastatic urothelial carcinoma whose disease had progressed after previous  platinum-based chemotherapy were enrolled from 70 major academic medical centres   and community oncology practices in Europe and North America. Key inclusion  criteria for enrolment were Eastern Cooperative Oncology Group performance status  of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid  Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function,  and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded   tumour specimens with sufficient viable tumour content were needed from all  patients before enrolment. Patients received treatment with intravenous  atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on  tumour-infiltrating immune cells (ICs) was assessed prospectively by  immunohistochemistry. The co-primary endpoints were the independent review  facility-assessed objective response rate according to RECIST v1.1 and the  investigator-assessed objective response rate according to immune-modified  RECIST, analysed by intention to treat. A hierarchical testing procedure was used  to assess whether the objective response rate was significantly higher than the  historical control rate of 10% at an alpha level of 0.05. This study is  registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between May 13,  2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled  into the study. Of these patients, 310 received atezolizumab treatment (five  enrolled patients later did not meet eligibility criteria and were not dosed with  study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in  the tumour microenvironment was defined by the percentage of PD-L1-positive  immune cells: IC0 (<1%), IC1 (>/=1% but <5%), and IC2/3 (>/=5%). The primary  analysis (data cutoff May 5, 2015) showed that compared with a historical control  overall response rate of 10%, treatment with atezolizumab resulted in a  significantly improved RECIST v1.1 objective response rate for each prespecified   immune cell group (IC2/3: 27% [95% CI 19-37], p<0.0001; IC1/2/3: 18% [13-24],  p=0.0004) and in all patients (15% [11-20], p=0.0058). With longer follow-up  (data cutoff Sept 14, 2015), by independent review, objective response rates were  26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15%   (11-19) overall in all 310 patients. With a median follow-up of 11.7 months (95%   CI 11.4-12.2), ongoing responses were recorded in 38 (84%) of 45 responders.  Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation   load to be independently predictive for response to atezolizumab. Grade 3-4  treatment-related adverse events, of which fatigue was the most common (five  patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4  immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with   pneumonitis, increased aspartate aminotransferase, increased alanine  aminotransferase, rash, and dyspnoea being the most common. No treatment-related   deaths occurred during the study. INTERPRETATION: Atezolizumab showed durable  activity and good tolerability in this patient population. Increased levels of  PD-L1 expression on immune cells were associated with increased response. This  report is the first to show the association of TCGA subtypes with response to  immune checkpoint inhibition and to show the importance of mutation load as a  biomarker of response to this class of agents in advanced urothelial carcinoma.  FUNDING: F Hoffmann-La Roche Ltd.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000549	26952546	Clinical research	Locally advanced and metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	315	N/A	A multicentre, single-arm, two-cohort, phase IV trial	Atezolizumab showed durable activity and good tolerability in this patient population. The median mutation load was significantly increased in responders compared with non-responders. 	Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2016 May 7	 Atezolizumab in patients with locally advanced and metastatic urothelial  carcinoma who have progressed following treatment with platinum-based  chemotherapy: a single-arm, multicentre, phase 2 trial.	 Lancet	 BACKGROUND: Patients with metastatic urothelial carcinoma have few treatment  options after failure of platinum-based chemotherapy. In this trial, we assessed   treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal  antibody that binds selectively to programmed death ligand 1 (PD-L1), in this  patient population. METHODS: For this multicentre, single-arm, two-cohort, phase   2 trial, patients (aged >/=18 years) with inoperable locally advanced or  metastatic urothelial carcinoma whose disease had progressed after previous  platinum-based chemotherapy were enrolled from 70 major academic medical centres   and community oncology practices in Europe and North America. Key inclusion  criteria for enrolment were Eastern Cooperative Oncology Group performance status  of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid  Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function,  and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded   tumour specimens with sufficient viable tumour content were needed from all  patients before enrolment. Patients received treatment with intravenous  atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on  tumour-infiltrating immune cells (ICs) was assessed prospectively by  immunohistochemistry. The co-primary endpoints were the independent review  facility-assessed objective response rate according to RECIST v1.1 and the  investigator-assessed objective response rate according to immune-modified  RECIST, analysed by intention to treat. A hierarchical testing procedure was used  to assess whether the objective response rate was significantly higher than the  historical control rate of 10% at an alpha level of 0.05. This study is  registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between May 13,  2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled  into the study. Of these patients, 310 received atezolizumab treatment (five  enrolled patients later did not meet eligibility criteria and were not dosed with  study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in  the tumour microenvironment was defined by the percentage of PD-L1-positive  immune cells: IC0 (<1%), IC1 (>/=1% but <5%), and IC2/3 (>/=5%). The primary  analysis (data cutoff May 5, 2015) showed that compared with a historical control  overall response rate of 10%, treatment with atezolizumab resulted in a  significantly improved RECIST v1.1 objective response rate for each prespecified   immune cell group (IC2/3: 27% [95% CI 19-37], p<0.0001; IC1/2/3: 18% [13-24],  p=0.0004) and in all patients (15% [11-20], p=0.0058). With longer follow-up  (data cutoff Sept 14, 2015), by independent review, objective response rates were  26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15%   (11-19) overall in all 310 patients. With a median follow-up of 11.7 months (95%   CI 11.4-12.2), ongoing responses were recorded in 38 (84%) of 45 responders.  Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation   load to be independently predictive for response to atezolizumab. Grade 3-4  treatment-related adverse events, of which fatigue was the most common (five  patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4  immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with   pneumonitis, increased aspartate aminotransferase, increased alanine  aminotransferase, rash, and dyspnoea being the most common. No treatment-related   deaths occurred during the study. INTERPRETATION: Atezolizumab showed durable  activity and good tolerability in this patient population. Increased levels of  PD-L1 expression on immune cells were associated with increased response. This  report is the first to show the association of TCGA subtypes with response to  immune checkpoint inhibition and to show the importance of mutation load as a  biomarker of response to this class of agents in advanced urothelial carcinoma.  FUNDING: F Hoffmann-La Roche Ltd.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000550	26970723	Clinical research	Previously treated non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Docetaxel	Immune checkpoint therapy	Atezolizumab (DB11595); docetaxel (DB01248); 	144	143	A multicentre, open-label, phase II randomised controlled	Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.	11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2016 Apr 30	 Atezolizumab versus docetaxel for patients with previously treated non-small-cell  lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled  trial.	 Lancet	 BACKGROUND: Outcomes are poor for patients with previously treated, advanced or  metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1  (PD-L1) antibody atezolizumab is clinically active against cancer, including  NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating  immune cells, or both. We assessed efficacy and safety of atezolizumab versus  docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on  tumour cells and tumour-infiltrating immune cells and in the intention-to-treat  population. METHODS: In this open-label, phase 2 randomised controlled trial,  patients with NSCLC who progressed on post-platinum chemotherapy were recruited  in 61 academic medical centres and community oncology practices across 13  countries in Europe and North America. Key inclusion criteria were Eastern  Cooperative Oncology Group performance status 0 or 1, measurable disease by  Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and  adequate haematological and end-organ function. Patients were stratified by PD-L1  tumour-infiltrating immune cell status, histology, and previous lines of therapy,  and randomly assigned (1:1) by permuted block randomisation (with a block size of  four) using an interactive voice or web system to receive intravenous  atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1  expression was scored by immunohistochemistry in tumour cells (as percentage of  PD-L1-expressing tumour cells TC3>/=50%, TC2>/=5% and <50%, TC1>/=1% and <5%, and  TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area:  IC3>/=10%, IC2>/=5% and <10%, IC1>/=1% and <5%, and IC0<1%). The primary endpoint  was overall survival in the intention-to-treat population and PD-L1 subgroups at   173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed  safety in all patients who received at least one dose of study drug. This study  is registered with ClinicalTrials.gov, number NCT01903993. FINDINGS: Patients  were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly  allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients  received at least one dose of atezolizumab and 135 received docetaxel. Overall  survival in the intention-to-treat population was 12.6 months (95% CI 9.7-16.4)  for atezolizumab versus 9.7 months (8.6-12.0) for docetaxel (hazard ratio [HR]  0.73 [95% CI 0.53-0.99]; p=0.04). Increasing improvement in overall survival was   associated with increasing PD-L1 expression (TC3 or IC3 HR 0.49 [0.22-1.07;  p=0.068], TC2/3 or IC2/3 HR 0.54 [0.33-0.89; p=0.014], TC1/2/3 or IC1/2/3 HR 0.59  [0.40-0.85; p=0.005], TC0 and IC0 HR 1.04 [0.62-1.75; p=0.871]). In our  exploratory analysis, patients with pre-existing immunity, defined by high  T-effector-interferon-gamma-associated gene expression, had improved overall  survival with atezolizumab. 11 (8%) patients in the atezolizumab group  discontinued because of adverse events versus 30 (22%) patients in the docetaxel   group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in  the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%)  patient in the atezolizumab group versus three (2%) patients in the docetaxel  group died from a treatment-related adverse event. INTERPRETATION: Atezolizumab  significantly improved survival compared with docetaxel in patients with  previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry   expression on tumour cells and tumour-infiltrating immune cells, suggesting that   PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well  tolerated, with a safety profile distinct from chemotherapy. FUNDING: F  Hoffmann-La Roche/Genentech Inc.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000551	26970723	Clinical research	Previously treated non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Docetaxel	Immune checkpoint therapy	Atezolizumab (DB11595); docetaxel (DB01248); 	144	143	A multicentre, open-label, phase II randomised controlled	Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.	11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumour-infiltrating immune cells	Gene expression signature on/in immune cell	 2016 Apr 30	 Atezolizumab versus docetaxel for patients with previously treated non-small-cell  lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled  trial.	 Lancet	 BACKGROUND: Outcomes are poor for patients with previously treated, advanced or  metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1  (PD-L1) antibody atezolizumab is clinically active against cancer, including  NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating  immune cells, or both. We assessed efficacy and safety of atezolizumab versus  docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on  tumour cells and tumour-infiltrating immune cells and in the intention-to-treat  population. METHODS: In this open-label, phase 2 randomised controlled trial,  patients with NSCLC who progressed on post-platinum chemotherapy were recruited  in 61 academic medical centres and community oncology practices across 13  countries in Europe and North America. Key inclusion criteria were Eastern  Cooperative Oncology Group performance status 0 or 1, measurable disease by  Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and  adequate haematological and end-organ function. Patients were stratified by PD-L1  tumour-infiltrating immune cell status, histology, and previous lines of therapy,  and randomly assigned (1:1) by permuted block randomisation (with a block size of  four) using an interactive voice or web system to receive intravenous  atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1  expression was scored by immunohistochemistry in tumour cells (as percentage of  PD-L1-expressing tumour cells TC3>/=50%, TC2>/=5% and <50%, TC1>/=1% and <5%, and  TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area:  IC3>/=10%, IC2>/=5% and <10%, IC1>/=1% and <5%, and IC0<1%). The primary endpoint  was overall survival in the intention-to-treat population and PD-L1 subgroups at   173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed  safety in all patients who received at least one dose of study drug. This study  is registered with ClinicalTrials.gov, number NCT01903993. FINDINGS: Patients  were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly  allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients  received at least one dose of atezolizumab and 135 received docetaxel. Overall  survival in the intention-to-treat population was 12.6 months (95% CI 9.7-16.4)  for atezolizumab versus 9.7 months (8.6-12.0) for docetaxel (hazard ratio [HR]  0.73 [95% CI 0.53-0.99]; p=0.04). Increasing improvement in overall survival was   associated with increasing PD-L1 expression (TC3 or IC3 HR 0.49 [0.22-1.07;  p=0.068], TC2/3 or IC2/3 HR 0.54 [0.33-0.89; p=0.014], TC1/2/3 or IC1/2/3 HR 0.59  [0.40-0.85; p=0.005], TC0 and IC0 HR 1.04 [0.62-1.75; p=0.871]). In our  exploratory analysis, patients with pre-existing immunity, defined by high  T-effector-interferon-gamma-associated gene expression, had improved overall  survival with atezolizumab. 11 (8%) patients in the atezolizumab group  discontinued because of adverse events versus 30 (22%) patients in the docetaxel   group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in  the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%)  patient in the atezolizumab group versus three (2%) patients in the docetaxel  group died from a treatment-related adverse event. INTERPRETATION: Atezolizumab  significantly improved survival compared with docetaxel in patients with  previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry   expression on tumour cells and tumour-infiltrating immune cells, suggesting that   PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well  tolerated, with a safety profile distinct from chemotherapy. FUNDING: F  Hoffmann-La Roche/Genentech Inc.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000552	26982623	Basic research	10 human lymphoma cell lines, 37 human cancer cell lines from different origins, and 2 normal cell lines	Cancer	EFO:0000311	Other	UNREGULATED NECROSIS (N/A); 	UNREGULATED NECROSIS; 	LTX-315	N/A	Tumor vaccine	LTX-315 (DB12748); 	Cell lines	N/A	Basic research	Collectively these data indicated that this peptide has potential to be developed as a new anticancer agent for intratumoral administration and is currently being evaluated in a phase I/IIa study.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2016 Apr 14	 Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class  Oncolytic Peptide.	 J Med Chem	 Oncolytic immunotherapies represent a new promising strategy in the treatment of   cancer. In our efforts to develop oncolytic peptides, we identified a series of  chemically modified 9-mer cationic peptides that were highly effective against  both drug-resistant and drug-sensitive cancer cells and with lower toxicity  toward normal cells. Among these peptides, LTX-315 displayed superior anticancer   activity and was selected as a lead candidate. This peptide showed relative high   plasma protein binding abilities and a human plasma half-life of 160 min,  resulting in formation of nontoxic metabolites. In addition, the lead candidate  demonstrated relatively low ability to inhibit CYP450 enzymes. Collectively these  data indicated that this peptide has potential to be developed as a new  anticancer agent for intratumoral administration and is currently being evaluated  in a phase I/IIa study.
CANIT0000553	26984745	Clinical research	Pediatric recurrent low-grade gliomas	Glioma	EFO:0005543	Brain	TLR3 (O15455); glioma-associated antigen epitopes (N/A)	TLR3; glioma-associated antigen epitopes	Vaccination with glioma-associated antigen peptides plus poly-ICLC	N/A	Tumor vaccine	Poly-ICLC (NCIT:C1198); glioma-associated antigen peptides vaccine (NCIT:C82661); 	14	N/A	N/A	GAA peptide  vaccination in children with recurrent LGGs is generally well tolerated, with  preliminary evidence of immunological and clinical activity.	Other than grade 3 urticaria in one child, no regimen-limiting toxicity was encountered. 	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Immune responses and outcome after vaccination with glioma-associated antigen  peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade  gliomas.	 Neuro Oncol	 BACKGROUND: Low-grade gliomas (LGGs) are the most common brain tumors of  childhood. Although surgical resection is curative for well-circumscribed  superficial lesions, tumors that are infiltrative or arise from deep structures  are therapeutically challenging, and new treatment approaches are needed. Having   identified a panel of glioma-associated antigens (GAAs) overexpressed in these  tumors, we initiated a pilot trial of vaccinations with peptides for GAA epitopes  in human leukocyte antigen-A2+ children with recurrent LGG that had progressed  after at least 2 prior regimens. METHODS: Peptide epitopes for 3 GAAs (EphA2,  IL-13Ralpha2, and survivin) were emulsified in Montanide-ISA-51 and administered   subcutaneously adjacent to intramuscular injections of polyinosinic-polycytidylic  acid stabilized by lysine and carboxymethylcellulose every 3 weeks for 8 courses,  followed by booster vaccines every 6 weeks. Primary endpoints were safety and  T-lymphocyte responses against GAA epitopes. Treatment response was evaluated  clinically and by MRI. RESULTS: Fourteen children were enrolled. Other than grade  3 urticaria in one child, no regimen-limiting toxicity was encountered.  Vaccination induced immunoreactivity to at least one vaccine-targeted GAA in all   12 evaluable patients: to IL-13Ralpha2 in 3, EphA2 in 11, and survivin in 3. One   child with a metastatic LGG had asymptomatic pseudoprogression noted 6 weeks  after starting vaccination, followed by dramatic disease regression with >75%  shrinkage of primary tumor and regression of metastatic disease, persisting >57  months. Three other children had sustained partial responses, lasting >10, >31,  and >45 months, and one had a transient response. CONCLUSIONS: GAA peptide  vaccination in children with recurrent LGGs is generally well tolerated, with  preliminary evidence of immunological and clinical activity.CI  - (c) The Author(s) 2016. Published by Oxford University Press on behalf of the  Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail:   journals.permissions@oup.com.
CANIT0000554	26988410	Case report	Stage IV squamous nonCsmall cell lung cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Allograft rejection	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Use of the PD-1 Pathway Inhibitor Nivolumab in a Renal Transplant Patient With  Malignancy.	 Am J Transplant	Unable to provide
CANIT0000555	26990271	Case report	Stage IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Collagenous colitis	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Anti-PD1-induced collagenous colitis in a melanoma patient.	 Melanoma Res	 Targeted immunotherapy has markedly improved the survival of melanoma patients.  We report the case of a melanoma patient who developed a collagenous colitis  under an anti-PD1 regimen. A 68-year-old woman was treated for a stage IV  melanoma. An anti-PD1, pembrolizumab, was introduced after the failure of a  first-line therapy with an anti-CTLA4. At cycle 14, pembrolizumab was interrupted  because of grade 3 diarrhea. Histologic analysis of colon mucosa showed a  thickened apical subepithelial collagen layer with irregular collagen deposition   of more than 25 microm thickness. Budesonide 9 mg/day and cholestyramin 8 g/day  were then introduced, leading to a decrease in the number of stools to grade 2.  Because of the prognosis of the disease, the efficacy of pembrolizumab in this  patient and the lack of other efficient treatments, pembrolizumab was restarted,   with no worsening of the diarrhea after a follow-up of 8 weeks. In the era of  immunotherapy, a new type of drug-induced colitis has emerged because of  monoclonal antibodies targeting immune checkpoints such as CTLA-4 and PD1.  Gastrointestinal tract immune-mediated adverse effects are now well described  with ipilimumab. To the best of our knowledge, this is the first report of a  collagenous colitis in a patient treated with pembrolizumab, thus suggesting a  new mechanism of toxicity. Classically, collagenous colitis first-line treatment   is based on discontinuation of the suspected treatment. However, there may be a  strong benefit to maintaining an anti-PD1 regimen in our patients. In this case,   symptomatic management associated with budesonide and cholestyramin enabled  continuation of pembrolizumab.
CANIT0000556	27000274	Clinical research	NSCLC 5 , Melanoma 3, Breast cancer 1, Extramammary Pagets disease 1 	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	A phase I clinical trial 	Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated  in Japanese patients with advanced solid tumors and showed encouraging anti-tumor  activity against melanoma and NSCLC.	No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in  Japanese patients with advanced solid tumors.	 Invest New Drugs	 Background This phase I study evaluated the safety and tolerability,  pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of   pembrolizumab in Japanese patients with advanced solid tumors. Methods Following   an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an  intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W)  until disease progression or unacceptable toxicity. Adverse events (AEs) were  assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1  and immune-related response criteria (irRC). Full pharmacokinetic sampling was  performed during cycle 1. Results Three patients received pembrolizumab at 2.0  mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during  cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1   or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and  aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2  each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised  grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis  (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety  and pharmacokinetic profiles of Japanese patients were similar to those  previously reported for Caucasian patients. A partial tumor response was observed  in one patient with non-small-cell lung cancer (NSCLC) and in one patient with  melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated  in Japanese patients with advanced solid tumors and showed encouraging anti-tumor  activity against melanoma and NSCLC.
CANIT0000557	27000274	Clinical research	NSCLC 5 , Melanoma 3, Breast cancer 1, Extramammary Pagets disease 1 	Extramammary pagets disease	EFO:1000249	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	A phase I clinical trial 	Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated  in Japanese patients with advanced solid tumors and showed encouraging anti-tumor  activity against melanoma and NSCLC.	No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in  Japanese patients with advanced solid tumors.	 Invest New Drugs	 Background This phase I study evaluated the safety and tolerability,  pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of   pembrolizumab in Japanese patients with advanced solid tumors. Methods Following   an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an  intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W)  until disease progression or unacceptable toxicity. Adverse events (AEs) were  assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1  and immune-related response criteria (irRC). Full pharmacokinetic sampling was  performed during cycle 1. Results Three patients received pembrolizumab at 2.0  mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during  cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1   or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and  aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2  each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised  grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis  (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety  and pharmacokinetic profiles of Japanese patients were similar to those  previously reported for Caucasian patients. A partial tumor response was observed  in one patient with non-small-cell lung cancer (NSCLC) and in one patient with  melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated  in Japanese patients with advanced solid tumors and showed encouraging anti-tumor  activity against melanoma and NSCLC.
CANIT0000558	27000274	Clinical research	NSCLC 5 , Melanoma 3, Breast cancer 1, Extramammary Pagets disease 1 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	A phase I clinical trial 	Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated  in Japanese patients with advanced solid tumors and showed encouraging anti-tumor  activity against melanoma and NSCLC.	No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in  Japanese patients with advanced solid tumors.	 Invest New Drugs	 Background This phase I study evaluated the safety and tolerability,  pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of   pembrolizumab in Japanese patients with advanced solid tumors. Methods Following   an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an  intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W)  until disease progression or unacceptable toxicity. Adverse events (AEs) were  assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1  and immune-related response criteria (irRC). Full pharmacokinetic sampling was  performed during cycle 1. Results Three patients received pembrolizumab at 2.0  mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during  cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1   or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and  aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2  each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised  grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis  (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety  and pharmacokinetic profiles of Japanese patients were similar to those  previously reported for Caucasian patients. A partial tumor response was observed  in one patient with non-small-cell lung cancer (NSCLC) and in one patient with  melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated  in Japanese patients with advanced solid tumors and showed encouraging anti-tumor  activity against melanoma and NSCLC.
CANIT0000559	27000274	Clinical research	NSCLC 5 , Melanoma 3, Breast cancer 1, Extramammary Pagets disease 1 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	A phase I clinical trial 	Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated  in Japanese patients with advanced solid tumors and showed encouraging anti-tumor  activity against melanoma and NSCLC.	No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in  Japanese patients with advanced solid tumors.	 Invest New Drugs	 Background This phase I study evaluated the safety and tolerability,  pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of   pembrolizumab in Japanese patients with advanced solid tumors. Methods Following   an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an  intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W)  until disease progression or unacceptable toxicity. Adverse events (AEs) were  assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1  and immune-related response criteria (irRC). Full pharmacokinetic sampling was  performed during cycle 1. Results Three patients received pembrolizumab at 2.0  mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during  cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1   or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and  aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2  each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised  grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis  (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety  and pharmacokinetic profiles of Japanese patients were similar to those  previously reported for Caucasian patients. A partial tumor response was observed  in one patient with non-small-cell lung cancer (NSCLC) and in one patient with  melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated  in Japanese patients with advanced solid tumors and showed encouraging anti-tumor  activity against melanoma and NSCLC.
CANIT0000560	27001570	Clinical research	Biallelic mismatch repair deficiency cancers	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	N/A	This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic  predisposition) or secondary MMRD.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Jul 1	 Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting  From Germline Biallelic Mismatch Repair Deficiency.	 J Clin Oncol	 PURPOSE: Recurrent glioblastoma multiforme (GBM) is incurable with current  therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant  childhood cancer syndrome often resulting in GBM characterized by a high  mutational burden. Evidence suggests that high mutation and neoantigen loads are   associated with response to immune checkpoint inhibition. PATIENTS AND METHODS:  We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and  compared them with childhood and adult brain neoplasms. Neoantigen prediction  bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two  siblings with recurrent multifocal bMMRD GBM were treated with the immune  checkpoint inhibitor nivolumab. RESULTS: All malignant tumors (n = 32) were  hypermutant. Although bMMRD brain tumors had the highest mutational load because   of secondary polymerase mutations (mean, 17,740 +/- standard deviation, 7,703),  all other high-grade tumors were hypermutant (mean, 1,589 +/- standard deviation,  1,043), similar to other cancers that responded favorably to immune checkpoint  inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic  pediatric and adult gliomas and all other brain tumors (P < .001). bMMRD GBM  harbored mean neoantigen loads seven to 16 times higher than those in  immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers  (P < .001). On the basis of these preclinical data, we treated two bMMRD siblings  with recurrent multifocal GBM with the anti-programmed death-1 inhibitor  nivolumab, which resulted in clinically significant responses and a profound  radiologic response. CONCLUSION: This report of initial and durable responses of   recurrent GBM to immune checkpoint inhibition may have implications for GBM in  general and other hypermutant cancers arising from primary (genetic  predisposition) or secondary MMRD.CI  - (c) 2016 by American Society of Clinical Oncology.
CANIT0000561	27012666	Case report	PMMR and microsatellite-stable gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Partial response	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Mar 24	 Case report: mismatch repair proficiency and microsatellite stability in gastric   cancer may not predict programmed death-1 blockade resistance.	 J Hematol Oncol	 BACKGROUND: Anti-programmed death-1 therapy has poor efficacy in mismatch  repair-proficient (pMMR) colorectal cancers; however, its efficacy in pMMR  gastric cancers remains undetermined. Here, we report the case of a patient with   pMMR and microsatellite-stable gastric cancer who exhibited a partial response to  salvage anti-programmed death-1 therapy with pembrolizumab. CASE PRESENTATION:  Initially, the patient underwent subtotal gastrectomy 4 years ago for early-stage  gastric cancer (pT1bN2M0, stage IIA). Immunohistochemical analysis of the tumor  revealed strongly positive for HER2/neu. He had received trastuzumab plus  pertuzumab, cisplatin, and capecitabine for recurrent tumors since September 2014  for 15 cycles. Disease progression of gastric cancer was found in August 2015.  Since September 2015, the patient has received pembrolizumab monotherapy (200 mg   as a fixed dose, every 3 weeks) for 3 months and the repeat computed tomography  demonstrated a confirmed partial response. The plasma carcinoembryonic antigen  also decreased dramatically. Both immunohistochemistry and a polymerase chain  reaction-based method revealed that the patient had pMMR gastric cancer.  CONCLUSIONS: This case report provides the first report that mismatch  repair-proficient and microsatellite-stable gastric cancers can respond well to  anti-PD-1 monotherapy and indicates both markers may not sufficiently be  predictive of anti-PD-1 therapy resistance in gastric cancer.
CANIT0000562	27012985	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Case	N/A	Thyroid dysfunction	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Nivolumab-induced thyroid dysfunction.	 Jpn J Clin Oncol	 Nivolumab (ONO-4538) is an anti-programmed death-1 specific monoclonal antibody,   which has become a standard treatment for metastatic malignant melanoma.  Nivolumab induces autoimmune adverse events, defined as immune-related adverse  events. Herein, we report a case of nivolumab-induced thyroid dysfunction in the   clinical setting. Fourteen patients were treated with nivolumab at our institute,  of which three developed thyroid dysfunction, an incidence higher than previously  reported in the initial clinical trials. Interestingly, one patient achieved  complete remission; suggesting that in some patients, the occurrence of  immune-related adverse events, including thyroid dysfunction, might reflect the  drug's antitumour efficacy. No patient died or discontinued nivolumab treatment  owing to thyroid dysfunction. Although thyroid dysfunction first appeared to be  asymptomatic, two of the three patients developed symptoms related to  hypothyroidism soon after, requiring hormone replacement therapy. Another patient  developed hyperthyroidism that was initially asymptomatic; the patient  subsequently developed myalgia with fever >39.5 degrees C after two additional  courses of nivolumab. Treatment with nivolumab was therefore discontinued, and  treatment with prednisolone was initiated. Symptoms resolved within a few days,  and thyroid function normalized. Thyroid dysfunction is sometimes difficult to  diagnose because its symptoms similar to those of many other diseases. In  addition, thyroid-related immune-related adverse events may present with unique  symptoms such as myalgia with high fever, abruptly worsening patients' quality of  life. Consequently, thyroid dysfunction should be considered as a possible  immune-related adverse event. Thus, it is important to test for thyroid  dysfunction at baseline and before the administration of each nivolumab dose if  possible.CI  - (c) The Author 2016. Published by Oxford University Press. All rights reserved.  For Permissions, please email: journals.permissions@oup.com.
CANIT0000563	27021586	Case report	Collecting duct carcinoma	Collecting duct carcinoma	EFO:0003016	Breast	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Partial response	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Anti-programmed Death Receptor 1 Blockade Induces Clinical Response in a Patient   With Metastatic Collecting Duct Carcinoma.	 Clin Genitourin Cancer	Unable to provide
CANIT0000564	27023060	Case report	Metastastic melanoma patient with a Churg-Strauss lung vasculitis and a prior ipilimumab-induced autoimmune colitis	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2016 May	 Successful Anti-PD-1 Antibody Treatment in a Metastatic Melanoma Patient With  Known Severe Autoimmune Disease.	 J Immunother	 Pembrolizumab, an anti-programmed death-1 monoclonal antibody, has been approved   by the Food and Drug Administration in 2014 on the basis of improved  progression-free and overall survival in metastatic melanoma. We report for the  first time a successful treatment with a programmed death-1 antibody in a  69-year-old metastastic melanoma patient with a Churg-Strauss lung vasculitis and  a prior ipilimumab-induced autoimmune colitis. This case report suggests that  pembrolizumab can be given with caution to patients with underlying autoimmune  disease. As the use of checkpoint inhibitors expands, knowledge about their  safety in patients with underlying autoimmune diseases will become increasingly  important, in particular because these patients are typically excluded from  clinical trials with immune-checkpoint inhibitors.
CANIT0000565	27029708	Clinical research	Breast cancer	Breast cancer	MONDO:0007254	Breast	GM-CSF (P04141); HER2 (P04626); 	GM-CSF; HER2	AE37 vaccine plus GM-CSF	GM-CSF	Tumor vaccine	GM-CSF (DB05386); AE37 vaccine (NCIT:C91719); 	153	145	A prospective, randomized, single-blinded, multicenter trial	The overall intention-to-treat analysis demonstrates no benefit to vaccination. However, the vaccination may have clinical benefit in patients with low HER2-expressing tumors, specifically TNBC.	Toxicities have been minimal.	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Primary analysis of a prospective, randomized, single-blinded phase II trial  evaluating the HER2 peptide AE37 vaccine in breast cancer patients to prevent  recurrence.	 Ann Oncol	 BACKGROUND: AE37 is the Ii-Key hybrid of the MHC class II peptide, AE36 (HER2  aa:776-790). Phase I studies showed AE37 administered with granulocyte macrophage  colony-stimulating factor (GM-CSF) to be safe and highly immunogenic. A  prospective, randomized, multicenter phase II adjuvant trial was conducted to  evaluate the vaccine's efficacy. METHODS: Clinically disease-free node-positive  and high-risk node-negative breast cancer patients with tumors expressing any  degree of HER2 [immunohistochemistry (IHC) 1-3+] were enrolled. Patients were  randomized to AE37 + GM-CSF versus GM-CSF alone. Toxicity was monitored. Clinical  recurrences were documented and disease-free survival (DFS) analyzed. RESULTS:  The trial enrolled 298 patients; 153 received AE37 + GM-CSF and 145 received  GM-CSF alone. The groups were well matched for clinicopathologic characteristics.  Toxicities have been minimal. At the time of the primary analysis, the recurrence  rate in the vaccinated group was 12.4% versus 13.8% in the control group  [relative risk reduction 12%, HR 0.885, 95% confidence interval (CI) 0.472-1.659,  P = 0.70]. The Kaplan-Meier estimated 5-year DFS rate was 80.8% in vaccinated  versus 79.5% in control patients. In planned subset analyses of patients with IHC  1+/2+ HER2-expressing tumors, 5-year DFS was 77.2% in vaccinated patients (n =  76) versus 65.7% in control patients (n = 78) (P = 0.21). In patients with  triple-negative breast cancer (HER2 IHC 1+/2+ and hormone receptor negative) DFS   was 77.7% in vaccinated patients (n = 25) versus 49.0% in control patients (n =  25) (P = 0.12). CONCLUSION: The overall intention-to-treat analysis demonstrates   no benefit to vaccination. However, the results confirm that the vaccine is safe   and suggest that vaccination may have clinical benefit in patients with low  HER2-expressing tumors, specifically TNBC. Further evaluation in a randomized  trial enrolling TNBC patients is warranted.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000566	27031538	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Acute generalized exanthematous pustulosis	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Ipilimumab-induced acute generalized exanthematous pustulosis in a patient with  metastatic melanoma.	 Melanoma Res	 Ipilimumab is a new anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody  that stimulates the immune response against melanoma. A 50-year-old man received   ipilimumab for metastatic melanoma as part of a clinical trial. Two weeks after  drug initiation, he developed a widespread oedematous erythema with sterile  pustules. The histological examination showed subcorneal pustulosis formation  with eosinophils. The clinical-pathological correlation was consistent with acute  generalized exanthematous pustulosis. The symptoms resolved within 25 days after   discontinuation of ipilimumab. We suspect that neutrophilic accumulation under  the epidermis in this patient is a phenomenon similar to intraepithelial  neutrophils aggregating on the surface epithelium over laminar propria in  ipilimumab-induced colitis. To our knowledge, this is the first reported case of   acute generalized exanthematous pustulosis associated with ipilimumab use in  metastatic melanoma patients.
CANIT0000567	27031539	Case report	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Case	N/A	Bullous pemphigoid	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); PD-L1 (Q9NZQ7); 	N/A	Gene expression signature on/in immune cell	 2016 Aug	 Bullous pemphigoid, an autoantibody-mediated disease, is a novel immune-related  adverse event in patients treated with anti-programmed cell death 1 antibodies.	 Melanoma Res	 Anti-programmed cell death 1 (anti-PD1) antibodies such as pembrolizumab have  shown improved progression-free and overall survival in patients with advanced  melanoma. Of 124 patients reviewed in Westmead Hospital from May 2012 to November  2015, treated with pembrolizumab for advanced melanoma, we encountered three  cases of bullous pemphigoid (BP). We have previously reported a case of BP. In  two recent cases, BP was diagnosed early and treated promptly with potent topical  or oral steroid. Patients on anti-PD1 antibodies are at a higher risk of  developing cutaneous immune-related adverse events such as lichenoid reactions,  eczema and vitiligo. No cases of BP were encountered in the previously published   cohort of 260 melanoma patients treated with BRAF inhibitors; as such, it appears  that BP is associated with anti-PD1 treatment rather than metastatic melanoma. BP  appears to be another immune-related adverse event, and clinicians should have a   low threshold for performing cutaneous biopsies and immunofluorescence studies in  patients on anti-PD1 therapies.
CANIT0000568	27037297	Case report	Non-small-cell lung cancer patients with poor performance status or brain metastases	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	32	N/A	Case	Severe exacerbation or manifestation of primary disease, we should monitor NSCLC patients with a poor PS or CNS metastases	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Severe exacerbation or manifestation of primary disease related to nivolumab in  non-small-cell lung cancer patients with poor performance status or brain  metastases.	 Ann Oncol	Unable to provide
CANIT0000569	27038231	Case report	Metastatic Merkel cell carcinoma	Merkel cell skin cancer	EFO:1001471	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	A positron emission tomography (PET) computed tomography scan performed after three cycles of pembrolizumab revealed responses to therapy with reduced size of the adrenal gland metastases and less PET activity in the adrenal gland and lymph node metastases. Treatment was resumed owing to disease progression after a treatment-free interval of > 4 months. During subsequent months of treatment, the size of the metastases stabilized and uptake of nuclide by all tumour sites once again decreased.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 PD-1 blockade: a therapeutic option for treatment of metastatic Merkel cell  carcinoma.	 Br J Dermatol	 The immune system is extremely important in the development and progression of  Merkel cell carcinoma (MCC). Immune checkpoint blockade has recently been shown  to enable efficacious treatment of a variety of tumours. We report the use of an   anti-programmed death receptor 1 (PD-1) antibody for treatment of a patient with   metastatic MCC. An 80-year-old patient with metastatic MCC received off-label  treatment with the anti-PD-1 antibody pembrolizumab after the disease had  progressed during therapy with oral etoposide. A positron emission tomography  (PET) computed tomography scan performed after three cycles of pembrolizumab  revealed responses to therapy with reduced size of the adrenal gland metastases  and less PET activity in the adrenal gland and lymph node metastases. Treatment  was resumed owing to disease progression after a treatment-free interval of > 4  months. During subsequent months of treatment, the size of the metastases  stabilized and uptake of nuclide by all tumour sites once again decreased. These   results reveal the potential efficacy of an anti-PD-1 antibody for treatment of  metastatic MCC. Thus, they contribute to currently limited data on the use of  anti-PD-1 antibodies for the treatment of MCC. Moreover, this is the first report  of successful resumption of treatment of metastatic MCC with an anti-PD-1  antibody. Results from ongoing trials will contribute to determination of the  relevance of PD-1 blockade in metastatic MCC.CI  - (c) 2016 British Association of Dermatologists.
CANIT0000570	27049531	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Surveillance is indispensable in children with a predisposition to melanoma and nonspecific symptoms such as bone pain, gait impairment or cytopenia, should always be taken into account.	N/A	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); PD-L1 (Q9NZQ7); 	PD-L1 expression levels on granulocytic monocytic myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2016 Sep	 Bone marrow metastasis of malignant melanoma in childhood arising within a  congenital melanocytic nevus.	 Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub	 BACKGROUND: Malignant melanoma in childhood is infrequent and can arise within  congenital melanocytic nevi. Spread of malignant melanoma to the bone marrow,  especially in children, is extremely rare. METHODS AND RESULTS: Reported is a  case of a 5-year-old boy with a congenital large melanocytic nevus of the head  and neck who presented with a short history of low back and leg pain, fever and  cervical lymphadenopathy. Despite regular follow-up by a dermatologist and  plastic surgeon and repeatedly negative histology of previous partial excisions,   diffuse bone marrow infiltration with malignant melanoma was diagnosed. The  primary site was identified in the post-excision area. The disease progressed  rapidly on ipilimumab immunotherapy and led to death at four months from the  diagnosis. CONCLUSION: Surveillance is indispensable in children with a  predisposition to melanoma and nonspecific symptoms such as bone pain, gait  impairment or cytopenia, should always be taken into account.
CANIT0000571	27058705	Clinical research	Metastasic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	11	N/A	A multicentre, retrospective cohort study	PFS observed in real-world patients was higher than that reported in clinical trials and OS was lower. The incidence of adverse events was higher.	The most commonly reported analytical adverse event was anemia, with all patients developing anemia in any grade. The most severe adverse event was neutropenia (n=6; 55%), with three patients developing grade 4 neutropenia (3/11; 27%).	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Effectiveness, toxicity, and economic evaluation of ipilimumab for the treatment   of patients with metastatic melanoma in the Spanish outpatient setting.	 Anticancer Drugs	 To evaluate the effectiveness and toxicity profile of ipilimumab treatment and to  examine the cost-effectiveness relation in a real-world sample of patients with  metastasic melanoma. This was a multicenter, observational, retrospective cohorts  study. To assess the effectiveness and safety of ipilimumab treatment  progression-free survival (PFS), overall survival (OS) and adverse events were  registered. An economic evaluation was performed and cost-effectiveness ratios  (CERs) were calculated. Eleven patients were included, mean age 59 (SD=11) years.  The median PFS was 3.83 months (95% confidence interval 0.98-9.80) and the median  OS was 5.15 months (95% confidence interval 1.70-8.48). None of the patients  included in the study achieved an objective response. A stable disease was  achieved in four (36%) patients. The most commonly reported analytical adverse  event was anemia, with all patients developing anemia in any grade. The most  severe adverse event was neutropenia (n=6; 55%), with three patients developing  grade 4 neutropenia (3/11; 27%). The total cost of ipilimumab treatment was  &OV0556;483 397, with a median of 43 033 (interquartile range=9555) euros per  patient. The median-based CER was 136 675 (28 539-474 865) euros per  progression-free year gained and the median-based CER was 100 112 (23 107-374  893) euros per life-year gained. PFS observed in real-world patients was higher  than that reported in clinical trials and OS was lower. The incidence of adverse   events was higher. The additional cost per progression-free year gained was  approximately &OV0556;136 675. The data from this study fill an important need  for information on the relative value of this treatment in terms of  cost-effectiveness.
CANIT0000572	27059553	Clinical research	Metastatic clear cell renal cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	70	N/A	A retrospective cohort study	The response rate was lower and the mPFS shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Safety and clinical activity of vascular endothelial growth factor receptor  (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor  treatment in patients with metastatic clear cell renal cell carcinoma.	 Ann Oncol	 BACKGROUND: Emerging agents blocking the programmed cell death 1 (PD-1) pathway  show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of  this study was to evaluate the efficacy and safety of vascular endothelial growth  factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after  PD-1 inhibition. PATIENTS AND METHODS: Patients with mRCC treated with anti-PD-1   antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab)  that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy   end points were objective response rate (ORR) and progression-free survival (PFS)  stratified by the type of prior PD-1 regimen. Safety by the type and PD-1  exposure was also evaluated. RESULTS: Seventy patients were included. Forty-nine   patients received prior therapy with immune checkpoint inhibitors (CPIs) alone  and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI   after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo)  (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower  than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%,  P = 0.039). In the multivariable analysis, patients treated with prior CPI alone   were more likely to achieve an objective response than those treated with aPD-1  in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was   a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone  group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had  VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common  adverse events (AEs) were asthenia, hypertension, and diarrhea. CONCLUSIONS: The   efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this  retrospective study. The response rate was lower and the median progression-free   survival was shorter in those patients who received prior PD-1 in combination  with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety  of subsequent VEGFR-TKI treatment.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000573	27059553	Clinical research	Metastatic clear cell renal cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	70	N/A	A retrospective cohort study	The response rate was lower and the mPFS shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Safety and clinical activity of vascular endothelial growth factor receptor  (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor  treatment in patients with metastatic clear cell renal cell carcinoma.	 Ann Oncol	 BACKGROUND: Emerging agents blocking the programmed cell death 1 (PD-1) pathway  show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of  this study was to evaluate the efficacy and safety of vascular endothelial growth  factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after  PD-1 inhibition. PATIENTS AND METHODS: Patients with mRCC treated with anti-PD-1   antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab)  that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy   end points were objective response rate (ORR) and progression-free survival (PFS)  stratified by the type of prior PD-1 regimen. Safety by the type and PD-1  exposure was also evaluated. RESULTS: Seventy patients were included. Forty-nine   patients received prior therapy with immune checkpoint inhibitors (CPIs) alone  and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI   after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo)  (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower  than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%,  P = 0.039). In the multivariable analysis, patients treated with prior CPI alone   were more likely to achieve an objective response than those treated with aPD-1  in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was   a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone  group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had  VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common  adverse events (AEs) were asthenia, hypertension, and diarrhea. CONCLUSIONS: The   efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this  retrospective study. The response rate was lower and the median progression-free   survival was shorter in those patients who received prior PD-1 in combination  with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety  of subsequent VEGFR-TKI treatment.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000574	27061281	Case report	Cutaneous melanoma metastases	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Pembrolizumab plus diphencyprone	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); diphencyprone (DB12173); 	1	N/A	Case	Definite regression	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Definite regression of cutaneous melanoma metastases upon addition of topical  contact sensitizer diphencyprone to immune checkpoint inhibitor treatment.	 Exp Dermatol	Unable to provide
CANIT0000575	27084345	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	496	N/A	N/A	Anti-PD-1 antibodies can induce a plethora of immune-related adverse events.	Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of  anti-PD-1 therapy.	 Eur J Cancer	 BACKGROUND: Anti-programmed cell death 1 (PD-1) antibodies represent an effective  treatment option for metastatic melanoma and other cancer entities. They act via   blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms  that limit immune responses against tumours. As reported for ipilimumab, the  anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related  adverse events (irAEs). These side-effects can involve skin, gastrointestinal  tract, liver, the endocrine system and other organ systems. Since  life-threatening and fatal irAEs have been reported, adequate diagnosis and  management are essential. METHODS AND FINDINGS: In total, 496 patients with  metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab  or nivolumab. Two hundred forty two side-effects in 138 patients have been  analysed. In 77 of the 138 patients side-effects affected the nervous system,  respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet  reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac  arrhythmia, asystolia, and paresis have been observed. Rare and difficult to  manage side-effects such as myasthenia gravis are described in detail.  CONCLUSION: Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of  them will allow prompt diagnosis and improve the management resulting in  decreased morbidity.CI  - Copyright (c) 2016. Published by Elsevier Ltd.
CANIT0000576	27084345	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	496	N/A	N/A	Anti-PD-1 antibodies can induce a plethora of immune-related adverse events.	Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of  anti-PD-1 therapy.	 Eur J Cancer	 BACKGROUND: Anti-programmed cell death 1 (PD-1) antibodies represent an effective  treatment option for metastatic melanoma and other cancer entities. They act via   blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms  that limit immune responses against tumours. As reported for ipilimumab, the  anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related  adverse events (irAEs). These side-effects can involve skin, gastrointestinal  tract, liver, the endocrine system and other organ systems. Since  life-threatening and fatal irAEs have been reported, adequate diagnosis and  management are essential. METHODS AND FINDINGS: In total, 496 patients with  metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab  or nivolumab. Two hundred forty two side-effects in 138 patients have been  analysed. In 77 of the 138 patients side-effects affected the nervous system,  respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet  reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac  arrhythmia, asystolia, and paresis have been observed. Rare and difficult to  manage side-effects such as myasthenia gravis are described in detail.  CONCLUSION: Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of  them will allow prompt diagnosis and improve the management resulting in  decreased morbidity.CI  - Copyright (c) 2016. Published by Elsevier Ltd.
CANIT0000577	27085692	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	496	N/A	N/A	Anti-PD1  antibodies can induce a plethora of immune-related adverse events.	242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of  anti-PD-1 therapy.	 Eur J Cancer	 BACKGROUND: Anti-programmed cell death receptor-1 (PD-1) antibodies represent an   effective treatment option for metastatic melanoma as well as for other cancer  entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell   effector mechanisms that limit immune responses against tumours. As reported for   ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce  immune-related adverse events (irAEs). These side-effects affect skin,  gastrointestinal tract, liver, endocrine system and other organ systems. Since  life-threatening and fatal irAEs have been reported, adequate diagnosis and  management are essential. METHODS AND FINDINGS: In total, 496 patients with  metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab  or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138   patients, side-effects affected the skin, gastrointestinal tract, liver,  endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen  planus, and pancreas insufficiency due to pancreatitis. CONCLUSION: Anti-PD1  antibodies can induce a plethora of irAEs. The knowledge of them will allow  prompt diagnosis and improve the management resulting in decreased morbidity.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000578	27085692	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	496	N/A	N/A	Anti-PD1  antibodies can induce a plethora of immune-related adverse events.	242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of  anti-PD-1 therapy.	 Eur J Cancer	 BACKGROUND: Anti-programmed cell death receptor-1 (PD-1) antibodies represent an   effective treatment option for metastatic melanoma as well as for other cancer  entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell   effector mechanisms that limit immune responses against tumours. As reported for   ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce  immune-related adverse events (irAEs). These side-effects affect skin,  gastrointestinal tract, liver, endocrine system and other organ systems. Since  life-threatening and fatal irAEs have been reported, adequate diagnosis and  management are essential. METHODS AND FINDINGS: In total, 496 patients with  metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab  or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138   patients, side-effects affected the skin, gastrointestinal tract, liver,  endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen  planus, and pancreas insufficiency due to pancreatitis. CONCLUSION: Anti-PD1  antibodies can induce a plethora of irAEs. The knowledge of them will allow  prompt diagnosis and improve the management resulting in decreased morbidity.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000579	27086658	Case report	3 Metastatic melanoma, 1 Metastatic squamous cell carcinoma of head and neck, 1 Metastatic urothelial carcinoma, 1 Recurrent adenocarcinoma of the lung	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	N/A	Bullous skin eruptions	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1  antibody therapy: a report on bullous skin eruptions.	 J Cutan Pathol	 Monoclonal antibodies against the immune checkpoint programmed cell death  receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed  tremendous promise in the treatment of advanced solid tumors and hematologic  malignancies. Reports of serious autoimmune dermatologic toxicities from immune  checkpoint blockade therapy, however, are emerging. We report our experience with  five patients who presented with pruritic vesicles and blisters on the skin while  treated with anti-PD-1 antibody immunotherapy with either nivolumab or  pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae  with immunohistochemical study for type IV collagen labeling the floor of the  blister cavity and direct immunofluorescence studies (in three of the four  patients tested) decorated linear IgG and C3 immune deposits on the blister roof,  diagnostic of bullous pemphigoid. One patient developed bullous erythema  multiforme. All patients had partial or complete resolution of skin lesions  following treatment with systemic corticosteroid and cessation of checkpoint  blockade. Recognition and treatment of rare immune-related bullous dermatologic  toxicities will become increasingly important as more patients are treated with  effective and newer immune checkpoint blockade therapy.CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0000580	27086658	Case report	3 Metastatic melanoma, 1 Metastatic squamous cell carcinoma of head and neck, 1 Metastatic urothelial carcinoma, 1 Recurrent adenocarcinoma of the lung	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Case	N/A	Bullous skin eruptions	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1  antibody therapy: a report on bullous skin eruptions.	 J Cutan Pathol	 Monoclonal antibodies against the immune checkpoint programmed cell death  receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed  tremendous promise in the treatment of advanced solid tumors and hematologic  malignancies. Reports of serious autoimmune dermatologic toxicities from immune  checkpoint blockade therapy, however, are emerging. We report our experience with  five patients who presented with pruritic vesicles and blisters on the skin while  treated with anti-PD-1 antibody immunotherapy with either nivolumab or  pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae  with immunohistochemical study for type IV collagen labeling the floor of the  blister cavity and direct immunofluorescence studies (in three of the four  patients tested) decorated linear IgG and C3 immune deposits on the blister roof,  diagnostic of bullous pemphigoid. One patient developed bullous erythema  multiforme. All patients had partial or complete resolution of skin lesions  following treatment with systemic corticosteroid and cessation of checkpoint  blockade. Recognition and treatment of rare immune-related bullous dermatologic  toxicities will become increasingly important as more patients are treated with  effective and newer immune checkpoint blockade therapy.CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0000581	27086658	Case report	3 Metastatic melanoma, 1 Metastatic squamous cell carcinoma of head and neck, 1 Metastatic urothelial carcinoma, 1 Recurrent adenocarcinoma of the lung	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	N/A	Bullous skin eruptions	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1  antibody therapy: a report on bullous skin eruptions.	 J Cutan Pathol	 Monoclonal antibodies against the immune checkpoint programmed cell death  receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed  tremendous promise in the treatment of advanced solid tumors and hematologic  malignancies. Reports of serious autoimmune dermatologic toxicities from immune  checkpoint blockade therapy, however, are emerging. We report our experience with  five patients who presented with pruritic vesicles and blisters on the skin while  treated with anti-PD-1 antibody immunotherapy with either nivolumab or  pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae  with immunohistochemical study for type IV collagen labeling the floor of the  blister cavity and direct immunofluorescence studies (in three of the four  patients tested) decorated linear IgG and C3 immune deposits on the blister roof,  diagnostic of bullous pemphigoid. One patient developed bullous erythema  multiforme. All patients had partial or complete resolution of skin lesions  following treatment with systemic corticosteroid and cessation of checkpoint  blockade. Recognition and treatment of rare immune-related bullous dermatologic  toxicities will become increasingly important as more patients are treated with  effective and newer immune checkpoint blockade therapy.CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0000582	27086658	Case report	3 Metastatic melanoma, 1 Metastatic squamous cell carcinoma of head and neck, 1 Metastatic urothelial carcinoma, 1 Recurrent adenocarcinoma of the lung	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Case	N/A	Bullous skin eruptions	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1  antibody therapy: a report on bullous skin eruptions.	 J Cutan Pathol	 Monoclonal antibodies against the immune checkpoint programmed cell death  receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed  tremendous promise in the treatment of advanced solid tumors and hematologic  malignancies. Reports of serious autoimmune dermatologic toxicities from immune  checkpoint blockade therapy, however, are emerging. We report our experience with  five patients who presented with pruritic vesicles and blisters on the skin while  treated with anti-PD-1 antibody immunotherapy with either nivolumab or  pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae  with immunohistochemical study for type IV collagen labeling the floor of the  blister cavity and direct immunofluorescence studies (in three of the four  patients tested) decorated linear IgG and C3 immune deposits on the blister roof,  diagnostic of bullous pemphigoid. One patient developed bullous erythema  multiforme. All patients had partial or complete resolution of skin lesions  following treatment with systemic corticosteroid and cessation of checkpoint  blockade. Recognition and treatment of rare immune-related bullous dermatologic  toxicities will become increasingly important as more patients are treated with  effective and newer immune checkpoint blockade therapy.CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0000583	27086658	Case report	3 Metastatic melanoma, 1 Metastatic squamous cell carcinoma of head and neck, 1 Metastatic urothelial carcinoma, 1 Recurrent adenocarcinoma of the lung	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Case	N/A	Bullous skin eruptions	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1  antibody therapy: a report on bullous skin eruptions.	 J Cutan Pathol	 Monoclonal antibodies against the immune checkpoint programmed cell death  receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed  tremendous promise in the treatment of advanced solid tumors and hematologic  malignancies. Reports of serious autoimmune dermatologic toxicities from immune  checkpoint blockade therapy, however, are emerging. We report our experience with  five patients who presented with pruritic vesicles and blisters on the skin while  treated with anti-PD-1 antibody immunotherapy with either nivolumab or  pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae  with immunohistochemical study for type IV collagen labeling the floor of the  blister cavity and direct immunofluorescence studies (in three of the four  patients tested) decorated linear IgG and C3 immune deposits on the blister roof,  diagnostic of bullous pemphigoid. One patient developed bullous erythema  multiforme. All patients had partial or complete resolution of skin lesions  following treatment with systemic corticosteroid and cessation of checkpoint  blockade. Recognition and treatment of rare immune-related bullous dermatologic  toxicities will become increasingly important as more patients are treated with  effective and newer immune checkpoint blockade therapy.CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0000584	27086658	Case report	3 Metastatic melanoma, 1 Metastatic squamous cell carcinoma of head and neck, 1 Metastatic urothelial carcinoma, 1 Recurrent adenocarcinoma of the lung	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Case	N/A	Bullous skin eruptions	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1  antibody therapy: a report on bullous skin eruptions.	 J Cutan Pathol	 Monoclonal antibodies against the immune checkpoint programmed cell death  receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed  tremendous promise in the treatment of advanced solid tumors and hematologic  malignancies. Reports of serious autoimmune dermatologic toxicities from immune  checkpoint blockade therapy, however, are emerging. We report our experience with  five patients who presented with pruritic vesicles and blisters on the skin while  treated with anti-PD-1 antibody immunotherapy with either nivolumab or  pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae  with immunohistochemical study for type IV collagen labeling the floor of the  blister cavity and direct immunofluorescence studies (in three of the four  patients tested) decorated linear IgG and C3 immune deposits on the blister roof,  diagnostic of bullous pemphigoid. One patient developed bullous erythema  multiforme. All patients had partial or complete resolution of skin lesions  following treatment with systemic corticosteroid and cessation of checkpoint  blockade. Recognition and treatment of rare immune-related bullous dermatologic  toxicities will become increasingly important as more patients are treated with  effective and newer immune checkpoint blockade therapy.CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0000585	27086747	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Foreign body reaction	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Foreign body reaction triggered by cytotoxic T lymphocyte-associated protein 4  blockade 25 years after dermal filler injection.	 Br J Dermatol	 Foreign body reactions are regularly seen as a late complication of cosmetic  treatment with synthetic dermal fillers. Often this foreign body reaction is  triggered by a systemic infection, but other systemic triggers are also reported.  In this case report, we present a woman in her 60s who was treated with  ipilimumab for metastatic melanoma. After two courses of treatment she developed   painless facial nodules. A foreign body reaction to dermal fillers was suspected   because the patient had received cosmetic treatment with dermal fillers 25 years   previously. This reaction was confirmed by excision and histological examination.  In the absence of other known triggers, this case revealed immunotherapy  (ipilimumab) and subsequent activation of the adaptive immune system as potential  triggers of foreign body reactions to dermal fillers. Immunotherapy is  increasingly used as anticancer treatment for an increasing number of tumour  types. Furthermore, synthetic dermal fillers have frequently been used in the  past. Therefore, physicians should be aware of this late-occurring complication  of synthetic filler treatment in patients who develop skin lesions during  immunotherapy.CI  - (c) 2016 British Association of Dermatologists.
CANIT0000586	27093365	Clinical research	Advanced Merkel-cell carcinoma	Merkel cell skin cancer	EFO:1001471	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	26	N/A	A multicenter, phase II, noncontrolled study	First-line  therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was  associated with an objective response rate of 56%. Responses were observed in  patients with virus-positive tumors and those with virus-negative tumors.	Drug-related grade 3 or 4 adverse events occurred in 15% of the patients.	N/A	N/A	Polyomavirus (NCIT:C14260); 	Merkel-cell polyomavirus-positive tumors	Microbiota	 2016 Jun 30	 PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma.	 N Engl J Med	 BACKGROUND: Merkel-cell carcinoma is an aggressive skin cancer that is linked to   exposure to ultraviolet light and the Merkel-cell polyomavirus (MCPyV). Advanced   Merkel-cell carcinoma often responds to chemotherapy, but responses are  transient. Blocking the programmed death 1 (PD-1) immune inhibitory pathway is of  interest, because these tumors often express PD-L1, and MCPyV-specific T cells  express PD-1. METHODS: In this multicenter, phase 2, noncontrolled study, we  assigned adults with advanced Merkel-cell carcinoma who had received no previous   systemic therapy to receive pembrolizumab (anti-PD-1) at a dose of 2 mg per  kilogram of body weight every 3 weeks. The primary end point was the objective  response rate according to Response Evaluation Criteria in Solid Tumors, version   1.1. Efficacy was correlated with tumor viral status, as assessed by serologic  and immunohistochemical testing. RESULTS: A total of 26 patients received at  least one dose of pembrolizumab. The objective response rate among the 25  patients with at least one evaluation during treatment was 56% (95% confidence  interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a  partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses   occurred in 2 of the 14 patients who had had a response (14%). The response  duration ranged from at least 2.2 months to at least 9.7 months. The rate of  progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17  of the 26 patients (65%) had virus-positive tumors. The response rate was 62%  among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those  with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse  events occurred in 15% of the patients. CONCLUSIONS: In this study, first-line  therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was  associated with an objective response rate of 56%. Responses were observed in  patients with virus-positive tumors and those with virus-negative tumors. (Funded  by the National Cancer Institute and Merck; ClinicalTrials.gov number,  NCT02267603.).
CANIT0000587	27111048	Case report	Hodgkin's lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Fatal graft-versus-host disease (GvHD)	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Fatal GvHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin's  lymphoma.	 Bone Marrow Transplant	Unable to provide
CANIT0000588	27113507	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Acute Interstitial Nephritis	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Association of Acute Interstitial Nephritis With Programmed Cell Death 1  Inhibitor Therapy in Lung Cancer Patients.	 Am J Kidney Dis	 Immune checkpoint inhibitors that target the programmed death 1 (PD-1) signaling   pathway have recently been approved for use in advanced pretreated non-small cell  lung cancer and melanoma. Clinical trial data suggest that these drugs may have  adverse effects on the kidney, but these effects have not been well described. We  present 6 cases of acute kidney injury in patients with lung cancer who received   anti-PD-1 antibodies, with each case displaying evidence of acute interstitial  nephritis (AIN) on kidney biopsy. All patients were also treated with other drugs  (proton pump inhibitors and nonsteroidal anti-inflammatory drugs) linked to AIN,   but in most cases, use of these drugs long preceded PD-1 inhibitor therapy. The  association of AIN with these drugs in our patients raises the possibility that  PD-1 inhibitor therapy may release suppression of T-cell immunity that normally  permits renal tolerance of drugs known to be associated with AIN.CI  - Copyright (c) 2016 National Kidney Foundation, Inc. Published by Elsevier Inc.  All rights reserved.
CANIT0000589	27113507	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Acute Interstitial Nephritis	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Association of Acute Interstitial Nephritis With Programmed Cell Death 1  Inhibitor Therapy in Lung Cancer Patients.	 Am J Kidney Dis	 Immune checkpoint inhibitors that target the programmed death 1 (PD-1) signaling   pathway have recently been approved for use in advanced pretreated non-small cell  lung cancer and melanoma. Clinical trial data suggest that these drugs may have  adverse effects on the kidney, but these effects have not been well described. We  present 6 cases of acute kidney injury in patients with lung cancer who received   anti-PD-1 antibodies, with each case displaying evidence of acute interstitial  nephritis (AIN) on kidney biopsy. All patients were also treated with other drugs  (proton pump inhibitors and nonsteroidal anti-inflammatory drugs) linked to AIN,   but in most cases, use of these drugs long preceded PD-1 inhibitor therapy. The  association of AIN with these drugs in our patients raises the possibility that  PD-1 inhibitor therapy may release suppression of T-cell immunity that normally  permits renal tolerance of drugs known to be associated with AIN.CI  - Copyright (c) 2016 National Kidney Foundation, Inc. Published by Elsevier Inc.  All rights reserved.
CANIT0000590	27113507	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Case	N/A	Acute Interstitial Nephritis	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Association of Acute Interstitial Nephritis With Programmed Cell Death 1  Inhibitor Therapy in Lung Cancer Patients.	 Am J Kidney Dis	 Immune checkpoint inhibitors that target the programmed death 1 (PD-1) signaling   pathway have recently been approved for use in advanced pretreated non-small cell  lung cancer and melanoma. Clinical trial data suggest that these drugs may have  adverse effects on the kidney, but these effects have not been well described. We  present 6 cases of acute kidney injury in patients with lung cancer who received   anti-PD-1 antibodies, with each case displaying evidence of acute interstitial  nephritis (AIN) on kidney biopsy. All patients were also treated with other drugs  (proton pump inhibitors and nonsteroidal anti-inflammatory drugs) linked to AIN,   but in most cases, use of these drugs long preceded PD-1 inhibitor therapy. The  association of AIN with these drugs in our patients raises the possibility that  PD-1 inhibitor therapy may release suppression of T-cell immunity that normally  permits renal tolerance of drugs known to be associated with AIN.CI  - Copyright (c) 2016 National Kidney Foundation, Inc. Published by Elsevier Inc.  All rights reserved.
CANIT0000591	27113507	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Nivolumab plus bevacizumab	Chemotherapy or targeted therapy	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); bevacizumab (DB00112); 	1	N/A	Case	N/A	Acute Interstitial Nephritis	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Association of Acute Interstitial Nephritis With Programmed Cell Death 1  Inhibitor Therapy in Lung Cancer Patients.	 Am J Kidney Dis	 Immune checkpoint inhibitors that target the programmed death 1 (PD-1) signaling   pathway have recently been approved for use in advanced pretreated non-small cell  lung cancer and melanoma. Clinical trial data suggest that these drugs may have  adverse effects on the kidney, but these effects have not been well described. We  present 6 cases of acute kidney injury in patients with lung cancer who received   anti-PD-1 antibodies, with each case displaying evidence of acute interstitial  nephritis (AIN) on kidney biopsy. All patients were also treated with other drugs  (proton pump inhibitors and nonsteroidal anti-inflammatory drugs) linked to AIN,   but in most cases, use of these drugs long preceded PD-1 inhibitor therapy. The  association of AIN with these drugs in our patients raises the possibility that  PD-1 inhibitor therapy may release suppression of T-cell immunity that normally  permits renal tolerance of drugs known to be associated with AIN.CI  - Copyright (c) 2016 National Kidney Foundation, Inc. Published by Elsevier Inc.  All rights reserved.
CANIT0000592	27116334	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	23	N/A	A retrospective cohort study	Immune checkpoint inhibitors appear to be effective and safe in metastatic melanoma patients with pre-existing HBV infection.	Immune-related adverse events were observed in 44% (4/9), 60% (6/10), 100% (4/4), and 61% (14/23) of patients receiving ipilimumab, pembrolizumab, concomitant ipilimumab and pembrolizumab, and any treatment, respectively. The most frequent immune-related adverse events were endocrine disorders (39%, 9/23), liver function abnormalities (22%, 5/23), and dermatological events (17%, 4/23). There were no gastrointestinal reactions. Toxicities were usually mild and easily managed; only 13% (3/23) of patients had grade 3 adverse events and none experienced grade 4 events or treatment-related death. No additional toxicity nor severe hepatotoxicity was observed in 11 patients who had previous HBV infection.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Safety of immune checkpoint inhibitors in Chinese patients with melanoma.	 Melanoma Res	 This study aimed to determine the tolerability of Chinese melanoma patients,  particularly those with hepatitis B virus (HBV) infection, to immune checkpoint  inhibitor therapy. Patients with metastatic melanoma who received anti-cytotoxic   T lymphocyte-associated antigen-4 antibody (ipilimumab) or anti-programmed death   1 antibody (pembrolizumab) therapy at our hospital between August 2012 and July  2015 were retrospectively reviewed. Adverse events were evaluated according to  the National Cancer Institute Common Terminology Criteria for Adverse Events,  version 3.0. Twenty-three patients with advanced melanoma were included; nine and  10 patients received infusions of ipilimumab and pembrolizumab, respectively,  whereas four patients received concurrent ipilimumab and pembrolizumab therapy.  There was no cessation of treatment because of agent-related adverse events in  any patient. Immune-related adverse events were observed in 44% (4/9), 60%  (6/10), 100% (4/4), and 61% (14/23) of patients receiving ipilimumab,  pembrolizumab, concomitant ipilimumab and pembrolizumab, and any treatment,  respectively. The most frequent immune-related adverse events were endocrine  disorders (39%, 9/23), liver function abnormalities (22%, 5/23), and  dermatological events (17%, 4/23). There were no gastrointestinal reactions.  Toxicities were usually mild and easily managed; only 13% (3/23) of patients had   grade 3 adverse events and none experienced grade 4 events or treatment-related  death. No additional toxicity nor severe hepatotoxicity was observed in 11  patients who had previous HBV infection. The recommended anti-cytotoxic T  lymphocyte-associated antigen-4 and anti-programmed death 1 antibody doses were  well tolerated by Chinese patients. Thus, immune checkpoint inhibitors appear to   be effective and safe in metastatic melanoma patients, including those with  pre-existing HBV infection.
CANIT0000593	27116334	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); ipilimumab (DB06186); 	23	N/A	A retrospective cohort study	Immune checkpoint inhibitors appear to be effective and safe in metastatic melanoma patients with pre-existing HBV infection.	Immune-related adverse events were observed in 44% (4/9), 60% (6/10), 100% (4/4), and 61% (14/23) of patients receiving ipilimumab, pembrolizumab, concomitant ipilimumab and pembrolizumab, and any treatment, respectively. The most frequent immune-related adverse events were endocrine disorders (39%, 9/23), liver function abnormalities (22%, 5/23), and dermatological events (17%, 4/23). There were no gastrointestinal reactions. Toxicities were usually mild and easily managed; only 13% (3/23) of patients had grade 3 adverse events and none experienced grade 4 events or treatment-related death. No additional toxicity nor severe hepatotoxicity was observed in 11 patients who had previous HBV infection.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Safety of immune checkpoint inhibitors in Chinese patients with melanoma.	 Melanoma Res	 This study aimed to determine the tolerability of Chinese melanoma patients,  particularly those with hepatitis B virus (HBV) infection, to immune checkpoint  inhibitor therapy. Patients with metastatic melanoma who received anti-cytotoxic   T lymphocyte-associated antigen-4 antibody (ipilimumab) or anti-programmed death   1 antibody (pembrolizumab) therapy at our hospital between August 2012 and July  2015 were retrospectively reviewed. Adverse events were evaluated according to  the National Cancer Institute Common Terminology Criteria for Adverse Events,  version 3.0. Twenty-three patients with advanced melanoma were included; nine and  10 patients received infusions of ipilimumab and pembrolizumab, respectively,  whereas four patients received concurrent ipilimumab and pembrolizumab therapy.  There was no cessation of treatment because of agent-related adverse events in  any patient. Immune-related adverse events were observed in 44% (4/9), 60%  (6/10), 100% (4/4), and 61% (14/23) of patients receiving ipilimumab,  pembrolizumab, concomitant ipilimumab and pembrolizumab, and any treatment,  respectively. The most frequent immune-related adverse events were endocrine  disorders (39%, 9/23), liver function abnormalities (22%, 5/23), and  dermatological events (17%, 4/23). There were no gastrointestinal reactions.  Toxicities were usually mild and easily managed; only 13% (3/23) of patients had   grade 3 adverse events and none experienced grade 4 events or treatment-related  death. No additional toxicity nor severe hepatotoxicity was observed in 11  patients who had previous HBV infection. The recommended anti-cytotoxic T  lymphocyte-associated antigen-4 and anti-programmed death 1 antibody doses were  well tolerated by Chinese patients. Thus, immune checkpoint inhibitors appear to   be effective and safe in metastatic melanoma patients, including those with  pre-existing HBV infection.
CANIT0000594	27116334	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	A retrospective cohort study	Immune checkpoint inhibitors appear to be effective and safe in metastatic melanoma patients with pre-existing HBV infection.	Immune-related adverse events were observed in 44% (4/9), 60% (6/10), 100% (4/4), and 61% (14/23) of patients receiving ipilimumab, pembrolizumab, concomitant ipilimumab and pembrolizumab, and any treatment, respectively. The most frequent immune-related adverse events were endocrine disorders (39%, 9/23), liver function abnormalities (22%, 5/23), and dermatological events (17%, 4/23). There were no gastrointestinal reactions. Toxicities were usually mild and easily managed; only 13% (3/23) of patients had grade 3 adverse events and none experienced grade 4 events or treatment-related death. No additional toxicity nor severe hepatotoxicity was observed in 11 patients who had previous HBV infection.	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Safety of immune checkpoint inhibitors in Chinese patients with melanoma.	 Melanoma Res	 This study aimed to determine the tolerability of Chinese melanoma patients,  particularly those with hepatitis B virus (HBV) infection, to immune checkpoint  inhibitor therapy. Patients with metastatic melanoma who received anti-cytotoxic   T lymphocyte-associated antigen-4 antibody (ipilimumab) or anti-programmed death   1 antibody (pembrolizumab) therapy at our hospital between August 2012 and July  2015 were retrospectively reviewed. Adverse events were evaluated according to  the National Cancer Institute Common Terminology Criteria for Adverse Events,  version 3.0. Twenty-three patients with advanced melanoma were included; nine and  10 patients received infusions of ipilimumab and pembrolizumab, respectively,  whereas four patients received concurrent ipilimumab and pembrolizumab therapy.  There was no cessation of treatment because of agent-related adverse events in  any patient. Immune-related adverse events were observed in 44% (4/9), 60%  (6/10), 100% (4/4), and 61% (14/23) of patients receiving ipilimumab,  pembrolizumab, concomitant ipilimumab and pembrolizumab, and any treatment,  respectively. The most frequent immune-related adverse events were endocrine  disorders (39%, 9/23), liver function abnormalities (22%, 5/23), and  dermatological events (17%, 4/23). There were no gastrointestinal reactions.  Toxicities were usually mild and easily managed; only 13% (3/23) of patients had   grade 3 adverse events and none experienced grade 4 events or treatment-related  death. No additional toxicity nor severe hepatotoxicity was observed in 11  patients who had previous HBV infection. The recommended anti-cytotoxic T  lymphocyte-associated antigen-4 and anti-programmed death 1 antibody doses were  well tolerated by Chinese patients. Thus, immune checkpoint inhibitors appear to   be effective and safe in metastatic melanoma patients, including those with  pre-existing HBV infection.
CANIT0000595	27117531	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	449	N/A	A phase II clinical trial	No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.	Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses.	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Systematic evaluation of pembrolizumab dosing in patients with advanced  non-small-cell lung cancer.	 Ann Oncol	 BACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable   antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC).   We sought to characterize the relationship between pembrolizumab dose, exposure,   and response to define an effective dose for these patients. PATIENTS AND  METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10  mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was  assessed every 9 weeks. The relationship between the estimated pembrolizumab area  under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks)  and the longitudinal change in tumor size (sum of longest diameters) was analyzed  by regression and non-linear mixed effects modeling. This model was  simultaneously fit to all tumor size data, then used to simulate response rates,   normalizing the trial data across dose for prognostic covariates (tumor PD-L1  expression and EGFR mutation status). The exposure-safety relationship was  assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence  of adverse events (AEs) of interest based on their immune etiology. RESULTS:  Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg   Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W.  Regression analyses of percentage change from baseline in tumor size versus  AUCss-6weeks indicated a flat relationship (regression slope P > 0.05).  Simulations showed the exposure-response relationship to be similarly flat, thus   indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near   the efficacy plateau. Exposure-safety analysis showed the AE incidence to be  similar among the clinically tested doses. CONCLUSIONS: No significant exposure  dependency on efficacy or safety was identified for pembrolizumab across doses of  2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients  with previously treated, advanced NSCLC. CLINICALTRIALSGOV REGISTRY: NCT01295827.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000596	27118102	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	177	N/A	A retrospective cohort study	These results provide insights into patient care with advanced melanoma in the era before ipilimumab and may serve as a benchmark for new agents in future real-world studies.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Real-world treatment practice in patients with advanced melanoma in the era  before ipilimumab: results from the IMAGE study.	 Cancer Med	 The therapeutic landscape for advanced melanoma has recently been transformed by   several novel agents (immune checkpoint inhibitors and molecular-targeted  agents). The prospective, multi-site, observational study IMAGE (ipilimumab:  management of advanced melanoma in real practice) included a retrospective cohort  to describe real-world treatment prior to approval of the immune checkpoint  inhibitor ipilimumab. This retrospective cohort of patients, who started  second-line/subsequent treatment (index therapy) for advanced melanoma within 3  years before ipilimumab approval, was selected randomly by chart review.  Collected data included treatment history, patient outcomes, and healthcare  resource utilization. All patients had >/=1 year of follow-up data. This analysis  included 177 patients from Europe (69%) and North America (31%). The most common   index therapies (used alone or in combination) were fotemustine (23%),  dacarbazine (21%), temozolomide (14%), and platinum-based chemotherapy (14%).  Most patients (89%) discontinued index treatment during the study period; the  most common reason was disease progression (59%). Among patients with tumor  assessment (153/177; 86%), 2% had complete response, 5% had partial response, and  12% had stable disease on last tumor assessment. At 1-year study follow-up,  median progression-free survival was 2.6 months (95% confidence interval [CI],  2.1-2.9) and median overall survival was 8.8 months (95% CI, 6.5-9.7). During  follow-up, 95% of the patients had healthcare visits for advanced melanoma, 74%  of whom were hospitalized or admitted to a hospice facility. These results  provide insights into patient care with advanced melanoma in the era before  ipilimumab and may serve as a benchmark for new agents in future real-world  studies.CI  - (c) 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0000597	27121245	Case report	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Myasthenia gravis	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Myasthenia gravis induced by nivolumab therapy in a patient with non-small-cell  lung cancer.	 Muscle Nerve	Unable to provide
CANIT0000598	27121719	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	104	N/A	N/A	The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR ( 5) were independent poor prognostic factors by multivariate analysis.	Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher.	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2017 Jan	 Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the  Korean Named-Patient Program Cohort.	 Cancer Res Treat	 PURPOSE: Ipilimumab improves survival in advanced melanoma patients. However, the  efficacy and safety of ipilimumab has not been evaluated in Asian melanoma  patients with a high frequency of mucosal and acral melanoma subtypes. MATERIALS   AND METHODS: Advanced melanoma patients treated with 3 mg/kg ipilimumab in a  Korean multicenter named-patient program (NPP) were evaluated between September  2014 and July 2015. Baseline characteristics and blood parameters including  neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse  events were evaluated according to subtypes. RESULTS: A total of 104 advanced  melanoma patients were treated. The primary sites were acral (31.7%), mucosal  (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients  (65.4%) experienced adverse events, and the most common toxicity was skin rash  (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The   median progression-free survival (PFS) was 2.73 months (95% confidence interval,   2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor  performance status, liver metastasis, and NLR (>/= 5) were independent poor  prognostic factors by multivariate analysis. CONCLUSION: In the Korean NPP  cohort, ipilimumab showed similar efficacy and tolerability compared to Western  patients, regardless of subtypes. All subtypes should benefit from ipilimumab  with consideration of performance status, liver metastasis, and NLR.
CANIT0000599	27121719	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	104	N/A	N/A	The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR ( 5) were independent poor prognostic factors by multivariate analysis.	Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher.	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Jan	 Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the  Korean Named-Patient Program Cohort.	 Cancer Res Treat	 PURPOSE: Ipilimumab improves survival in advanced melanoma patients. However, the  efficacy and safety of ipilimumab has not been evaluated in Asian melanoma  patients with a high frequency of mucosal and acral melanoma subtypes. MATERIALS   AND METHODS: Advanced melanoma patients treated with 3 mg/kg ipilimumab in a  Korean multicenter named-patient program (NPP) were evaluated between September  2014 and July 2015. Baseline characteristics and blood parameters including  neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse  events were evaluated according to subtypes. RESULTS: A total of 104 advanced  melanoma patients were treated. The primary sites were acral (31.7%), mucosal  (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients  (65.4%) experienced adverse events, and the most common toxicity was skin rash  (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The   median progression-free survival (PFS) was 2.73 months (95% confidence interval,   2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor  performance status, liver metastasis, and NLR (>/= 5) were independent poor  prognostic factors by multivariate analysis. CONCLUSION: In the Korean NPP  cohort, ipilimumab showed similar efficacy and tolerability compared to Western  patients, regardless of subtypes. All subtypes should benefit from ipilimumab  with consideration of performance status, liver metastasis, and NLR.
CANIT0000600	27121719	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	104	N/A	N/A	The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR ( 5) were independent poor prognostic factors by multivariate analysis.	Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher.	N/A	N/A	Poor performance (NCIT:C115331); 	Performance status	Disease status	 2017 Jan	 Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the  Korean Named-Patient Program Cohort.	 Cancer Res Treat	 PURPOSE: Ipilimumab improves survival in advanced melanoma patients. However, the  efficacy and safety of ipilimumab has not been evaluated in Asian melanoma  patients with a high frequency of mucosal and acral melanoma subtypes. MATERIALS   AND METHODS: Advanced melanoma patients treated with 3 mg/kg ipilimumab in a  Korean multicenter named-patient program (NPP) were evaluated between September  2014 and July 2015. Baseline characteristics and blood parameters including  neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse  events were evaluated according to subtypes. RESULTS: A total of 104 advanced  melanoma patients were treated. The primary sites were acral (31.7%), mucosal  (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients  (65.4%) experienced adverse events, and the most common toxicity was skin rash  (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The   median progression-free survival (PFS) was 2.73 months (95% confidence interval,   2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor  performance status, liver metastasis, and NLR (>/= 5) were independent poor  prognostic factors by multivariate analysis. CONCLUSION: In the Korean NPP  cohort, ipilimumab showed similar efficacy and tolerability compared to Western  patients, regardless of subtypes. All subtypes should benefit from ipilimumab  with consideration of performance status, liver metastasis, and NLR.
CANIT0000601	27124339	Clinical research	Metastatic melanoma after prior anti-PD-1 therapy	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	40	N/A	A retrospective cohort study	Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.	Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient.	N/A	N/A	N/A	N/A	N/A	 2016 May 10	 Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in  patients with metastatic melanoma after prior anti-PD-1 therapy.	 Br J Cancer	 BACKGROUND: Recent phase III clinical trials have established the superiority of   the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4  antibody ipilimumab in the first-line treatment of patients with advanced  melanoma. Ipilimumab will be considered for second-line treatment after the  failure of anti-PD-1 therapy. METHODS: We retrospectively identified a cohort of   40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy   with pembrolizumab or nivolumab and were treated on progression with ipilimumab  at a dose of 3 mg kg(-1) for a maximum of four doses. RESULTS: Ten percent of  patients achieved an objective response to ipilimumab, and an additional 8%  experienced prolonged (>6 months) stable disease. Thirty-five percent of patients  developed grade 3-5 immune-related toxicity associated with ipilimumab therapy.  The most common high-grade immune-related toxicity was diarrhoea. Three patients   (7%) developed grade 3-5 pneumonitis leading to death in one patient.  CONCLUSIONS: Ipilimumab therapy can induce responses in patients who fail the  anti-PD-1 therapy with response rates comparable to previous reports. There  appears to be an increased frequency of high-grade immune-related adverse events   including pneumonitis that warrants close surveillance.
CANIT0000602	27132023	Basic research	A20.2J cells (mouse B-cell lymphoma) 	B-cell lymphoma	EFO:1001938	Blood and lymph nodes	TLR4 (O00206); Alpha-GALCER (N/A); 	TLR4; Alpha-GALCER	PyCS protein plus WT1 antigen plus 7DW8-5 plus monophosphoryl lipid A	N/A	Tumor vaccine	Monophosphoryl lipid A (NCIT:C87754); Alpha Galactosylceramide (NCIT:C1720); WT1 vaccine (NCIT:C104738); Plasmodium yoelii circumsporozoite protein (N/A); 	Cell lines	N/A	Basic research	Our study indicates that 7DW8-5 greatly enhances important synergistic pathways associated to memory immune responses when co-administered with MPLA, thus rendering this combination of adjuvants a novel vaccine adjuvant formulation.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2016 Jul	 Co-administration of alpha-GalCer analog and TLR4 agonist induces robust CD8(+)  T-cell responses to PyCS protein and WT-1 antigen and activates memory-like  effector NKT cells.	 Clin Immunol	 In the present study, the combined adjuvant effect of 7DW8-5, a potent  alpha-GalCer-analog, and monophosphoryl lipid A (MPLA), a TLR4 agonist, on the  induction of vaccine-induced CD8(+) T-cell responses and protective immunity was   evaluated. Mice were immunized with peptides corresponding to the CD8(+) T-cell  epitopes of a malaria antigen, a circumsporozoite protein of Plasmodium yoelii,  and a tumor antigen, a Wilms Tumor antigen-1 (WT-1), together with 7DW8-5 and  MPLA, as an adjuvant. These immunization regimens were able to induce higher  levels of CD8(+) T-cell responses and, ultimately, enhanced levels of protection   against malaria and tumor challenges compared to the levels induced by  immunization with peptides mixed with 7DW8-5 or MPLA alone. Co-administration of   7DW8-5 and MPLA induces activation of memory-like effector natural killer T (NKT)  cells, i.e. CD44(+)CD62L(-)NKT cells. Our study indicates that 7DW8-5 greatly  enhances important synergistic pathways associated to memory immune responses  when co-administered with MPLA, thus rendering this combination of adjuvants a  novel vaccine adjuvant formulation.CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
CANIT0000603	27138582	Clinical research	Triple-negative breast cancer	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	32	N/A	A multicenter, nonrandomized phase Ib	This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with heavily pretreated, advanced TNBC.	Common toxicities were mild and similar to those observed in other tumor cohorts (eg, arthralgia, fatigue, myalgia, and nausea), and included five (15.6%) patients with grade  3 toxicity and one treatment-related death.	N/A	N/A	N/A	N/A	N/A	 2016 Jul 20	 Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib  KEYNOTE-012 Study.	 J Clin Oncol	 PURPOSE: Immune checkpoint inhibition has been demonstrated to be an effective  anticancer strategy. Several lines of evidence support the study of immunotherapy  in triple-negative breast cancer (TNBC). We assessed the safety and antitumor  activity of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab in  patients with advanced TNBC. METHODS: KEYNOTE-012 (ClinicalTrials.gov identifier:  NCT01848834) was a multicenter, nonrandomized phase Ib trial of single-agent  pembrolizumab given intravenously at 10 mg/kg every 2 weeks to patients with  advanced PD-L1-positive (expression in stroma or >/= 1% of tumor cells by  immunohistochemistry) TNBC, gastric cancer, urothelial cancer, and head and neck   cancer. This report focuses on the TNBC cohort. RESULTS: Among 111 patients with   TNBC whose tumor samples were screened for PD-L1 expression, 58.6% had  PD-L1-positive tumors. Thirty-two women (median age, 50.5 years; range, 29 to 72   years) were enrolled and assessed for safety and antitumor activity. The median  number of doses administered was five (range, 1 to 36 doses). Common toxicities  were mild and similar to those observed in other tumor cohorts (eg, arthralgia,  fatigue, myalgia, and nausea), and included five (15.6%) patients with grade >/=   3 toxicity and one treatment-related death. Among the 27 patients who were  evaluable for antitumor activity, the overall response rate was 18.5%, the median  time to response was 17.9 weeks (range, 7.3 to 32.4 weeks), and the median  duration of response was not yet reached (range, 15.0 to >/= 47.3 weeks).  CONCLUSION: This phase Ib study describes preliminary evidence of clinical  activity and a potentially acceptable safety profile of pembrolizumab given every  2 weeks to patients with heavily pretreated, advanced TNBC. A single-agent phase   II study examining a 200-mg dose given once every 3 weeks (ClinicalTrials.gov  identifier: NCT02447003) is ongoing.CI  - (c) 2016 by American Society of Clinical Oncology.
CANIT0000604	27145284	Basic research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies	N/A	Immune checkpoint therapy	CART-anti-PD-L1 antibodies (NCIT:C150682); 	Cell lines/ animal models	N/A	Basic research	These armed second-generation CAR T cells empowered to secrete human anti-PD-L1 antibodies in the ccRCC milieu to combat T cell exhaustion is an innovation in this field that should provide renewed potential for CAR T cell immunotherapy of solid tumors where limited efficacy is currently seen.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2016 Jun 7	 Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more  effectively regress renal cell carcinoma in a humanized mouse model.	 Oncotarget	 Advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC)  have led to improved progression-free survival of many patients; however the  therapies are toxic, rarely achieve durable long-term complete responses and are   not curative. Herein we used a single bicistronic lentiviral vector to develop a   new combination immunotherapy that consists of human anti-carbonic anhydrase IX  (CAIX)-targeted chimeric antigen receptor (CAR) T cells engineered to secrete  human anti-programmed death ligand 1 (PD-L1) antibodies at the tumor site. The  local antibody delivery led to marked immune checkpoint blockade. Tumor growth  diminished 5 times and tumor weight reduced 50-80% when compared with the  anti-CAIX CAR T cells alone in a humanized mice model of ccRCC. The expression of  PD-L1 and Ki67 in the tumors decreased and an increase in granzyme B levels was  found in CAR T cells. The anti-PD-L1 IgG1 isotype, which is capable of mediating   ADCC, was also able to recruit human NK cells to the tumor site in vivo. These  armed second-generation CAR T cells empowered to secrete human anti-PD-L1  antibodies in the ccRCC milieu to combat T cell exhaustion is an innovation in  this field that should provide renewed potential for CAR T cell immunotherapy of   solid tumors where limited efficacy is currently seen.
CANIT0000605	27159395	Clinical research	POLE-mutant endometrial cancer	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	N/A	Together, these data suggest that cancers harboring POLE mutations are good  candidates for immune checkpoint inhibitor therapy.	N/A	N/A	N/A	POLE (Q07864); 	POLE R114 mutation	Mutational status	 2016 Jun 1	 Immune activation and response to pembrolizumab in POLE-mutant endometrial  cancer.	 J Clin Invest	 Antibodies that target the immune checkpoint receptor programmed cell death  protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a  variety of human cancers. However, anti-PD-1 therapy in some patients provides no  benefit and/or results in adverse side effects. The factors that determine  whether patients will be drug sensitive or resistant are not fully understood;  therefore, genomic assessment of exceptional responders can provide important  insight into patient response. Here, we identified a patient with endometrial  cancer who had an exceptional response to the anti-PD-1 antibody pembrolizumab.  Clinical grade targeted genomic profiling of a pretreatment tumor sample from  this individual identified a mutation in DNA polymerase epsilon (POLE) that  associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas  (TCGA) revealed that the presence of POLE mutation associates with high  mutational burden and elevated expression of several immune checkpoint genes.  Together, these data suggest that cancers harboring POLE mutations are good  candidates for immune checkpoint inhibitor therapy.
CANIT0000606	27159395	Clinical research	POLE-mutant endometrial cancer	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	N/A	Together, these data suggest that cancers harboring POLE mutations are good  candidates for immune checkpoint inhibitor therapy.	N/A	N/A	N/A	POLE (Q07864); 	POLE V411L mutation	Mutational status	 2016 Jun 1	 Immune activation and response to pembrolizumab in POLE-mutant endometrial  cancer.	 J Clin Invest	 Antibodies that target the immune checkpoint receptor programmed cell death  protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a  variety of human cancers. However, anti-PD-1 therapy in some patients provides no  benefit and/or results in adverse side effects. The factors that determine  whether patients will be drug sensitive or resistant are not fully understood;  therefore, genomic assessment of exceptional responders can provide important  insight into patient response. Here, we identified a patient with endometrial  cancer who had an exceptional response to the anti-PD-1 antibody pembrolizumab.  Clinical grade targeted genomic profiling of a pretreatment tumor sample from  this individual identified a mutation in DNA polymerase epsilon (POLE) that  associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas  (TCGA) revealed that the presence of POLE mutation associates with high  mutational burden and elevated expression of several immune checkpoint genes.  Together, these data suggest that cancers harboring POLE mutations are good  candidates for immune checkpoint inhibitor therapy.
CANIT0000607	27169593	Clinical research	Glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	CTLA-4 (P16410); VEGF (P15692); 	CTLA-4; VEGF	Ipilimumab plus bevacizumab	N/A	Immune checkpoint therapy plus Target therapy	Ipilimumab (DB06186); bevacizumab (DB00112); 	20	N/A	N/A	Ipilimumab and bevacizumab in combination show promising activity with a predictable and manageable toxicity profile, warranting further clinical studies.	The treatment combination was well tolerated, with treatment terminated before completion due to adverse events in two patients. Autoimmune toxicity was manageable with systemic corticosteroid therapy.	N/A	N/A	N/A	N/A	N/A	 2016 Oct	 Ipilimumab and Bevacizumab in Glioblastoma.	 Clin Oncol (R Coll Radiol)	 The median survival in glioblastoma is just over a year, with no standard  second-line therapy. Ipilimumab is an immune checkpoint inhibitor that activates   the anti-tumour immune response by cytotoxic T-lymphocyte antigen-4 blockade.  There is significant evidence supporting its role in the treatment of malignant  melanoma, including in patients with brain metastases. The addition of the  anti-angiogenesis agent, bevacizumab, seems to offer additional benefit and limit  the immune-related side-effects of ipilimumab in melanoma. To date there have  been no clinical trials investigating this combination in glioblastoma. In this  single practice case series, 20 patients with glioblastoma were consented for and  treated with ipilimumab and bevacizumab in combination. Safety, tolerability and   the response to treatment were reviewed for all patients. Three patients were  treated after palliative first-line radiotherapy, one patient after first-line  chemoradiation and 16 patients were treated with recurrent disease. Sixty-five  per cent of patients completed four cycles of 3 weekly ipilimumab therapy,  administered with 2 weekly bevacizumab. Radiographic responses for patients with   recurrent disease were evaluated by Response Assessment in Neuro-oncology (RANO)   criteria; 31% of patients showed a partial response, 31% had stable disease and  38% had disease progression. The treatment combination was well tolerated, with  treatment terminated before completion due to adverse events in two patients.  Autoimmune toxicity was manageable with systemic corticosteroid therapy.  Ipilimumab and bevacizumab in combination show promising activity with a  predictable and manageable toxicity profile, warranting further clinical studies.CI  - Copyright (c) 2016 The Royal College of Radiologists. Published by Elsevier Ltd.   All rights reserved.
CANIT0000608	27169993	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	82	N/A	N/A	Increases in absolute lymphocyte counts (ALC) 2 to 8 weeks (P = 0.003) was correlated with improved survival.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2016 Oct 1	 Increases in Absolute Lymphocytes and Circulating CD4+ and CD8+ T Cells Are  Associated with Positive Clinical Outcome of Melanoma Patients Treated with  Ipilimumab.	 Clin Cancer Res	 PURPOSE: To investigate changes of peripheral blood biomarkers and their impact  on clinical outcome following treatment with ipilimumab in advanced melanoma  patients. EXPERIMENTAL DESIGN: Changes in blood counts and the frequency of  circulating immune cell populations analyzed by flow cytometry were investigated   in 82 patients to compare baseline values with different time-points after  starting ipilimumab. Endpoints were overall survival (OS) and best clinical  response. Statistical calculations were done by Wilcoxon-matched pairs tests,  Fisher exact test, Kaplan-Meier analysis, and Cox regression analysis. RESULTS:  Increases in absolute lymphocyte counts (ALC) 2 to 8 weeks (P = 0.003) and in  percentages of CD4(+) and CD8(+) T cells 8 to 14 weeks (P = 0.001 and P = 0.02)  after the first dose of ipilimumab were correlated with improved survival. These   associations did not meet significance criteria, when conservatively adjusted for  multiple testing, but were additionally correlated with clinical responses (all P  < 0.05). However, validation is required. Increases in all three factors were  observed in 36% of patients, who had a favorable outcome and survival  probabilities of 93.3% and 63.8% at 12 and 24 months, respectively. A partial or   complete response was observed in 71% of these patients compared with only 8% in   patients with decreases in >/=1 of the 3 factors, respectively. Changes of  regulatory T cells or myeloid-derived suppressor cells were not associated with  OS. CONCLUSIONS: Increases of ALC observed 2 to 8 weeks after initiation of  ipilimumab and delayed increases in CD4(+) and CD8(+) T cells reflect changes  associated with positive outcome. These changes represent surrogate marker  candidates and warrant further validation. Clin Cancer Res; 22(19); 4848-58.  (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000609	27169993	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	82	N/A	N/A	Increases in percentages of CD4+ T cells 8 to 14 weeks (P = 0.001) after the first dose of ipilimumab was correlated with improved survival.	N/A	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	Percentage of CD4(+) T-cell 	Gene expression signature on/in immune cell	 2016 Oct 1	 Increases in Absolute Lymphocytes and Circulating CD4+ and CD8+ T Cells Are  Associated with Positive Clinical Outcome of Melanoma Patients Treated with  Ipilimumab.	 Clin Cancer Res	 PURPOSE: To investigate changes of peripheral blood biomarkers and their impact  on clinical outcome following treatment with ipilimumab in advanced melanoma  patients. EXPERIMENTAL DESIGN: Changes in blood counts and the frequency of  circulating immune cell populations analyzed by flow cytometry were investigated   in 82 patients to compare baseline values with different time-points after  starting ipilimumab. Endpoints were overall survival (OS) and best clinical  response. Statistical calculations were done by Wilcoxon-matched pairs tests,  Fisher exact test, Kaplan-Meier analysis, and Cox regression analysis. RESULTS:  Increases in absolute lymphocyte counts (ALC) 2 to 8 weeks (P = 0.003) and in  percentages of CD4(+) and CD8(+) T cells 8 to 14 weeks (P = 0.001 and P = 0.02)  after the first dose of ipilimumab were correlated with improved survival. These   associations did not meet significance criteria, when conservatively adjusted for  multiple testing, but were additionally correlated with clinical responses (all P  < 0.05). However, validation is required. Increases in all three factors were  observed in 36% of patients, who had a favorable outcome and survival  probabilities of 93.3% and 63.8% at 12 and 24 months, respectively. A partial or   complete response was observed in 71% of these patients compared with only 8% in   patients with decreases in >/=1 of the 3 factors, respectively. Changes of  regulatory T cells or myeloid-derived suppressor cells were not associated with  OS. CONCLUSIONS: Increases of ALC observed 2 to 8 weeks after initiation of  ipilimumab and delayed increases in CD4(+) and CD8(+) T cells reflect changes  associated with positive outcome. These changes represent surrogate marker  candidates and warrant further validation. Clin Cancer Res; 22(19); 4848-58.  (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000610	27169993	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	82	N/A	N/A	Increases in percentages of CD8+ T cells 8 to 14 weeks (P = 0.02) after the first dose of ipilimumab was correlated with improved survival.	N/A	N/A	N/A	Effector-memory type 1 T-cells (NCIT:C126419); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Percentage of CD8(+) effector-memory type 1 T-cell 	Gene expression signature on/in immune cell	 2016 Oct 1	 Increases in Absolute Lymphocytes and Circulating CD4+ and CD8+ T Cells Are  Associated with Positive Clinical Outcome of Melanoma Patients Treated with  Ipilimumab.	 Clin Cancer Res	 PURPOSE: To investigate changes of peripheral blood biomarkers and their impact  on clinical outcome following treatment with ipilimumab in advanced melanoma  patients. EXPERIMENTAL DESIGN: Changes in blood counts and the frequency of  circulating immune cell populations analyzed by flow cytometry were investigated   in 82 patients to compare baseline values with different time-points after  starting ipilimumab. Endpoints were overall survival (OS) and best clinical  response. Statistical calculations were done by Wilcoxon-matched pairs tests,  Fisher exact test, Kaplan-Meier analysis, and Cox regression analysis. RESULTS:  Increases in absolute lymphocyte counts (ALC) 2 to 8 weeks (P = 0.003) and in  percentages of CD4(+) and CD8(+) T cells 8 to 14 weeks (P = 0.001 and P = 0.02)  after the first dose of ipilimumab were correlated with improved survival. These   associations did not meet significance criteria, when conservatively adjusted for  multiple testing, but were additionally correlated with clinical responses (all P  < 0.05). However, validation is required. Increases in all three factors were  observed in 36% of patients, who had a favorable outcome and survival  probabilities of 93.3% and 63.8% at 12 and 24 months, respectively. A partial or   complete response was observed in 71% of these patients compared with only 8% in   patients with decreases in >/=1 of the 3 factors, respectively. Changes of  regulatory T cells or myeloid-derived suppressor cells were not associated with  OS. CONCLUSIONS: Increases of ALC observed 2 to 8 weeks after initiation of  ipilimumab and delayed increases in CD4(+) and CD8(+) T cells reflect changes  associated with positive outcome. These changes represent surrogate marker  candidates and warrant further validation. Clin Cancer Res; 22(19); 4848-58.  (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000611	27170423	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Late presentation of generalised bullous pemphigoid-like reaction	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Late presentation of generalised bullous pemphigoid-like reaction in a patient  treated with pembrolizumab for metastatic melanoma.	 Australas J Dermatol	 Dermatological toxicity is one of the most commonly reported immune-related  adverse events in patients receiving checkpoint inhibitor immunotherapy. We  report the gradual development of a widespread bullous pemphigoid-like reaction  in a metastatic melanoma patient 8 months after commencing treatment with the  programmed-death-1 (PD-1) inhibitor pembrolizumab, requiring prolonged  corticosteroid therapy. This case highlights the potential for insidious and late  development of severe cutaneous toxicity following PD-1 inhibitor therapy and  suggests that even prolonged immunosuppression may not necessarily compromise the  efficacy of PD-1 inhibition in advanced melanoma.CI  - (c) 2016 The Australasian College of Dermatologists.
CANIT0000612	27178742	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	56	50	N/A	Low levels of MDSCs before CTLA-4 therapy correlated with an objective clinical response, long-term survival, increased CD247 expression in T cells, and an improved clinical status.	N/A	N/A	N/A	HLA (P04439); CD11 (P11215); CD33 (P20138); Monocytic myeloid-derived suppressor cells (NCIT:C129908); 	CD33(+)CD11b(+)HLA-DR-myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2016 Dec 1	 Clinical Significance of Circulating CD33+CD11b+HLA-DR- Myeloid Cells in Patients  with Stage IV Melanoma Treated with Ipilimumab.	 Clin Cancer Res	 PURPOSE: High levels of circulating myeloid-derived suppressor cells (MDSCs) in  various cancer types, including melanoma, were shown to correlate with poor  survival. We investigated whether frequencies of circulating  CD33(+)CD11b(+)HLA-DR(-) MDSCs could be used as immune system monitoring  biomarkers to predict response and survival of patients with stage IV melanoma  treated with anti-CTLA4 (ipilimumab) therapy. EXPERIMENTAL DESIGN: Peripheral  blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for  CD33(+)CD11b(+)HLA-DR(-) MDSC percentage, NO(-), and hROS levels by flow  cytometry. We determined whether MDSC levels and suppressive features detected  before anti-CTLA4 therapy correlate with the patients' response and overall  survival (OS). RESULTS: Patients with melanoma had significantly higher levels of  circulating CD33(+)CD11b(+)HLA-DR(-) MDSCs with suppressive phenotype when  compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an  objective clinical response, long-term survival, increased CD247 expression in T   cells, and an improved clinical status. No predictive impact was observed for  lactate dehydrogenase (LDH). Kaplan-Meier and log-rank tests performed on the 56   patients showed that the presence of more than 55.5% of circulating  CD33(+)CD11b(+) out of the HLA-DR(-) cells, were associated with significant  short OS (P < 0.003), a median of 6.5 months, in comparison with the group  showing lower MDSC frequencies, with a median survival of 15.6 months.  CONCLUSIONS: Our study suggests the use of CD33(+)CD11b(+)HLA-DR(-) cells as a  predictive and prognostic biomarker in patients with stage IV melanoma treated  with anti-CTLA4 therapy. This monitoring system may aid in the development of  combinatorial modalities, targeting the suppressive environment in conjunction  with iplimumab, toward facilitating better disease outcomes. Clin Cancer Res;  22(23); 5661-72. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000613	27178742	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	56	50	N/A	No predictive impact was observed for lactate dehydrogenase (LDH).  Our study suggests the use of CD33(+)CD11b(+)HLA-DR(-) cells as a  predictive and prognostic biomarker in patients with stage IV melanoma treated  with anti-CTLA4 therapy. This monitoring system may aid in the development of  combinatorial modalities, targeting the suppressive environment in conjunction  with iplimumab, toward facilitating better disease outcomes. 	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Dec 1	 Clinical Significance of Circulating CD33+CD11b+HLA-DR- Myeloid Cells in Patients  with Stage IV Melanoma Treated with Ipilimumab.	 Clin Cancer Res	 PURPOSE: High levels of circulating myeloid-derived suppressor cells (MDSCs) in  various cancer types, including melanoma, were shown to correlate with poor  survival. We investigated whether frequencies of circulating  CD33(+)CD11b(+)HLA-DR(-) MDSCs could be used as immune system monitoring  biomarkers to predict response and survival of patients with stage IV melanoma  treated with anti-CTLA4 (ipilimumab) therapy. EXPERIMENTAL DESIGN: Peripheral  blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for  CD33(+)CD11b(+)HLA-DR(-) MDSC percentage, NO(-), and hROS levels by flow  cytometry. We determined whether MDSC levels and suppressive features detected  before anti-CTLA4 therapy correlate with the patients' response and overall  survival (OS). RESULTS: Patients with melanoma had significantly higher levels of  circulating CD33(+)CD11b(+)HLA-DR(-) MDSCs with suppressive phenotype when  compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an  objective clinical response, long-term survival, increased CD247 expression in T   cells, and an improved clinical status. No predictive impact was observed for  lactate dehydrogenase (LDH). Kaplan-Meier and log-rank tests performed on the 56   patients showed that the presence of more than 55.5% of circulating  CD33(+)CD11b(+) out of the HLA-DR(-) cells, were associated with significant  short OS (P < 0.003), a median of 6.5 months, in comparison with the group  showing lower MDSC frequencies, with a median survival of 15.6 months.  CONCLUSIONS: Our study suggests the use of CD33(+)CD11b(+)HLA-DR(-) cells as a  predictive and prognostic biomarker in patients with stage IV melanoma treated  with anti-CTLA4 therapy. This monitoring system may aid in the development of  combinatorial modalities, targeting the suppressive environment in conjunction  with iplimumab, toward facilitating better disease outcomes. Clin Cancer Res;  22(23); 5661-72. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000614	27178742	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	56	50	N/A	Our study suggests the use of CD33(+)CD11b(+)HLA-DR(-) cells as a  predictive and prognostic biomarker in patients with stage IV melanoma treated  with anti-CTLA4 therapy. This monitoring system may aid in the development of  combinatorial modalities, targeting the suppressive environment in conjunction  with iplimumab, toward facilitating better disease outcomes.No predictive impact was observed for lactate dehydrogenase (LDH). 	N/A	N/A	N/A	HLA (P04439); CD11 (P11215); CD33 (P20138); Monocytic myeloid-derived suppressor cells (NCIT:C129908); 	CD33(+)CD11b(+)HLA-DR-myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2016 Dec 1	 Clinical Significance of Circulating CD33+CD11b+HLA-DR- Myeloid Cells in Patients  with Stage IV Melanoma Treated with Ipilimumab.	 Clin Cancer Res	 PURPOSE: High levels of circulating myeloid-derived suppressor cells (MDSCs) in  various cancer types, including melanoma, were shown to correlate with poor  survival. We investigated whether frequencies of circulating  CD33(+)CD11b(+)HLA-DR(-) MDSCs could be used as immune system monitoring  biomarkers to predict response and survival of patients with stage IV melanoma  treated with anti-CTLA4 (ipilimumab) therapy. EXPERIMENTAL DESIGN: Peripheral  blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for  CD33(+)CD11b(+)HLA-DR(-) MDSC percentage, NO(-), and hROS levels by flow  cytometry. We determined whether MDSC levels and suppressive features detected  before anti-CTLA4 therapy correlate with the patients' response and overall  survival (OS). RESULTS: Patients with melanoma had significantly higher levels of  circulating CD33(+)CD11b(+)HLA-DR(-) MDSCs with suppressive phenotype when  compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an  objective clinical response, long-term survival, increased CD247 expression in T   cells, and an improved clinical status. No predictive impact was observed for  lactate dehydrogenase (LDH). Kaplan-Meier and log-rank tests performed on the 56   patients showed that the presence of more than 55.5% of circulating  CD33(+)CD11b(+) out of the HLA-DR(-) cells, were associated with significant  short OS (P < 0.003), a median of 6.5 months, in comparison with the group  showing lower MDSC frequencies, with a median survival of 15.6 months.  CONCLUSIONS: Our study suggests the use of CD33(+)CD11b(+)HLA-DR(-) cells as a  predictive and prognostic biomarker in patients with stage IV melanoma treated  with anti-CTLA4 therapy. This monitoring system may aid in the development of  combinatorial modalities, targeting the suppressive environment in conjunction  with iplimumab, toward facilitating better disease outcomes. Clin Cancer Res;  22(23); 5661-72. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000615	27181090	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Fulminant type 1 diabetes mellitus	N/A	N/A	PD-L1 (Q9NZQ7); 	N/A	Gene expression signature on/in tumor cell	 2016 Nov	 Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy.	 J Diabetes Investig	 Anti-programmed cell death-1 (PD-1) antibodies are regarded as a risk factor for   insulin-dependent diabetes mellitus as a side-effect. While a small number of  cases have been reported, evidence remains limited. This is the first report of  an Asian patient developing insulin-dependent diabetes during anti-PD-1 therapy.   A 55-year-old euglycemic woman receiving nivolumab for malignant melanoma showed   abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and   hemoglobin A1c (7.0%). Over the next 2 weeks, serum C-peptide levels fell below  the limit of detection. Islet autoantibodies were negative, and the patient  showed a human leukocyte antigen haplotype associated with type 1 diabetes.  Anti-PD-1 therapy can cause rapid onset of insulin-dependent diabetes, possibly  because of inappropriate activation of T cells. Human leukocyte antigen  haplotypes might be related to the onset of this disease. Physicians should be  aware of this serious adverse event and carry out routine blood glucose testing  during anti-PD-1 therapy.CI  - (c) 2016 The Authors. Journal of Diabetes Investigation published by Asian  Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia,  Ltd.
CANIT0000616	27197063	Clinical research	Metastatic melanoma who progressed on ipilimumab	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	116	N/A	A retrospective cohort study	This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Prolonged Benefit from Ipilimumab Correlates with Improved Outcomes from  Subsequent Pembrolizumab.	 Cancer Immunol Res	 Patients with metastatic melanoma whose disease progresses on ipilimumab can  clearly derive benefit from subsequent anti-programmed death-1 (PD-1). However,  patients experience heterogeneous outcomes with ipilimumab, including rapid or  delayed progression, and it is unclear whether patterns of ipilimumab progression  influence subsequent clinical responses to anti-PD-1. We retrospectively reviewed  data from 116 patients with metastatic melanoma who progressed on ipilimumab and   were subsequently treated with pembrolizumab. The study objectives were to  determine whether progression-free survival (PFS) with ipilimumab was associated   with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR +  stable disease) with pembrolizumab. Patients with PFS >/=90 days after treatment   with ipilimumab generally had superior outcomes with subsequent pembrolizumab  treatment compared with patients with PFS <90 days (ORR, 49% vs. 35%, P = 0.12;  CBR, 66% vs. 46%, P = 0.03). Patients with prolonged ipilimumab benefit (PFS >/=   180 days) had excellent outcomes with pembrolizumab compared with rapid  progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249  vs. 50 days). Using logistic regression models, PFS with ipilimumab was  independently correlated with response to pembrolizumab (odds ratio, 1.22; 95%  CI, 1.02-1.51). This study shows that prolonged PFS with ipilimumab predicts  excellent outcomes with subsequent pembrolizumab treatment, offering valuable  prognostic information for clinicians. Cancer Immunol Res; 4(7); 569-73. (c)2016   AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000617	27243803	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	168	N/A	A blinded, randomized, multicenter, phase 2 dose-ranging  trial	In this subgroup analysis, a proportion of patients who continued treatment beyond RECIST-defined first progression demonstrated sustained reductions in tumor burden or stabilization in the size of target lesions, with an acceptable safety profile. Further analysis will help  define the clinical benefit for patients with mRCC treated with nivolumab beyond progression.	The incidence of treatment-related adverse events was higher in patients treated beyond progression (n = 29 [81%]) vs those not treated beyond progression (n = 61 [66%]); however, after adjusting for length of treatment exposure, incidence was lower in patients treated beyond progression (322.9 vs 518.7 incidence rate/100 patient-years for patients treated vs not treated beyond progression).	N/A	N/A	N/A	N/A	N/A	 2016 Sep 1	 Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma  Treated Beyond Progression: A Subgroup Analysis of a Randomized Clinical Trial.	 JAMA Oncol	 IMPORTANCE: Response patterns with immunotherapy may differ from those of other  treatments. This warrants further investigation because some patients may benefit  from continued immunotherapy beyond Response Evaluation Criteria in Solid Tumors   (RECIST)-defined first progression. OBJECTIVE: To evaluate the safety and  potential benefit of treatment with nivolumab, a programmed cell death 1 immune  checkpoint inhibitor, beyond investigator-assessed first progression in patients   with metastatic renal cell carcinoma (mRCC). DESIGN, SETTING, AND PARTICIPANTS:  Subgroup analysis of a blinded, randomized, multicenter, phase 2 dose-ranging  trial initiated May 31, 2011, including patients with clear-cell mRCC previously   treated with antiangiogenic therapy. Data cutoffs for this subgroup analysis were  May 15, 2013, for progression-free survival and objective response rate and March  5, 2014, for overall survival and duration of response. In this analysis,  patients treated beyond first progression received their last dose of nivolumab  more than 6 weeks after RECIST-defined progression, and patients not treated  beyond first progression discontinued nivolumab before or at RECIST-defined  progression. INTERVENTIONS: Nivolumab 0.3, 2, or 10 mg/kg intravenously every 3  weeks. MAIN OUTCOMES AND MEASURES: Safety and efficacy of nivolumab treatment.  RESULTS: Of 168 patients (median [range] age, 61 [37-81] years; 72% male)  randomized to nivolumab, 154 experienced progression (36 were treated beyond  first progression, 26 were treated beyond first progression for </=6 weeks, and  92 were not treated beyond first progression), 13 were treated and did not  experience progression, and 1 was not treated. Prior to first progression, the  RECIST-defined objective response rate was 14% (5 patients) and 16% (15  patients), and median progression-free survival was 4.2 (95% CI, 2.8-5.5) and 2.6  (95% CI, 1.5-3.9) months in patients treated and not treated beyond progression,   respectively. Following initial progression, 25 (69%) patients treated beyond  progression experienced subsequent tumor reduction or stabilization in target  lesion size. The incidence of treatment-related adverse events was higher in  patients treated beyond progression (n = 29 [81%]) vs those not treated beyond  progression (n = 61 [66%]); however, after adjusting for length of treatment  exposure, incidence was lower in patients treated beyond progression (322.9 vs  518.7 incidence rate/100 patient-years for patients treated vs not treated beyond  progression). CONCLUSIONS AND RELEVANCE: In this subgroup analysis, a proportion   of patients who continued treatment beyond RECIST-defined first progression  demonstrated sustained reductions in tumor burden or stabilization in the size of  target lesions, with an acceptable safety profile. Further analysis will help  define the clinical benefit for patients with mRCC treated with nivolumab beyond   progression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01354431.
CANIT0000618	27247226	Clinical research	Recurrent or metastatic squamous cell carcinoma of the head and neck	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	60	N/A	An open-label, multicentre, phase Ib	Pembrolizumab was well tolerated and demonstrated clinically meaningful antitumour activity in recurrent or metastatic squamous cell carcinoma of the head and neck, supporting further study of  pembrolizumab as anticancer therapy for advanced head and neck cancers. The proportion of patients with an overall response by central imaging review was  18% (eight of 45 patients; 95% CI 8-32) in all patients and was 25% (four of 16  patients; 7-52) in HPV-positive patients and 14% (four of 29 patients; 4-32) in  HPV-negative patients.	Pembrolizumab was well tolerated, with 10 (17%) of 60 patients having grade 3-4 drug-related adverse events, the most common of which were increases in alanine aminotransferase and in aspartate aminotransferase, and hyponatraemia, each occurring in two of 60 patients; one patient developed a grade 3 drug-related rash. 27 (45%) of 60 patients experienced a serious adverse event. There were no drug-related deaths.	N/A	N/A	HPV (NCIT:C14226); 	HPV-positive	Microbiota	 2016 Jul	 Safety and clinical activity of pembrolizumab for treatment of recurrent or  metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an  open-label, multicentre, phase 1b trial.	 Lancet Oncol	 BACKGROUND: Patients with recurrent or metastatic squamous cell carcinoma of the   head and neck have few treatment options. We aimed to assess the safety,  tolerability, and antitumour activity of pembrolizumab, a humanised  anti-programmed death receptor 1 (PD-1) antibody, in patients with PD-L1-positive  recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS:  This study was an open-label, multicentre, phase 1b trial of patients with  recurrent or metastatic squamous cell carcinoma of the head and neck. Patients  were eligible for enrolment if they were aged 18 years or older, had a confirmed   diagnosis of recurrent or metastatic squamous cell carcinoma of the head and  neck, and had any level of PD-L1 expression (ie, at least 1% of tumour cells or  stroma that were PD-L1-positive by immunohistochemistry). Patients received  pembrolizumab 10 mg/kg intravenously every 2 weeks. Primary outcomes were safety   in the per-protocol population and the proportion of patients with centrally  reviewed overall response per Response Evaluation Criteria In Solid Tumors  (RECIST, version 1.1). Overall response was analysed in the full analysis set,  which was defined as all patients who had received at least one dose of  pembrolizumab, had measurable disease at baseline, and one post-baseline scan or   patients without a post-baseline scan who discontinued therapy because of disease  progression or a drug-related adverse event. The study is registered with  ClinicalTrials.gov, number NCT01848834 and is ongoing, but no longer enrolling  patients. FINDINGS: Of the 104 patients screened between June 7, 2013, and Oct 3,  2013, 81 (78%) were PD-L1-positive. Of these, 60 patients with PD-L1-positive  squamous cell carcinoma of the head and neck were enrolled and treated: 23 (38%)   were HPV-positive and 37 (62%) were HPV-negative. Pembrolizumab was well  tolerated, with 10 (17%) of 60 patients having grade 3-4 drug-related adverse  events, the most common of which were increases in alanine aminotransferase and  in aspartate aminotransferase, and hyponatraemia, each occurring in two of 60  patients; one patient developed a grade 3 drug-related rash. 27 (45%) of 60  patients experienced a serious adverse event. There were no drug-related deaths.   The proportion of patients with an overall response by central imaging review was  18% (eight of 45 patients; 95% CI 8-32) in all patients and was 25% (four of 16  patients; 7-52) in HPV-positive patients and 14% (four of 29 patients; 4-32) in  HPV-negative patients. INTERPRETATION: Pembrolizumab was well tolerated and  demonstrated clinically meaningful antitumour activity in recurrent or metastatic  squamous cell carcinoma of the head and neck, supporting further study of  pembrolizumab as anticancer therapy for advanced head and neck cancers. FUNDING:   Merck & Co.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000619	27254075	Case report	Symptomatic brain metastases in melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Complete remission	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Oct	 Rapid remission of symptomatic brain metastases in melanoma by  programmed-death-receptor-1 inhibition.	 Melanoma Res	 Although approximately 40% of patients with metastatic melanoma develop brain  metastases, the presence of brain metastases often precludes enrolment in  clinical trials for advanced melanoma. However, the development of symptomatic  brain metastases markedly increases mortality. The  antiprogrammed-death-receptor-1 antibody pembrolizumab achieves extracranial  metastases disease response rates of up to 50%. Here, we report the rapid and  sustained response of symptomatic multifocal brain metastases in a melanoma  ipilimumab-pretreated patient under pembrolizumab, combined with high-dose  dexamethasone therapy during the induction phase of therapy. Complete remission  has been maintained for over 1 year of follow-up and has correlated with the  response rate observed in the extracranial metastases. Radiological disease  response was identified during the first follow-up visit in the absence of  adjuvant radiotherapy. This report highlights the need for further clinical  studies to specifically address the therapeutic potential of  antiprogrammed-death-receptor-1 monotherapy in the management of untreated brain   metastases in melanoma.
CANIT0000620	27260623	Case report	Malignant cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Vitreous metastasis	N/A	N/A	N/A	N/A	N/A	 2017 Feb	 [Vitreous metastasis of malignant cutaneous melanoma during treatment with  ipilimumab].	 Ophthalmologe	 An isolated metastasis of the vitreous body from a malignant cutaneous melanoma  without involvement of the choroid is an extremely rare occurrence. We report on   the case of a 59-year-old female patient who presented with a vitreous body  metastasis during systemic treatment with the anti-cytotoxic T  lymphocyte-associated antigen (anti-CTLA 4) antibody ipilimumab. This case report  underlines the diagnostic difficulties in such cases and points out the risk of  metastasis in immune-privileged sites under systemic immunotherapy.
CANIT0000621	27267608	Clinical research	Patients with melanoma or non-small-cell lung cancer	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	52	N/A	A non-randomised, open-label, phase II	Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases.	Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort.	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Pembrolizumab for patients with melanoma or non-small-cell lung cancer and  untreated brain metastases: early analysis of a non-randomised, open-label, phase  2 trial.	 Lancet Oncol	 BACKGROUND: Immunotherapy targeting the PD-1 axis has activity in several tumour   types. We aimed to establish the activity and safety of the PD-1 inhibitor  pembrolizumab in patients with untreated brain metastases from melanoma or  non-small-cell lung cancer (NSCLC). METHODS: In this non-randomised, open-label,   phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC  with untreated brain metastases from the Yale Cancer Center. Patients had at  least one untreated or progressive brain metastasis between 5 and 20 mm in  diameter without associated neurological symptoms or the need for  corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1  expression; this was not required for patients with melanoma. Patients were given  10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was   brain metastasis response assessed in all treated patients. The trial is ongoing   and here we present an early analysis. The study is registered with  ClinicalTrials.gov, number NCT02085070. FINDINGS: Between March 31, 2014, and May  31, 2015, we screened 52 patients with untreated or progressive brain metastases   (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with  NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18  patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses   were durable, with all but one patient with NSCLC who responded showing an  ongoing response at the time of data analysis on June 30, 2015. Treatment-related  serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1  [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis  (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and  grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically  significant neurological adverse events included transient grade 3 cognitive  dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort.  INTERPRETATION: Pembrolizumab shows activity in brain metastases in patients with  melanoma or NSCLC with an acceptable safety profile, which suggests that there  might be a role for systemic immunotherapy in patients with untreated or  progressive brain metastases. FUNDING: Merck and the Yale Cancer Center.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000622	27267608	Clinical research	Patients with melanoma or non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	52	N/A	A non-randomised, open-label, phase II	Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases.	Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort.	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Pembrolizumab for patients with melanoma or non-small-cell lung cancer and  untreated brain metastases: early analysis of a non-randomised, open-label, phase  2 trial.	 Lancet Oncol	 BACKGROUND: Immunotherapy targeting the PD-1 axis has activity in several tumour   types. We aimed to establish the activity and safety of the PD-1 inhibitor  pembrolizumab in patients with untreated brain metastases from melanoma or  non-small-cell lung cancer (NSCLC). METHODS: In this non-randomised, open-label,   phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC  with untreated brain metastases from the Yale Cancer Center. Patients had at  least one untreated or progressive brain metastasis between 5 and 20 mm in  diameter without associated neurological symptoms or the need for  corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1  expression; this was not required for patients with melanoma. Patients were given  10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was   brain metastasis response assessed in all treated patients. The trial is ongoing   and here we present an early analysis. The study is registered with  ClinicalTrials.gov, number NCT02085070. FINDINGS: Between March 31, 2014, and May  31, 2015, we screened 52 patients with untreated or progressive brain metastases   (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with  NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18  patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses   were durable, with all but one patient with NSCLC who responded showing an  ongoing response at the time of data analysis on June 30, 2015. Treatment-related  serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1  [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis  (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and  grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically  significant neurological adverse events included transient grade 3 cognitive  dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort.  INTERPRETATION: Pembrolizumab shows activity in brain metastases in patients with  melanoma or NSCLC with an acceptable safety profile, which suggests that there  might be a role for systemic immunotherapy in patients with untreated or  progressive brain metastases. FUNDING: Merck and the Yale Cancer Center.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000623	27269940	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	MART1-specific CTLs followed by ipilimumab	N/A	Chemotherapy followed by Immune checkpoint therapy	MART1-specific CTLs (NCIT:C91088); ipilimumab (DB06186); 	10	N/A	N/A	Combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses, highlighting the promise of this strategy.	The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy.	N/A	N/A	N/A	N/A	N/A	 2016 Nov 1	 T-Cell Therapy Using Interleukin-21-Primed Cytotoxic T-Cell Lymphocytes Combined   With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell  Persistence and Durable Tumor Regression.	 J Clin Oncol	 Purpose Peripheral blood-derived antigen-specific cytotoxic T cells (CTLs)  provide a readily available source of effector cells that can be administered  with minimal toxicity in an outpatient setting. In metastatic melanoma, this  approach results in measurable albeit modest clinical responses in patients  resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell  lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor  activity of adoptively transferred CTLs. Patients and Methods Autologous  MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells  in the presence of interleukin-21 and enriched by peptide-major  histocompatibility complex multimer-guided cell sorting. This expeditiously  yielded polyclonal CTL lines uniformly expressing markers associated with an  enhanced survival potential. In this first-in-human strategy, 10 patients with  stage IV melanoma received the MART1-specific CTLs followed by a standard course   of anti-CTLA-4 (ipilimumab). Results The toxicity profile of the combined  treatment was comparable to that of ipilimumab monotherapy. Evaluation of best  responses at 12 weeks yielded two continuous complete remissions, one partial  response (PR) using RECIST criteria (two PRs using immune-related response  criteria), and three instances of stable disease. Infused CTLs persisted with  frequencies up to 2.9% of CD8(+) T cells for as long as the patients were  monitored (up to 40 weeks). In patients who experienced complete remissions, PRs,  or stable disease, the persisting CTLs acquired phenotypic and functional  characteristics of long-lived memory cells. Moreover, these patients also  developed responses to nontargeted tumor antigens (epitope spreading). Conclusion  We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe   and produces durable clinical responses, likely reflecting both enhanced activity  of transferred cells and improved recruitment of new responses, highlighting the   promise of this strategy.
CANIT0000624	27271951	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	Early recognition and treatment of autoimmune encephalitis in patients receiving immune checkpoint blockade therapy will likely be essential for maximizing clinical recovery and minimizing the effect of drug-related toxic effects.	Autoimmune encephalitis	N/A	N/A	N/A	N/A	N/A	 2016 Aug 1	 Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor   Treatment for Metastatic Cancer.	 JAMA Neurol	 IMPORTANCE: Paraneoplastic encephalitides usually precede a diagnosis of cancer  and are often refractory to immunosuppressive therapy. Conversely, autoimmune  encephalitides are reversible conditions that can occur in the presence or  absence of cancer. OBJECTIVE: To report the induction of autoimmune encephalitis   in 2 patients after treatment of metastatic cancer with a combination of the  immune checkpoint inhibitors nivolumab and ipilimumab. DESIGN, SETTING, AND  PARTICIPANTS: A retrospective case study was conducted of the clinical and  management course of 2 patients with progressive, treatment-refractory metastatic  cancer who were treated with a single dose each (concomitantly) of the immune  checkpoint inhibitors nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg. EXPOSURES:  Nivolumab and ipilimumab. MAIN OUTCOMES AND MEASURES: The clinical response to  immunosuppressive therapy in suspected autoimmune encephalitis in the setting of   immune checkpoint inhibitor use. RESULTS: Autoantibody testing confirmed  identification of anti-N-methyl-D-aspartate receptor antibodies in the  cerebrospinal fluid of 1 patient. Withdrawal of immune checkpoint inhibitors and   initiation of immunosuppressive therapy, consisting of intravenous  methylprednisolone sodium succinate equivalent to 1000 mg of methylprednisolone  for 5 days, 0.4 mg/kg/d of intravenous immunoglobulin for 5 days, and 2 doses of   rituximab, 1000 mg, in 1 patient and oral prednisone, 60 mg/d, in the other  patient, resulted in improved neurologic symptoms. CONCLUSIONS AND RELEVANCE:  Immune checkpoint inhibition may favor the development of immune responses  against neuronal antigens, leading to autoimmune encephalitis. Early recognition   and treatment of autoimmune encephalitis in patients receiving immune checkpoint   blockade therapy will likely be essential for maximizing clinical recovery and  minimizing the effect of drug-related toxic effects. The mechanisms by which  immune checkpoint inhibition may contribute to autoimmune encephalitis require  further study.
CANIT0000625	27271951	Case report	Metastatic small cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	Early recognition and treatment of autoimmune encephalitis in patients receiving immune checkpoint blockade therapy will likely be essential for maximizing clinical recovery and minimizing the effect of drug-related toxic effects.	Autoimmune encephalitis	N/A	N/A	N/A	N/A	N/A	 2016 Aug 1	 Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor   Treatment for Metastatic Cancer.	 JAMA Neurol	 IMPORTANCE: Paraneoplastic encephalitides usually precede a diagnosis of cancer  and are often refractory to immunosuppressive therapy. Conversely, autoimmune  encephalitides are reversible conditions that can occur in the presence or  absence of cancer. OBJECTIVE: To report the induction of autoimmune encephalitis   in 2 patients after treatment of metastatic cancer with a combination of the  immune checkpoint inhibitors nivolumab and ipilimumab. DESIGN, SETTING, AND  PARTICIPANTS: A retrospective case study was conducted of the clinical and  management course of 2 patients with progressive, treatment-refractory metastatic  cancer who were treated with a single dose each (concomitantly) of the immune  checkpoint inhibitors nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg. EXPOSURES:  Nivolumab and ipilimumab. MAIN OUTCOMES AND MEASURES: The clinical response to  immunosuppressive therapy in suspected autoimmune encephalitis in the setting of   immune checkpoint inhibitor use. RESULTS: Autoantibody testing confirmed  identification of anti-N-methyl-D-aspartate receptor antibodies in the  cerebrospinal fluid of 1 patient. Withdrawal of immune checkpoint inhibitors and   initiation of immunosuppressive therapy, consisting of intravenous  methylprednisolone sodium succinate equivalent to 1000 mg of methylprednisolone  for 5 days, 0.4 mg/kg/d of intravenous immunoglobulin for 5 days, and 2 doses of   rituximab, 1000 mg, in 1 patient and oral prednisone, 60 mg/d, in the other  patient, resulted in improved neurologic symptoms. CONCLUSIONS AND RELEVANCE:  Immune checkpoint inhibition may favor the development of immune responses  against neuronal antigens, leading to autoimmune encephalitis. Early recognition   and treatment of autoimmune encephalitis in patients receiving immune checkpoint   blockade therapy will likely be essential for maximizing clinical recovery and  minimizing the effect of drug-related toxic effects. The mechanisms by which  immune checkpoint inhibition may contribute to autoimmune encephalitis require  further study.
CANIT0000626	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Bladder cancer	EFO:0000292	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000627	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	 nivolumab (DB09035); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000628	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000629	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000630	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	 nivolumab (DB09035); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000631	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000632	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000633	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	 nivolumab (DB09035); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000634	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000635	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000636	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	 nivolumab (DB09035); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000637	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000638	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000639	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	 nivolumab (DB09035); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000640	27282937	Clinical research	9 Melanoma, 1 NSCLC, 1 Pancreatic Cancer, 1 Hodgkins Lymphoma, 1 Bladder cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	13	N/A	N/A	Glucocorticoids appear to be a potentially effective treatment strategy for acute kidney injury associated with immune checkpoint inhibitors.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Clinicopathological features of acute kidney injury associated with immune  checkpoint inhibitors.	 Kidney Int	 Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory  receptors expressed on T cells, represent an emerging class of immunotherapy used  in treating solid organ and hematologic malignancies. We describe the clinical  and histologic features of 13 patients with CPI-induced acute kidney injury (AKI)  who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91  (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine  protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal  immune-related adverse event occurred prior to the onset of AKI in 7 patients.  Median peak serum creatinine was 4.5 (interquartile range, 3.6-7.3) mg/dl with 4   patients requiring hemodialysis. The prevalent pathologic lesion was acute  tubulointerstitial nephritis in 12 patients, with 3 having granulomatous  features, and 1 thrombotic microangiopathy. Among the 12 patients with acute  tubulointerstitial nephritis, 10 received treatment with glucocorticoids,  resulting in complete or partial improvement in renal function in 2 and 7  patients, respectively. However, the 2 patients with acute tubulointerstitial  nephritis not given glucocorticoids had no improvement in renal function. Thus,  CPI-induced AKI is a new entity that presents with clinical and histologic  features similar to other causes of drug-induced acute tubulointerstitial  nephritis, though with a longer latency period. Glucocorticoids appear to be a  potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by  a unique mechanism of action linked to reprogramming of the immune system,  leading to loss of tolerance.CI  - Copyright (c) 2016 International Society of Nephrology. Published by Elsevier  Inc. All rights reserved.
CANIT0000641	27283863	Clinical research	Advanced renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	Everolimus	Immune checkpoint therapy	Nivolumab (DB09035); everolimus (DB01590); 	410	411	A randomised, open-label, phase III	Nivolumab was associated with HRQoL improvement compared with everolimus in previously treated patients with advanced renal cell carcinoma.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Quality of life in patients with advanced renal cell carcinoma given nivolumab  versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial.	 Lancet Oncol	 BACKGROUND: In the phase 3 CheckMate 025 study, previously treated patients with   advanced renal cell carcinoma who were randomly assigned to nivolumab had an  overall survival benefit compared with those assigned to everolimus. We aimed to   compare health-related quality of life (HRQoL) between treatment groups in this  trial. METHODS: CheckMate 025 was an open-label study done at 146 oncology  centres in 24 countries. Patients were randomly assigned to treatment between Oct  22, 2012, and March 11, 2014. Patients with advanced renal cell carcinoma were  randomly assigned (1:1, block size of four) to receive nivolumab every 2 weeks or  everolimus once per day. The study was stopped early at the planned interim  analysis in July, 2015, because the study met its primary endpoint. A protocol  amendment permitted patients in the everolimus group to cross over to nivolumab  treatment. All patients not on active study therapy are being followed up for  survival. At the interim analysis, HRQoL was assessed with the Functional  Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms  (FKSI-DRS) and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D)  questionnaires. Prespecified endpoints were to assess, in each treatment group,  disease-related symptom progression rate based on the FKSI-DRS and changes in  reported global health outcomes based on the EQ-5D. Other endpoints were post  hoc. We calculated the proportion of FKSI-DRS questionnaires completed using the   number of patients with non-missing data at baseline and at least one  post-baseline visit. We defined FKSI-DRS completion as completion of five or more  of the nine items in the questionnaire; otherwise data were treated as missing.  FKSI-DRS symptom index score was prorated for missing items. We made no  adjustments for missing EQ-5D data. We used descriptive statistics and  multivariate analyses, including mixed-effects model repeated-measures, for  between group comparisons. Analyses were powered according to the original study   protocol, and we analysed FKSI-DRS and EQ-5D data for all patients who underwent   randomisation and had a baseline assessment and at least one post-baseline  assessment. CheckMate 025 is registered with ClinicalTrials.gov, number  NCT01668784. FINDINGS: HRQoL data were collected at baseline for 362 (88%) of 410  patients in the nivolumab group and 344 (84%) of 411 patients in the everolimus  group. The mean difference in FKSI-DRS scores between the nivolumab and  everolimus groups was 1.6 (95% CI 1.4-1.9; p<0.0001) with descriptive statistics   and 1.7 (1.2-2.1; p<0.0001) with mixed-effects model repeated-measures analysis.   In terms of FKSI-DRS score, more patients had a clinically meaningful (ie, an  increase of at least 2 points from baseline) HRQoL improvement with nivolumab  (200 [55%] of 361 patients) versus everolimus (126 [37%] of 343 patients;  p<0.0001). Median time to HRQoL improvement was shorter in patients given  nivolumab (4.7 months, 95% CI 3.7-7.5) than in patients given everolimus (median   not reached, NE-NE). INTERPRETATION: Nivolumab was associated with HRQoL  improvement compared with everolimus in previously treated patients with advanced  renal cell carcinoma. FUNDING: Bristol-Myers Squibb.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000642	27291635	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Pulmonary sarcoid-like granulomatosis	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Pulmonary sarcoid-like granulomatosis induced by nivolumab.	 Br J Dermatol	 The use of antibodies against programmed death (PD)1, such as nivolumab and  pembrolizumab, has dramatically improved the prognosis of patients with advanced   melanoma. Nivolumab is also approved in advanced squamous cell nonsmall-cell lung  cancer. These immunotherapies are associated with a unique set of toxicities  termed immune-related adverse events, which are different from toxicities  observed with conventional cytotoxic chemotherapy. We report the case of a  56-year-old man who was diagnosed with metastatic melanoma and who received  nivolumab. One week after the second infusion, he developed pulmonary symptoms,  dry eye syndrome and a bilateral swelling of the parotid glands. Investigations  were negative for infection. The bronchoalveolar lavage differential cell count  showed 32% lymphocytes with an increased CD4 : CD8 ratio, and bronchial biopsies   revealed noncaseating epithelioid granulomas, without malignant cells. The  clinical and radiological courses were rapidly favourable with oral  corticosteroid. This case illustrates that sarcoidosis can be induced by  nivolumab treatment. With the increasing use of anti-PD1 inhibitors in patients  with advanced melanoma and squamous cell nonsmall-cell lung cancer, clinicians  should be aware of this potential associated immune-related adverse event.CI  - (c) 2016 British Association of Dermatologists.
CANIT0000643	27294163	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	N/A (N/A); 	N/A; 	Autologous melanoma vaccine	N/A	Tumor vaccine	Autologous melanoma vaccine (NCIT:C1981); 	126	N/A	N/A	Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity.	N/A	N/A	N/A	Delayed type hypersensitivity response (NCIT:C3115); 	Delayed type hypersensitivity response	Immune response	2016	 Adjuvant Autologous Melanoma Vaccine for Macroscopic Stage III Disease: Survival,  Biomarkers, and Improved Response to CTLA-4 Blockade.	 J Immunol Res	 Background. There is not yet an agreed adjuvant treatment for melanoma patients  with American Joint Committee on Cancer stages III B and C. We report  administration of an autologous melanoma vaccine to prevent disease recurrence.  Patients and Methods. 126 patients received eight doses of irradiated autologous   melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type  hypersensitivity (DTH) response to unmodified melanoma cells was determined on  the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors  from patients with good or poor survival. Results. Median overall survival was 88  months with a 5-year survival of 54%. Patients attaining a strong DTH response  had a significantly better (p = 0.0001) 5-year overall survival of 75% compared  with 44% in patients without a strong response. Gene expression array linked a  50-gene signature to prognosis, including a cluster of four cancer testis  antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who  received an autologous vaccine, followed by ipilimumab for progressive disease,  had a significantly improved 3-year survival of 46% compared with 19% in  nonvaccinated patients treated with ipilimumab alone (p = 0.007). Conclusion.  Improved survival in patients attaining a strong DTH and increased response rate   with subsequent ipilimumab suggests that the autologous vaccine confers  protective immunity.
CANIT0000644	27294607	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus electrochemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Electrochemotherapy (NCIT:C15632); ipilimumab (DB06186); 	33	N/A	A multicentre, retrospective cohort study	Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.	Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed.	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Immune checkpoint blockade with concurrent electrochemotherapy in advanced  melanoma: a retrospective multicenter analysis.	 Cancer Immunol Immunother	 Growing evidence suggests that concurrent loco-regional and systemic treatment  modalities may lead to synergistic anti-tumor effects in advanced melanoma. In  this retrospective multicenter study, we evaluate the use of electrochemotherapy   (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with   unresectable or metastatic melanoma who received the combination of ECT and  immune checkpoint blockade for distant or cutaneous metastases within 4 weeks.  Clinical and laboratory data were collected and analyzed with respect to safety  and efficacy. A total of 33 patients from 13 centers were identified with a  median follow-up time of 9 months. Twenty-eight patients received ipilimumab,  while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3,  nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic   ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The  median duration of response was not reached in either group. The median time to  disease progression was 2.5 months for the entire population with 2 months for  ipilimumab and 5 months for PD-1 blockade. The median overall survival was not  reached in patients with ipilimumab and 15 months in the PD-1 group. Severe  systemic adverse events were detected in 25.0 % in the ipilimumab group. No  treatment-related deaths were observed. This is the first reported evaluation of   ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT  with concurrent ipilimumab. The local response was lower than reported for ECT  only. Ipilimumab combined with ECT was feasible, tolerable and showed a high  systemic response rate.
CANIT0000645	27294607	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus electrochemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Electrochemotherapy (NCIT:C15632); nivolumab (DB09035); 	33	N/A	A multicentre, retrospective cohort study	Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.	Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed.	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Immune checkpoint blockade with concurrent electrochemotherapy in advanced  melanoma: a retrospective multicenter analysis.	 Cancer Immunol Immunother	 Growing evidence suggests that concurrent loco-regional and systemic treatment  modalities may lead to synergistic anti-tumor effects in advanced melanoma. In  this retrospective multicenter study, we evaluate the use of electrochemotherapy   (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with   unresectable or metastatic melanoma who received the combination of ECT and  immune checkpoint blockade for distant or cutaneous metastases within 4 weeks.  Clinical and laboratory data were collected and analyzed with respect to safety  and efficacy. A total of 33 patients from 13 centers were identified with a  median follow-up time of 9 months. Twenty-eight patients received ipilimumab,  while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3,  nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic   ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The  median duration of response was not reached in either group. The median time to  disease progression was 2.5 months for the entire population with 2 months for  ipilimumab and 5 months for PD-1 blockade. The median overall survival was not  reached in patients with ipilimumab and 15 months in the PD-1 group. Severe  systemic adverse events were detected in 25.0 % in the ipilimumab group. No  treatment-related deaths were observed. This is the first reported evaluation of   ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT  with concurrent ipilimumab. The local response was lower than reported for ECT  only. Ipilimumab combined with ECT was feasible, tolerable and showed a high  systemic response rate.
CANIT0000646	27294607	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus electrochemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Electrochemotherapy (NCIT:C15632); pembrolizumab (DB09037); 	33	N/A	A multicentre, retrospective cohort study	Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.	Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed.	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Immune checkpoint blockade with concurrent electrochemotherapy in advanced  melanoma: a retrospective multicenter analysis.	 Cancer Immunol Immunother	 Growing evidence suggests that concurrent loco-regional and systemic treatment  modalities may lead to synergistic anti-tumor effects in advanced melanoma. In  this retrospective multicenter study, we evaluate the use of electrochemotherapy   (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with   unresectable or metastatic melanoma who received the combination of ECT and  immune checkpoint blockade for distant or cutaneous metastases within 4 weeks.  Clinical and laboratory data were collected and analyzed with respect to safety  and efficacy. A total of 33 patients from 13 centers were identified with a  median follow-up time of 9 months. Twenty-eight patients received ipilimumab,  while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3,  nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic   ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The  median duration of response was not reached in either group. The median time to  disease progression was 2.5 months for the entire population with 2 months for  ipilimumab and 5 months for PD-1 blockade. The median overall survival was not  reached in patients with ipilimumab and 15 months in the PD-1 group. Severe  systemic adverse events were detected in 25.0 % in the ipilimumab group. No  treatment-related deaths were observed. This is the first reported evaluation of   ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT  with concurrent ipilimumab. The local response was lower than reported for ECT  only. Ipilimumab combined with ECT was feasible, tolerable and showed a high  systemic response rate.
CANIT0000647	27296105	Clinical research	Extensive-stage SCLC	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	39	N/A	A phase I clinical trial 	Ipilimumab in combination with carboplatin and etoposide might benefit a subgroup of patients with advanced SCLC.	All patients experienced at least one adverse event; at least one grade 3 or higher toxicity developed in 35 of 39 patients (89.7%); in 27 patients (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. Positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity.	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Outcome and Biomarker Analysis from a Multicenter Phase 2 Study of Ipilimumab in   Combination with Carboplatin and Etoposide as First-Line Therapy for  Extensive-Stage SCLC.	 J Thorac Oncol	 OBJECTIVES: Our aim was to evaluate the safety and efficacy of ipilimumab  combined with standard first-line chemotherapy for patients with extensive-stage   SCLC. METHODS: Patients with chemotherapy-naive extensive-stage SCLC were treated  with carboplatin and etoposide for up to six cycles. Ipilimumab, 10 mg/kg, was  given on day 1 of cycles 3 to 6 and every 12 weeks. Response was assessed by the   Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and  immune-related response criteria. The primary end point was 1-year  progression-free survival (PFS) according to RECIST. Secondary end points  included PFS according to immune-related PFS and overall survival. Autoantibody  serum levels were evaluated and correlated with clinical outcomes. RESULTS: A  total of 42 patients were enrolled between September 2011 and April 2014; 39 were  evaluable for safety and 38 for efficacy. Six of 38 patients (15.8% [95%  confidence interval (CI): 7.4-30.4]) were alive and progression-free at 1-year by  RECIST. Median PFS was 6.9 months (95% CI: 5.5-7.9). Median immune-related PFS  was 7.3 months (95% CI: 5.5-8.8). Median overall survival was 17.0 months (95%  CI: 7.9-24.3). Of the patients evaluable for response, 21 of 29 (72.4%) achieved   an objective response by RECIST and 28 of 33 (84.8%) achieved an objective  response by the immune-related response criteria. All patients experienced at  least one adverse event; at least one grade 3 or higher toxicity developed in 35   of 39 patients (89.7%); in 27 patients (69.2%) this was related to ipilimumab.  Five deaths were reported to be related to ipilimumab. Positivity of an  autoimmune profile at baseline was associated with improved outcomes and severe  neurological toxicity. CONCLUSIONS: Ipilimumab in combination with carboplatin  and etoposide might benefit a subgroup of patients with advanced SCLC.  Autoantibody analysis correlates with treatment benefit and toxicity and warrants  further investigation.CI  - Copyright (c) 2016 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0000648	27297738	Case report	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Fulminant type 1 diabetes	N/A	N/A	N/A	N/A	N/A	 2016 Jun	 Nivolumab, an Anti-Programmed Cell Death-1 Antibody, Induces Fulminant Type 1  Diabetes.	 Tohoku J Exp Med	 Programmed cell death-1 (PD-1), an immunoreceptor, is located on T cells and  pro-B cells and interacts with its ligands to inhibit T cell activation and  proliferation, thereby promoting immunological self-tolerance. Nivolumab, an  anti-PD1 antibody, blocks PD-1 and can restore anticancer immune responses by  abrogating PD-1 pathway-mediated T-cell inhibition. Autoimmune adverse events are  expected with PD-1 therapy. Fulminant type 1 diabetes is the subtype of type 1  diabetes. The clinical feature is the extremely rapid progression of  hyperglycemia and ketoacidosis. Here we describe a 66-year-old woman with  advanced melanoma who was treated with nivolumab. After 4 months and six doses of  the medicine, the patient was admitted to the hospital with complaints of nausea   and vomiting. The laboratory data showed ketonuria, hyperglycemia (531 mg/dl),  high anion gap metabolic acidosis, HbA1c (7.3%), and absence of insulin-secreting  capacity. These data are compatible with the criteria of fulminant type 1  diabetes. The patient was diagnosed with diabetic ketoacidosis because of  fulminant type 1 diabetes. The findings of this case indicated that nivolumab can  cause fulminant type 1 diabetes. Diabetic ketoacidosis due to fulminant type 1  diabetes is potentially fatal condition. Thus, diabetic ketoacidosis due to  fulminant type 1 diabetes should be considered in the differential diagnosis when  patients treated with nivolumab complain of gastrointestinal symptoms.
CANIT0000649	27298410	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Talimogene laherparepvec followed by ipilimumab	N/A	Tumor vaccine followed by Immune checkpoint therapy	Ipilimumab (DB06186); talimogene laherparepvec (DB13896); 	19	N/A	An open-label, multicenter, phase Ib	T-VEC with ipilimumab had a tolerable  safety profile, and the combination appeared to have greater efficacy than either  T-VEC or ipilimumab monotherapy.	Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab.	N/A	N/A	N/A	N/A	N/A	 2016 Aug 1	 Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated,   Unresectable Stage IIIB-IV Melanoma.	 J Clin Oncol	 PURPOSE: Combining immunotherapeutic agents with different mechanisms of action  may enhance efficacy. We describe the safety and efficacy of talimogene  laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a  cytotoxic T-lymphocyte-associated antigen 4 checkpoint inhibitor) in patients  with advanced melanoma. METHODS: In this open-label, multicenter, phase Ib trial   of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in  week 1 (10(6) plaque-forming units/mL), then in week 4 and every 2 weeks  thereafter (10(8) plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered  intravenously every 3 weeks for four infusions, beginning in week 6. The primary   end point was incidence of dose-limiting toxicities. Secondary end points were  objective response rate by immune-related response criteria and safety. RESULTS:   Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4  weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4   months). Nineteen patients were included in the safety analysis. No dose-limiting  toxicities occurred, and no new safety signals were detected. Grade 3/4  treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had   AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The  objective response rate was 50%, and 44% of patients had a durable response  lasting >/= 6 months. Eighteen-month progression-free survival was 50%; 18-month   overall survival was 67%. CONCLUSION: T-VEC with ipilimumab had a tolerable  safety profile, and the combination appeared to have greater efficacy than either  T-VEC or ipilimumab monotherapy.CI  - (c) 2016 by American Society of Clinical Oncology.
CANIT0000650	27307501	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 	Sicca syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic  T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1  (PD-1) pathways have demonstrated survival improvements in multiple advanced  cancers, but also cause immune-related adverse events (IRAEs). IRAEs with  clinical features similar to rheumatic diseases have not been well described. We   report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.  METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics  from 2012 to 2016 identified as having new rheumatological symptoms in the  context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1)  for solid tumours. RESULTS: We identified 13 patients who received ICIs and  developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included  melanoma, non-small cell lung cancer, small cell lung cancer and renal cell  carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or  combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an  inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1  MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca  syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis,  colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were  positive in 5 out of 13 patients. All 13 patients were treated with  corticosteroids with varying response. Two patients were treated with  methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.  CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases  of rheumatic IRAEs are likely to emerge. Further research is required to  understand mechanisms, determine risk factors and develop management algorithms  for rheumatic IRAEs.CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not  already granted under a licence) please go to  http://www.bmj.com/company/products-services/rights-and-licensing/.
CANIT0000651	27307501	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	Partial response, Progressive disease,  Stable disease by Response Evaluation Criteria In Solid Tumors (RECIST) 	Inflammatory arthritis, Sicca syndrome.	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic  T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1  (PD-1) pathways have demonstrated survival improvements in multiple advanced  cancers, but also cause immune-related adverse events (IRAEs). IRAEs with  clinical features similar to rheumatic diseases have not been well described. We   report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.  METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics  from 2012 to 2016 identified as having new rheumatological symptoms in the  context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1)  for solid tumours. RESULTS: We identified 13 patients who received ICIs and  developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included  melanoma, non-small cell lung cancer, small cell lung cancer and renal cell  carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or  combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an  inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1  MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca  syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis,  colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were  positive in 5 out of 13 patients. All 13 patients were treated with  corticosteroids with varying response. Two patients were treated with  methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.  CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases  of rheumatic IRAEs are likely to emerge. Further research is required to  understand mechanisms, determine risk factors and develop management algorithms  for rheumatic IRAEs.CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not  already granted under a licence) please go to  http://www.bmj.com/company/products-services/rights-and-licensing/.
CANIT0000652	27307501	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	No measureable disease by Response Evaluation Criteria In Solid Tumors (RECIST) 	Sicca syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic  T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1  (PD-1) pathways have demonstrated survival improvements in multiple advanced  cancers, but also cause immune-related adverse events (IRAEs). IRAEs with  clinical features similar to rheumatic diseases have not been well described. We   report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.  METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics  from 2012 to 2016 identified as having new rheumatological symptoms in the  context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1)  for solid tumours. RESULTS: We identified 13 patients who received ICIs and  developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included  melanoma, non-small cell lung cancer, small cell lung cancer and renal cell  carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or  combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an  inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1  MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca  syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis,  colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were  positive in 5 out of 13 patients. All 13 patients were treated with  corticosteroids with varying response. Two patients were treated with  methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.  CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases  of rheumatic IRAEs are likely to emerge. Further research is required to  understand mechanisms, determine risk factors and develop management algorithms  for rheumatic IRAEs.CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not  already granted under a licence) please go to  http://www.bmj.com/company/products-services/rights-and-licensing/.
CANIT0000653	27307501	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	Partial response, Stable disease by Response Evaluation Criteria In Solid Tumors (RECIST) 	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic  T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1  (PD-1) pathways have demonstrated survival improvements in multiple advanced  cancers, but also cause immune-related adverse events (IRAEs). IRAEs with  clinical features similar to rheumatic diseases have not been well described. We   report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.  METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics  from 2012 to 2016 identified as having new rheumatological symptoms in the  context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1)  for solid tumours. RESULTS: We identified 13 patients who received ICIs and  developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included  melanoma, non-small cell lung cancer, small cell lung cancer and renal cell  carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or  combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an  inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1  MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca  syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis,  colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were  positive in 5 out of 13 patients. All 13 patients were treated with  corticosteroids with varying response. Two patients were treated with  methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.  CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases  of rheumatic IRAEs are likely to emerge. Further research is required to  understand mechanisms, determine risk factors and develop management algorithms  for rheumatic IRAEs.CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not  already granted under a licence) please go to  http://www.bmj.com/company/products-services/rights-and-licensing/.
CANIT0000654	27307501	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Partial response, Stable disease by Response Evaluation Criteria In Solid Tumors (RECIST) 	Inflammatory arthritis, Sicca syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic  T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1  (PD-1) pathways have demonstrated survival improvements in multiple advanced  cancers, but also cause immune-related adverse events (IRAEs). IRAEs with  clinical features similar to rheumatic diseases have not been well described. We   report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.  METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics  from 2012 to 2016 identified as having new rheumatological symptoms in the  context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1)  for solid tumours. RESULTS: We identified 13 patients who received ICIs and  developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included  melanoma, non-small cell lung cancer, small cell lung cancer and renal cell  carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or  combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an  inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1  MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca  syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis,  colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were  positive in 5 out of 13 patients. All 13 patients were treated with  corticosteroids with varying response. Two patients were treated with  methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.  CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases  of rheumatic IRAEs are likely to emerge. Further research is required to  understand mechanisms, determine risk factors and develop management algorithms  for rheumatic IRAEs.CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not  already granted under a licence) please go to  http://www.bmj.com/company/products-services/rights-and-licensing/.
CANIT0000655	27307501	Case report	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	Partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 	Sicca syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic  T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1  (PD-1) pathways have demonstrated survival improvements in multiple advanced  cancers, but also cause immune-related adverse events (IRAEs). IRAEs with  clinical features similar to rheumatic diseases have not been well described. We   report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.  METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics  from 2012 to 2016 identified as having new rheumatological symptoms in the  context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1)  for solid tumours. RESULTS: We identified 13 patients who received ICIs and  developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included  melanoma, non-small cell lung cancer, small cell lung cancer and renal cell  carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or  combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an  inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1  MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca  syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis,  colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were  positive in 5 out of 13 patients. All 13 patients were treated with  corticosteroids with varying response. Two patients were treated with  methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.  CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases  of rheumatic IRAEs are likely to emerge. Further research is required to  understand mechanisms, determine risk factors and develop management algorithms  for rheumatic IRAEs.CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not  already granted under a licence) please go to  http://www.bmj.com/company/products-services/rights-and-licensing/.
CANIT0000656	27307501	Case report	Small cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	Partial response by Response Evaluation Criteria In Solid Tumors (RECIST) 	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic  T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1  (PD-1) pathways have demonstrated survival improvements in multiple advanced  cancers, but also cause immune-related adverse events (IRAEs). IRAEs with  clinical features similar to rheumatic diseases have not been well described. We   report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.  METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics  from 2012 to 2016 identified as having new rheumatological symptoms in the  context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1)  for solid tumours. RESULTS: We identified 13 patients who received ICIs and  developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included  melanoma, non-small cell lung cancer, small cell lung cancer and renal cell  carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or  combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an  inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1  MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca  syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis,  colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were  positive in 5 out of 13 patients. All 13 patients were treated with  corticosteroids with varying response. Two patients were treated with  methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.  CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases  of rheumatic IRAEs are likely to emerge. Further research is required to  understand mechanisms, determine risk factors and develop management algorithms  for rheumatic IRAEs.CI  - Published by the BMJ Publishing Group Limited. For permission to use (where not  already granted under a licence) please go to  http://www.bmj.com/company/products-services/rights-and-licensing/.
CANIT0000657	27311362	Case report	Metastatic clear cell renal cell carcinoma on dialysis	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Feasible treatment option	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Response to Nivolumab in a Patient With Metastatic Clear Cell Renal Cell  Carcinoma and End-stage Renal Disease on Dialysis.	 Eur Urol	Unable to provide
CANIT0000658	27349506	Case report	Advanced HER2-positive lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Dramatic antitumor activity	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Dramatic Antitumor Activity of Nivolumab in Advanced HER2-Positive Lung Cancer.	 Clin Lung Cancer	Unable to provide
CANIT0000659	27351142	Case report	Metastatic melanoma and multiple sclerosis	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis.	 Ann Neurol	 We investigated a patient who developed multiple sclerosis (MS) during treatment   with the CTLA4-blocking antibody ipilimumab for metastatic melanoma. Initially he  showed subclinical magnetic resonance imaging (MRI) changes (radiologically  isolated syndrome). Two courses of ipilimumab were each followed by a clinical  episode of MS, 1 of which was accompanied by a massive increase of MRI activity.   Brain biopsy confirmed active, T-cell type MS. Quantitative next generation  sequencing of T-cell receptor genes revealed distinct oligoclonal CD4(+) and  CD8(+) T-cell repertoires in the primary melanoma and cerebrospinal fluid. Our  results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint  and therapeutic target in MS. Ann Neurol 2016;80:294-300.CI  - (c) 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on  behalf of American Neurological Association.
CANIT0000660	27352410	Case report	Metastatic renal cell carcinoma presenting as painful chewing	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus sunitinib	N/A	Immune checkpoint therapy plus Target therapy	Sunitinib (DB01268); nivolumab (DB09035); 	1	N/A	Case	Successfully treated	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Summer	 Metastatic Renal Cell Carcinoma Presenting as Painful Chewing Successfully  Treated with Combined Nivolumab and Sunitinib.	 Perm J	 INTRODUCTION: Metastatic renal cell carcinoma (RCC) to the head and neck is rare.  It is the third-most common cause of distant metastasis to the head and neck,  after breast cancer and lung cancer. Several drugs are available to treat  metastatic RCC including high-dose interleukin and targeted therapy.  Immunotherapy with nivolumab was recently approved by the US Food and Drug  Administration (FDA) as a second-line treatment for patients with metastatic RCC.  CASE PRESENTATION: We present a case of metastatic RCC in a 71-year-old man with   a single complaint of a 1-year history of pain while chewing food. Positron  emission tomography-computed tomography showed diffuse metastatic disease.  Nivolumab, off-label use before its recent FDA approval, was combined with  sunitinib and resulted in an excellent and ongoing response. DISCUSSION: RCC is  the third-most common cause of distant metastasis to the head and neck. The  patient described in this case did not have any symptoms commonly seen in RCC,  such as painless hematuria, weight loss, anorexia, fatigue, or anemia, despite  the bulk of his disease. The other important aspect of this case is the almost  complete response of his metastatic disease to the combination of nivolumab and  sunitinib that was used off label before the FDA issued the approval. Future  clinical trials should look at combining immunotherapy with targeted therapy in  metastatic RCC.
CANIT0000661	27354476	Clinical research	Classical Hodgkin Lymphoma	Classic hodgkin lymphoma	MONDO:0009348	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	31	N/A	A multicohort, open-label, phase Ib trial KEYNOTE-013	Pembrolizumab was associated with a favorable safety profile. Pembrolizumab treatment induced favorable responses in a heavily pretreated patient cohort, justifying further studies.	Five patients (16%) experienced grade 3 drug-related adverse events (AEs); there were no grade 4 AEs or deaths related to treatment.	N/A	N/A	N/A	N/A	N/A	 2016 Nov 1	 Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin  Lymphoma After Brentuximab Vedotin Failure.	 J Clin Oncol	 Purpose Classical Hodgkin lymphoma (HL) frequently exhibits genetic alterations  leading to overexpression of the programmed death-1 (PD-1) ligands, suggesting a   possible vulnerability to PD-1 blockade. The phase Ib study KEYNOTE-013  (NCT01953692) tested the safety and efficacy of the anti-PD-1 antibody  pembrolizumab in patients with hematologic malignancies. Based on its genetics,  HL was included as an independent cohort. Methods We enrolled patients with  relapsed or refractory HL whose disease progressed on or after treatment with  brentuximab vedotin. Patients received pembrolizumab, 10 mg/kg every 2 weeks,  until disease progression occurred. Response to treatment was assessed at week 12  and every 8 weeks thereafter. Principal end points were safety and complete  remission (CR) rate. Results Thirty-one patients were enrolled; 55% had more than  four lines of prior therapy, and 71% had relapsed after autologous stem cell  transplantation. Five patients (16%) experienced grade 3 drug-related adverse  events (AEs); there were no grade 4 AEs or deaths related to treatment. The CR  rate was 16% (90% CI, 7% to 31%). In addition, 48% of patients achieved a partial  remission, for an overall response rate of 65% (90% CI, 48% to 79%). Most of the   responses (70%) lasted longer than 24 weeks (range, 0.14+ to 74+ weeks), with a  median follow-up of 17 months. The progression-free survival rate was 69% at 24  weeks and 46% at 52 weeks. Biomarker analyses demonstrated a high prevalence of  PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural  killer cells, and activation of interferon-gamma, T-cell receptor, and expanded  immune-related signaling pathways. Conclusions Pembrolizumab was associated with   a favorable safety profile. Pembrolizumab treatment induced favorable responses  in a heavily pretreated patient cohort, justifying further studies.
CANIT0000662	27354481	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); chemotherapy (NCIT:C15632); 	56	N/A	A phase II clinical trial	The safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.	No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2016 Sep 1	 Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line   Treatment of Advanced Non-Small-Cell Lung Cancer.	 J Clin Oncol	 PURPOSE: Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune  checkpoint inhibitor antibody, has demonstrated improved survival in previously  treated patients with advanced non-small-cell lung cancer (NSCLC). CheckMate 012,  a phase I, multicohort study, was conducted to explore the safety and efficacy of  nivolumab as monotherapy or combined with current standard therapies in  first-line advanced NSCLC. Here, we report results for nivolumab plus  platinum-based doublet chemotherapy (PT-DC). PATIENTS AND METHODS: Patients (N =   56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for   four cycles followed by nivolumab alone until progression or unacceptable  toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous)   or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus  paclitaxel-carboplatin (all histologies). The primary objective was to assess  safety and tolerability. Secondary objectives included objective response rate  and 24-week progression-free survival rate (per Response Evaluation Criteria in  Solid Tumors version 1.1); exploratory objectives included overall survival (OS)   and response by tumor programmed death ligand-1 expression. RESULTS: No  dose-limiting toxicities occurred during the first 6 weeks of treatment.  Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4  treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis.  Twenty-one percent of patients (n = 12) discontinued all study therapy as a  result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg   plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin,  nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus  paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week  progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year  OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved  regardless of tumor programmed death ligand-1 expression. CONCLUSION: The safety   profile of nivolumab plus PT-DC was consistent with that expected for individual   agents; however, treatment discontinuation related to AEs was greater with the  combination. Encouraging activity was observed, especially for the nivolumab 5  mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.CI  - (c) 2016 by American Society of Clinical Oncology.
CANIT0000663	27354485	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	52	N/A	A phase II clinical trial	First-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC.	Any-grade treatment-related adverse events (AEs) occurred in 71% of patients, most commonly: fatigue (29%), rash (19%), nausea (14%), diarrhea (12%), pruritus (12%), and arthralgia (10%). Ten patients (19%) reported grade 3 to 4 treatment-related AEs; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient (n = 2; 4%). Six patients (12%) discontinued because of a treatment-related AE. 	N/A	N/A	N/A	N/A	N/A	 2016 Sep 1	 Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung  Cancer.	 J Clin Oncol	 PURPOSE: Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor  antibody, has demonstrated improved survival over docetaxel in previously treated  advanced non-small-cell lung cancer (NSCLC). First-line monotherapy with  nivolumab for advanced NSCLC was evaluated in the phase I, multicohort, Checkmate  012 trial. METHODS: Fifty-two patients received nivolumab 3 mg/kg intravenously  every 2 weeks until progression or unacceptable toxicity; postprogression  treatment was permitted per protocol. The primary objective was to assess safety;  secondary objectives included objective response rate (ORR) and 24-week  progression-free survival (PFS) rate; overall survival (OS) was an exploratory  end point. RESULTS: Any-grade treatment-related adverse events (AEs) occurred in   71% of patients, most commonly: fatigue (29%), rash (19%), nausea (14%), diarrhea  (12%), pruritus (12%), and arthralgia (10%). Ten patients (19%) reported grade 3   to 4 treatment-related AEs; grade 3 rash was the only grade 3 to 4 event  occurring in more than one patient (n = 2; 4%). Six patients (12%) discontinued  because of a treatment-related AE. The confirmed ORR was 23% (12 of 52),  including four ongoing complete responses. Nine of 12 responses (75%) occurred by  first tumor assessment (week 11); eight (67%) were ongoing (range, 5.3+ to 25.8+   months) at the time of data lock. ORR was 28% (nine of 32) in patients with any  degree of tumor PD-ligand 1 expression and 14% (two of 14) in patients with no  PD-ligand 1 expression. Median PFS was 3.6 months, and the 24-week PFS rate was  41% (95% CI, 27 to 54). Median OS was 19.4 months, and the 1-year and 18-month OS  rates were 73% (95% CI, 59 to 83) and 57% (95% CI, 42 to 70), respectively.  CONCLUSION: First-line nivolumab monotherapy demonstrated a tolerable safety  profile and durable responses in first-line advanced NSCLC.CI  - (c) 2016 by American Society of Clinical Oncology.
CANIT0000664	27377654	Clinical research	Recurrent central nervous system tumors	Central nervous system cancer	EFO:0000326	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	22	N/A	A retrospective cohort study	In this series of 22 patients with recurrent primary brain tumors, PBL showed no clinical or histologic efficacy. We do not recommend further use of PBL for recurrent PBT unless convincing prospective  clinical trial data are published.	Side effects were minimal.	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Pembrolizumab: first experience with recurrent primary central nervous system  (CNS) tumors.	 J Neurooncol	 Patients with progressive primary brain tumors (PBT) are attracted to promising  new treatments, even prior to convincing data. Anti-PD1 immunotherapies have been  in the spotlight since publication of groundbreaking results for metastatic  melanoma with pembrolizumab (PBL). Our objective was to report on the response  and toxicity of PBL in patients with advanced PBT. We retrospectively reviewed  the charts of 22 patients (17 adults and 5 children) with recurrent central  nervous system tumors treated with PBL. We analyzed prior antineoplastic  therapies, steroid usage, and outcomes. Patients received a median of two  neoplastic therapies prior to PBL, and a median of three infusions of PBL in  adults and four in children. Twelve patients (9 adults and 3 children) started  PBL on steroids (median dose in adults 4 mg; range 2-8, and in children 1.5 mg,  range 0.5-4) and five patients received steroids later during PBL treatment.  Twelve patients (10 adults and 2 children) received concomitant bevacizumab with   PBL. Side effects were minimal. All patients showed progressive tumor growth  during therapy. Median OS from the start of PBL was 2.6 months in adults and 3.2   months in children. Two GB patients underwent tumor resection following treatment  with PBL. Tumor-lymphocytic response in these cases was unremarkable, and PD-L1  immuno-staining was negative. In this series of 22 patients with recurrent  primary brain tumors, PBL showed no clinical or histologic efficacy. We do not  recommend further use of PBL for recurrent PBT unless convincing prospective  clinical trial data are published.
CANIT0000665	27378345	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus IDO long	N/A	Immune checkpoint therapy plus Chemotherapy	IDO Peptide Vaccine (NCIT:C159498); ipilimumab (DB06186); 	10	N/A	A phase I clinical trial 	Treatment with IDOlong synthetic  peptide vaccine in combination with ipi was generally safe and without augmented toxicity. The vaccine induced readily detectable T-cell responses in a subset of   patients. Treatment showed signs of clinical activity, although not exceeding  efficacy of ipi alone. Results should be confirmed in a larger study.	Treatment was generally safe and well tolerated. Vaccine related adverse reactions included grade I and II erythema, oedema and pruritus at the vaccination site, which were manageable with mild topical corticosteroids. One patient developed presumed ipi-induced colitis. It initially responded to high-dose parenteral corticosteroids but later relapsed while the patient was admitted to a local hospital, where he died after receiving suboptimal therapy.	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Safety, immune and clinical responses in metastatic melanoma patients vaccinated   with a long peptide derived from indoleamine 2,3-dioxygenase in combination with   ipilimumab.	 Cytotherapy	 BACKGROUND AIM: Indoleamine 2,3-dioxygenase (IDO) is an emerging new target in  cancer therapy that can be targeted with active immunotherapy (e.g. through  peptide vaccination). Furthermore, IDO has been identified as a key mechanism  underlying resistance to treatment with the checkpoint blocking antibody  ipilimumab (ipi). METHODS: Ten patients with metastatic melanoma participated in   a phase I first-in-human clinical study assessing safety of combining ipi with a   21-mer synthetic peptide vaccine from IDO denoted IDOlong. Secondary and tertiary  end points included vaccine and clinical response. RESULTS: Treatment was  generally safe and well tolerated. Vaccine related adverse reactions included  grade I and II erythema, oedema and pruritus at the vaccination site, which were   manageable with mild topical corticosteroids. One patient developed presumed  ipi-induced colitis. It initially responded to high-dose parenteral  corticosteroids but later relapsed while the patient was admitted to a local  hospital, where he died after receiving suboptimal therapy. Vaccine-specific  T-cell responses were detectable ex vivo in three patients. At first evaluation,   five of the 10 treated patients were in stable disease, one of whom had an  unconfirmed partial response. CONCLUSIONS: Treatment with IDOlong synthetic  peptide vaccine in combination with ipi was generally safe and without augmented   toxicity. The vaccine induced readily detectable T-cell responses in a subset of   patients. Treatment showed signs of clinical activity, although not exceeding  efficacy of ipi alone. Results should be confirmed in a larger study.CI  - Copyright (c) 2016 International Society for Cellular Therapy. Published by  Elsevier Inc. All rights reserved.
CANIT0000666	27380808	Case report	Stage IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Chronic inflammatory demyelinating polyradiculoneuropathy mimicking rapid-onset Guillain-Barr syndrome	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Nivolumab-induced chronic inflammatory demyelinating polyradiculoneuropathy  mimicking rapid-onset Guillain-Barre syndrome: a case report.	 Jpn J Clin Oncol	 Nivolumab, an anti-programmed death-1-specific monoclonal antibody, has  demonstrated a durable response and effect on overall survival and has become one  of the standard treatments for patients with advanced melanoma. Reported herein  is a case of nivolumab-induced chronic inflammatory demyelinating  polyradiculoneuropathy, in which an 85-year-old woman with stage IV melanoma  developed grade 1 paresthesia 2 weeks after the initial dose of nivolumab was  administered. With continued treatment, the neurological deficiency deteriorated   rapidly, mimicking Guillain-Barre syndrome, causing such a dramatic decrease in  her activities of daily living that she could no longer function in daily life.  Thus, nivolumab treatment was discontinued. A course of intravenous  immunoglobulin infusion yielded a dramatic clinical improvement; in particular,  improved motor control was observed within a few days. Her initial presentation  was suggestive of acute inflammatory demyelinating polyradiculoneuropathy, a  subtype of Guillain-Barre syndrome; however, the good response to steroids and  exacerbation 8 weeks after the onset were suggestive of chronic inflammatory  demyelinating polyradiculoneuropathy induced by nivolumab. This is the first case  of Guillain-Barre syndrome-like autoimmune polyradiculoneuropathy induced by  programmed death-1/programmed death-ligand 1 inhibitors. Although neurological  adverse events related to nivolumab are rare, they can become severe, requiring  early diagnosis and intervention. Intravenous immunoglobulin may be considered as  an effective initial treatment for patients who develop acute autoimmune nervous   system disorders due to nivolumab.CI  - (c) The Author 2016. Published by Oxford University Press. All rights reserved.  For Permissions, please email: journals.permissions@oup.com.
CANIT0000667	27389724	Case report	Stage III squamous cell lung cancer	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Feasible treatment option	In the next few months, she experienced a variety of side effects, some of which were potentially life-threatening.	N/A	N/A	N/A	N/A	N/A	 2016 Jul 7	 Battling regional (stage III) lung cancer: bumpy road of a cancer survivor in the  immunotherapy age.	 BMJ Case Rep	 A 58-year-old woman, a heavy smoker, was diagnosed with stage III squamous cell  lung cancer. She was treated with concurrent chemotherapy and radiotherapy, with   partial response. 2 months later, she had haemoptysis caused by brisk bleeding  from the radiated right upper lobe. Fortunately, her bleed was self-limited. 4  months later, a rapidly enlarging renal mass was discovered and turned out to be   metastatic from the lung primary. Second-line chemotherapy with docetaxel and  ramucirumab did not have effects on the renal mass after 2 cycles. Despite not  being eligible for a durvalumab trial because of lack of PD-L1 expression, she  had a meaningful response to nivolumab. Once every 2 weeks, infusion of nivolumab  resulted in rapid tumour shrinkage in multiple areas. In the next few months, she  experienced a variety of side effects, some of which were potentially  life-threatening. She had disease progression 9 months into treatment.CI  - 2016 BMJ Publishing Group Ltd.
CANIT0000668	27391442	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); IL2R (A2N4P8); 	CTLA-4; IL2R	Intratumoral ipilimumab plus IL2	N/A	Immune checkpoint therapy plus Immune cytokine	Ipilimumab (DB06186); IL2 (NCIT:C24498); 	12	N/A	A phase I clinical trial 	Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.	There was no dose limiting toxicity.	N/A	N/A	N/A	N/A	N/A	 2016 Sep 27	 A phase I study of intratumoral ipilimumab and interleukin-2 in patients with  advanced melanoma.	 Oncotarget	 PURPOSE: Intratumoral interleukin-2 (IL-2) is effective but does not generate  systemic immunity. Intravenous ipilimumab produces durable clinical response in a  minority of patients, with potentially severe toxicities. Circulating anti-tumor   T cells activated by ipilimumab may differ greatly from tumor-infiltrating  lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality.  The objective of this study was to primarily assess the safety of intratumoral  ipilimumab/IL-2 combination and to obtain data on clinical efficacy. RESULTS:  There was no dose limiting toxicity. While local response of injected lesions was  observed in 67% patients (95% CI, 40%-93%), an abscopal response was seen in 89%   (95% CI, 68%-100%). The overall response rate and clinical benefit rate by  immune-related response criteria (irRC) was 40% (95% CI, 10%-70%) and 50% (95%  CI, 19%-81%), respectively. Enhanced systemic immune response was observed in  most patients and correlated with clinical responses. EXPERIMENTAL DESIGN: Twelve  patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3  design was employed to assess highest tolerable intratumoral dose of ipilimumab  and IL-2 based on toxicity during the first three weeks. Escalated doses of  ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of  three patients. A fixed dose of IL-2 was injected three times a week into the  same lesion for two weeks, followed by two times a week for six weeks.  CONCLUSIONS: Intratumoral injection with the combination of ipilimumab/IL-2 is  well tolerated and generates responses in both injected and non-injected lesions   in the majority of patients.
CANIT0000669	27393510	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab followed by radiotherapy	N/A	Immune checkpoint therapy followed by Radiotherapy	Radiotherapy (NCIT:C15313); ipilimumab (DB06186); 	16	N/A	A phase II clinical trial	In this study of radiation as definitive or post-operative treatment following neo-adjuvant chemotherapy including ipilimumab for locally advanced NSCLC was feasible and well tolerated with limited toxicity.	There were seven patients identified who received definitive radiation and nine who received post-operative radiation. There was no grade 3 or greater toxicity in the definitive treatment group although one patient stopped treatment early due to back pain secondary to progression outside of the treatment field. In the post-operative treatment group, one patient required a one week break due to grade 2 odynophagia and no grade 3 or greater toxicity was observed.	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Toxicity of definitive and post-operative radiation following ipilimumab in  non-small cell lung cancer.	 Lung Cancer	 To determine the feasibility and toxicity of radiation therapy, delivered either   as definitive treatment or following surgery, following neo-adjuvant immune  checkpoint inhibition for locally advanced NSCLC sixteen patients who received  neo-adjuvant chemotherapy including ipilimumab as part of a phase II study were  identified. Patients were analyzed by intent of radiation and toxicity graded  based on CTCAE 4.0. There were seven patients identified who received definitive   radiation and nine who received post-operative radiation. There was no grade 3 or  greater toxicity in the definitive treatment group although one patient stopped  treatment early due to back pain secondary to progression outside of the  treatment field. In the post-operative treatment group, one patient required a  one week break due to grade 2 odynophagia and no grade 3 or greater toxicity was   observed. In this study of radiation as definitive or post-operative treatment  following neo-adjuvant chemotherapy including ipilimumab for locally advanced  NSCLC was feasible and well tolerated with limited toxicity.CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
CANIT0000670	27393516	Case report	NSCLC patients with untreated or progressing CNS metastases	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	Having intracranial activity and favorable safety profile	No treatment-related or CNS metastases-related grade3 adverse events	N/A	N/A	N/A	N/A	N/A	 2016 Aug	 Intracranial response to nivolumab in NSCLC patients with untreated or  progressing CNS metastases.	 Lung Cancer	 Central nervous system (CNS) metastases occur in 30% of patients with advanced  non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases  result in delays in systemic therapy administration and are associated with  neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is  approved as a second-line treatment of NSCLC. Data regarding the intracranial  activity of nivolumab is lacking. We retrospectively reviewed the efficacy and  safety of nivolumab in five patients with advanced NSCLC and new/progressing  intracranial metastases. Intracranial response was assessed by magnetic resonance  imaging (MRI) using mRECIST v. 1.1 criteria. All patients had parenchymal brain  metastases; two patients had leptomeningeal carcinomatosis diagnosed according to  radiological criteria. All patients were asymptomatic and did not require  corticosteroids or immediate local therapy. We observed one complete and one  partial response in the brain. Stabilization of leptomeningeal carcinomatosis for  10 weeks was achieved in one additional patient. Two patients progressed in the  CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still  ongoing at the time of the report (24+ and 28+ weeks since start of treatment).  Systemic responses and intracranial responses were largely concordant. No  treatment-related or CNS metastases-related grade>/=3 adverse events were  observed. Nivolumab might have intracranial activity and favorable safety profile  in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity  warrants further evaluation.CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
CANIT0000671	27396730	Case report	Multifocal Renal Cell Carcinoma in a Solitary Kidney	Adrenocortical carcinoma	MONDO:0008734	Adrenal gland	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Dramatic response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Feb	 Treatment of Multifocal Renal Cell Carcinoma in a Solitary Kidney With Nivolumab.	 Clin Genitourin Cancer	Unable to provide
CANIT0000672	27400322	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	109	109	N/A	Higher frequencies of V2+ cells (39%) were associated with longer survival (p = 0.031) independent of the M category or lactate dehydrogenase level.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	Percentage of V2(+) cells	Cell percentage/counts in blood	 2016 Sep	 Proportions of blood-borne Vdelta1+ and Vdelta2+ T-cells are associated with  overall survival of melanoma patients treated with ipilimumab.	 Eur J Cancer	 Human gammadelta T-cells possess regulatory and cytotoxic capabilities, and could  potentially influence the efficacy of immunotherapies. We analysed the  frequencies of peripheral gammadelta T-cells, including their most prominent  subsets (Vdelta1+ and Vdelta2+ cells) and differentiation states in 109 melanoma   patients and 109 healthy controls. We additionally analysed the impact of  gammadelta T-cells on overall survival (OS) calculated from the first dose of  ipilimumab in melanoma patients. Higher median frequencies of Vdelta1+ cells and   lower median frequencies of Vdelta2+ cells were identified in patients compared  to healthy subjects (Vdelta1+: 30% versus 15%, Vdelta2+: 39% versus 64%, both p <  0.001). Patients with higher frequencies of Vdelta1+ cells (>/=30%) had poorer OS  (p = 0.043) and a Vdelta1+ differentiation signature dominated by  late-differentiated phenotypes. In contrast, higher frequencies of Vdelta2+ cells  (>/=39%) were associated with longer survival (p = 0.031) independent of the M  category or lactate dehydrogenase level. Patients with decreasing frequencies of   Vdelta2+ cells under ipilimumab treatment had worse OS and a lower rate of  clinical benefit than patients without such decreases. Therefore, we suggest  frequencies of both Vdelta1+ and Vdelta2+ cells as candidate biomarkers for  outcome in melanoma patients following ipilimumab. Further studies are needed to   validate these results and to clarify whether they represent prognostic  associations or whether gammadelta T-cells are specifically and/or functionally  linked to the mode of action of ipilimumab.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000673	27400322	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	109	109	N/A	Patients with higher frequencies of V1+ cells (30%) had poorer OS (p = 0.043) and a V1+ differentiation signature dominated by late-differentiated phenotypes.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	Percentage of V1(+) cells	Cell percentage/counts in blood	 2016 Sep	 Proportions of blood-borne Vdelta1+ and Vdelta2+ T-cells are associated with  overall survival of melanoma patients treated with ipilimumab.	 Eur J Cancer	 Human gammadelta T-cells possess regulatory and cytotoxic capabilities, and could  potentially influence the efficacy of immunotherapies. We analysed the  frequencies of peripheral gammadelta T-cells, including their most prominent  subsets (Vdelta1+ and Vdelta2+ cells) and differentiation states in 109 melanoma   patients and 109 healthy controls. We additionally analysed the impact of  gammadelta T-cells on overall survival (OS) calculated from the first dose of  ipilimumab in melanoma patients. Higher median frequencies of Vdelta1+ cells and   lower median frequencies of Vdelta2+ cells were identified in patients compared  to healthy subjects (Vdelta1+: 30% versus 15%, Vdelta2+: 39% versus 64%, both p <  0.001). Patients with higher frequencies of Vdelta1+ cells (>/=30%) had poorer OS  (p = 0.043) and a Vdelta1+ differentiation signature dominated by  late-differentiated phenotypes. In contrast, higher frequencies of Vdelta2+ cells  (>/=39%) were associated with longer survival (p = 0.031) independent of the M  category or lactate dehydrogenase level. Patients with decreasing frequencies of   Vdelta2+ cells under ipilimumab treatment had worse OS and a lower rate of  clinical benefit than patients without such decreases. Therefore, we suggest  frequencies of both Vdelta1+ and Vdelta2+ cells as candidate biomarkers for  outcome in melanoma patients following ipilimumab. Further studies are needed to   validate these results and to clarify whether they represent prognostic  associations or whether gammadelta T-cells are specifically and/or functionally  linked to the mode of action of ipilimumab.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000674	27405322	Clinical research	Treatment-na ve advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	Dacarbazine	Immune checkpoint therapy	Nivolumab (DB09035); dacarbazine (DB00851); 	210	208	A phase III clinical trial 	In addition to prolonged survival, these exploratory HRQoL results  show that nivolumab maintains baseline HRQoL levels to provide long-term quality   of survival benefit, compared with dacarbazine in patients with advanced  melanoma.	N/A	N/A	N/A	Health-related quality of life (NCIT:C142570); 	Baseline health-related quality of life levels	Disease status	 2016 Oct	 Effect of nivolumab on health-related quality of life in patients with  treatment-naive advanced melanoma: results from the phase III CheckMate 066  study.	 Ann Oncol	 BACKGROUND: Nivolumab has shown significant survival benefit and a favorable  safety profile compared with dacarbazine chemotherapy among treatment-naive  patients with metastatic melanoma in the CheckMate 066 phase III study. Results  from the health-related quality of life (HRQoL) analyses from CheckMate 066 are  presented. PATIENTS AND METHODS: HRQoL was evaluated at baseline and every 6  weeks while on treatment using the European Organisation for Research and  Treatment of Care (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and the  EuroQoL Five Dimensions Questionnaire (EQ-5D). Via a multi-step statistical plan,  data were analyzed descriptively, cross-sectionally, and longitudinally,  adjusting for baseline covariates, in patients having baseline plus >/=1  post-baseline assessment. RESULTS: Baseline-adjusted completion rates for all  HRQoL questionnaires across treatment arms were 65% and 70% for dacarbazine and  nivolumab, respectively, and remained similar throughout treatment. The mean  baseline HRQoL scores were similar for patients treated with nivolumab and  dacarbazine. Baseline HRQoL levels with nivolumab were maintained over time. This  exploratory analysis showed a between-arm difference in favor of nivolumab on the  EQ-5D utility index and clinically meaningful EQ-5D improvements from baseline at  several time points for patients receiving nivolumab. Patients treated with  nivolumab did not show increased symptom burden as assessed by the EORTC QLQ-C30.  No HRQoL change was noted with dacarbazine patients up to week 43, although the  high attrition rate after week 13 did not allow any meaningful analyses. Patients  receiving nivolumab deteriorated significantly later than those receiving  dacarbazine on several EORTC QLQ-C30 scales and the EQ-5D utility index.  CONCLUSIONS: In addition to prolonged survival, these exploratory HRQoL results  show that nivolumab maintains baseline HRQoL levels to provide long-term quality   of survival benefit, compared with dacarbazine in patients with advanced  melanoma.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology.
CANIT0000675	27410923	Clinical research	Relapsed hematologic cancer after allogeneic HSCT	Hematopoietic and lymphoid cell neoplasm	MONDO:0044881	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	28	N/A	A phase I/Ib, open-label, investigator-initiated, single-group, multicenter study	Administration of ipilimumab was feasible in patients with  recurrent hematologic cancers after allogeneic HSCT, although immune-mediated  toxic effects and GVHD occurred. Durable responses were observed in association  with several histologic subtypes of these cancers, including extramedullary acute  myeloid leukemia.	Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%).	N/A	N/A	N/A	N/A	N/A	 2016 Jul 14	 Ipilimumab for Patients with Relapse after Allogeneic Transplantation.	 N Engl J Med	 BACKGROUND: Loss of donor-mediated immune antitumor activity after allogeneic  hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic  cancers. We hypothesized that immune checkpoint blockade established by targeting  cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore  antitumor reactivity through a graft-versus-tumor effect. METHODS: We conducted a  phase 1/1b multicenter, investigator-initiated study to determine the safety and   efficacy of ipilimumab in patients with relapsed hematologic cancer after  allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of  3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with  additional doses every 12 weeks for up to 60 weeks in patients who had a clinical  benefit. RESULTS: A total of 28 patients were enrolled. Immune-related adverse  events, including one death, were observed in 6 patients (21%), and  graft-versus-host disease (GVHD) that precluded further administration of  ipilimumab was observed in 4 patients (14%). No responses that met formal  response criteria occurred in patients who received a dose of 3 mg per kilogram.   Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a  complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor  burden. Complete responses occurred in 4 patients with extramedullary acute  myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into   acute myeloid leukemia. Four patients had a durable response for more than 1  year. Responses were associated with in situ infiltration of cytotoxic CD8+ T  cells, decreased activation of regulatory T cells, and expansion of  subpopulations of effector T cells in the blood. CONCLUSIONS: Our early-phase  data showed that administration of ipilimumab was feasible in patients with  recurrent hematologic cancers after allogeneic HSCT, although immune-mediated  toxic effects and GVHD occurred. Durable responses were observed in association  with several histologic subtypes of these cancers, including extramedullary acute  myeloid leukemia. (Funded by the National Institutes of Health and others;  ClinicalTrials.gov number, NCT01822509.).
CANIT0000676	27420474	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Myasthenic crisis and polymyositis	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Myasthenic crisis and polymyositis induced by one dose of nivolumab.	 Cancer Sci	 An 80-year-old man, who developed multiple lymph node and skin metastasis of  malignant melanoma, received nivolumab monotherapy. Two weeks after the first  dose, he experienced anorexia and fatigue, and suffered from progressive, severe   dyspnea and muscle weakness. We diagnosed him with myocarditis, myositis, and  myasthenic crisis induced by nivolumab. We commenced steroid therapy, immune  absorption therapy, plasma exchange therapy, and i.v. immunoglobulin therapy, and  succeeded in saving his life. Because his serum level of anti-acetylcholine  receptor antibodies in a sample collected before nivolumab treatment were  positive and were elevated significantly after nivolumab, we suspected that  nivolumab triggered a severe autoimmune response, which progressed subclinical  myasthenia gravis to myasthenic crisis. We carried out T cell receptor repertoire  analysis using next-generation sequencing technologies and identified  infiltration of clonally expanded T cell populations in the skeletal muscle after  nivolumab treatment, implying a very strong T cell immune response against  muscular cells. To avoid severe immune-related adverse events, the exclusion of  patients with subclinical autoimmune disease is very important for treatment with  immune checkpoint inhibitors.CI  - (c) 2016 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0000677	27423391	Clinical research	NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	N/A	N/A	Pulmonary tuberculosis	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Anti-PD1 Antibody Treatment and the Development of Acute Pulmonary Tuberculosis.	 J Thorac Oncol	 Recently, cancer immunotherapy by immune checkpoint inhibitors has been  considered one of the pillars for the treatment of cancer. Nivolumab is the first  immune checkpoint inhibitor approved for lung cancer treatment in Japan. Although  nivolumab has superior survival benefits and fewer adverse events than cytotoxic   agents, it can generate dysimmune toxicities, known as immune-related adverse  events. Although autoimmune manifestations are well-known immune-related adverse   events, the development of infectious diseases is rare. Here, we report on a  patient with advanced NSCLC in whom pulmonary tuberculosis developed rapidly  during nivolumab treatment and discuss the potential mechanisms as well as what  is known about infections during checkpoint inhibitor therapy.CI  - Copyright (c) 2016 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0000678	27429197	Clinical research	Metastatic castration resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	A phase II clinical trial	The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer.	There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response.	N/A	N/A	N/A	N/A	N/A	 2016 Aug 16	 Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer.	 Oncotarget	 While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor  efficacy in several solid tumors, prior results in men with metastatic castration  resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report   unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1  antibody pembrolizumab. Patients with evidence of progression on enzalutamide  were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses;  pembrolizumab was added to standard dose enzalutamide. Three of the first ten  patients enrolled in this ongoing phase II trial experienced rapid prostate  specific antigen (PSA) reductions to </= 0.2 ng/ml. Two of these three patients  had measurable disease upon study entry; both achieved a partial response. There   were three patients with significant immune-related adverse events. One had grade  2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism.  None of these patients had a response. Two of the three responders had a baseline  tumor biopsy. Immunohistochemistry from those biopsies showed the presence of  CD3+, CD8+, and CD163+ leukocyte infiltrates and PD-L1 expression. Genetic  analysis of the two responders revealed markers of microsatellite instability in   one. The surprising and robust responses seen in this study should lead to  re-examination of PD-1 inhibition in prostate cancer.
CANIT0000679	27433843	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	N/A	Acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	B2M (P61769); 	B2M mutational status	Mutational status	 2016 Sep 1	 Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.	 N Engl J Med	 BACKGROUND: Approximately 75% of objective responses to anti-programmed death 1  (PD-1) therapy in patients with melanoma are durable, lasting for years, but  delayed relapses have been noted long after initial objective tumor regression  despite continuous therapy. Mechanisms of immune escape in this context are  unknown. METHODS: We analyzed biopsy samples from paired baseline and relapsing  lesions in four patients with metastatic melanoma who had had an initial  objective tumor regression in response to anti-PD-1 therapy (pembrolizumab)  followed by disease progression months to years later. RESULTS: Whole-exome  sequencing detected clonal selection and outgrowth of the acquired resistant  tumors and, in two of the four patients, revealed resistance-associated  loss-of-function mutations in the genes encoding interferon-receptor-associated  Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the  wild-type allele. A truncating mutation in the gene encoding the  antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third  patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to  interferon gamma, including insensitivity to its antiproliferative effects on  cancer cells. The B2M truncating mutation led to loss of surface expression of  major histocompatibility complex class I. CONCLUSIONS: In this study, acquired  resistance to PD-1 blockade immunotherapy in patients with melanoma was  associated with defects in the pathways involved in interferon-receptor signaling  and in antigen presentation. (Funded by the National Institutes of Health and  others.).
CANIT0000680	27433843	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	N/A	Acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	JAK1/2 (P23458); 	JAK1/2 mutational status	Mutational status	 2016 Sep 1	 Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.	 N Engl J Med	 BACKGROUND: Approximately 75% of objective responses to anti-programmed death 1  (PD-1) therapy in patients with melanoma are durable, lasting for years, but  delayed relapses have been noted long after initial objective tumor regression  despite continuous therapy. Mechanisms of immune escape in this context are  unknown. METHODS: We analyzed biopsy samples from paired baseline and relapsing  lesions in four patients with metastatic melanoma who had had an initial  objective tumor regression in response to anti-PD-1 therapy (pembrolizumab)  followed by disease progression months to years later. RESULTS: Whole-exome  sequencing detected clonal selection and outgrowth of the acquired resistant  tumors and, in two of the four patients, revealed resistance-associated  loss-of-function mutations in the genes encoding interferon-receptor-associated  Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the  wild-type allele. A truncating mutation in the gene encoding the  antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third  patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to  interferon gamma, including insensitivity to its antiproliferative effects on  cancer cells. The B2M truncating mutation led to loss of surface expression of  major histocompatibility complex class I. CONCLUSIONS: In this study, acquired  resistance to PD-1 blockade immunotherapy in patients with melanoma was  associated with defects in the pathways involved in interferon-receptor signaling  and in antigen presentation. (Funded by the National Institutes of Health and  others.).
CANIT0000681	27436004	Case report	Advanced lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Psoriasis and psoriatic arthritis	N/A	N/A	N/A	N/A	N/A	 2016 Nov	 Psoriasis and psoriatic arthritis induced by nivolumab in a patient with advanced  lung cancer.	 Rheumatology (Oxford)	Unable to provide
CANIT0000682	27440853	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Suspected autoimmune myocarditis and cardiac conduction abnormalities	N/A	N/A	N/A	N/A	N/A	 2016 Jul 20	 Suspected autoimmune myocarditis and cardiac conduction abnormalities with  nivolumab therapy for non-small cell lung cancer.	 BMJ Case Rep	 Checkpoint inhibitors such as nivolumab represent a novel class of agents that  are being increasingly used in the treatment of various cancers. Their toxicities  represent unique challenges to the oncologists prescribing them, patients'  primary care physicians and other specialists who may encounter these patients  during consultations. It is important for physicians to remain vigilant and  include autoimmune toxicities in the list of potential differential diagnoses in   patients receiving novel cancer therapeutics who present with unusual toxicities.  We report the unusual case of a 68-year-old woman with advanced lung cancer on  the novel chemotherapeutic Nivolumab whom we suspect developed autoimmune  myocarditis with significant cardiac conduction disease as an unintended, and as   of yet unrecognised, side effect from this medication.CI  - 2016 BMJ Publishing Group Ltd.
CANIT0000683	27442668	Case report	Advanced primary malignant melanoma of the esophagus	Esophagus melanoma	EFO:0000756	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Bi-cytopenia	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Bi-cytopenia possibly induced by anti-PD-1 antibody for primary malignant  melanoma of the esophagus: A case report.	 Medicine (Baltimore)	 BACKGROUND: Anti-programmed cell death 1 antibody nivolumab is a promising agent   for various cancers. Immune-related adverse events are recognized; however,  bi-cytopenia with nivolumab has not been reported. CASE PRESENTATION: A  73-year-old man was diagnosed with advanced primary malignant melanoma of the  esophagus with liver, lung, and lymph node metastases. Previous therapies  including dacarbazine and radiation of 39 Gy to the esophageal region were  performed, but the liver metastases deteriorated. The patient was then  administered nivolumab (2 mg/kg, every 3 weeks). After 3 cycles, the esophageal  tumor and lymph nodes showed marked reductions in size, the lung metastases  disappeared, and the liver metastases shrank partially. The treatment continued  with 7 cycles for 4 months. However, severe anemia and thrombocytopenia appeared   in the 6th cycle, and intermittent blood transfusions were required. The patient   received high-dose intravenous methylprednisolone therapy for bi-cytopenia, but  it was ineffective. Seven months after the initiation of nivolumab, the patient  died of tumor. Although the mechanisms of bi-cytopenia were unclear, it could  have been induced by nivolumab. CONCLUSION: The present case shows a rare but  serious life-threatening bi-cytopenia possibly associated with nivolumab and  suggests the importance of awareness of hematological adverse events during  nivolumab therapy.
CANIT0000684	27447748	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); BRAF (P15056); 	CTLA-4; BRAF	Dabrafenib plus trametinib followed by ipilimumab	N/A	Target therapy followed by Immune checkpoint therapy	Ipilimumab (DB06186); trametinib (DB08911); dabrafenib (DB08912); 	1	N/A	Case	Pathological complete response	Fatal gastrointestinal toxicity	N/A	N/A	N/A	N/A	N/A	 2016 Aug 30	 Fatal gastrointestinal toxicity with ipilimumab after BRAF/MEK inhibitor  combination in a melanoma patient achieving pathological complete response.	 Oncotarget	 Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several   treatment options including the combination of BRAF and MEK inhibitors  (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have  been shown to improve survival in these patients. Although preclinical data  support the synergistic effect of both modalities in combination, data confirming  the activity and tolerability of these combinations are not yet available in the   clinical setting. Herein, we report the case of a melanoma patient treated with  sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4  antibody ipilimumab who achieved a pathological complete response. Unfortunately,  the patient died due to fatal gastrointestinal (GI) toxicity. Analysis of the  BRAFV600E mutation in circulating tumoral DNA (ctDNA) from peripheral blood  samples and serial tumor tissue biopsies throughout treatment demonstrated a good  correlation with clinical evolution.
CANIT0000685	27451390	Clinical research	Classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin	Classic hodgkin lymphoma	MONDO:0009348	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	80	N/A	A multicentre, multicohort, single-arm phase II	Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkin's lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin.	The most common drug-related adverse events (those that occurred in 15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or 4 adverse events were neutropenia (four [5%] patients) and increased lipase concentrations (four [5%]). The most common serious adverse event (any grade) was pyrexia (three [4%] patients). Three patients died during the study; none of these deaths were judged to be treatment related.	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Nivolumab for classical Hodgkin's lymphoma after failure of both autologous  stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort,  single-arm phase 2 trial.	 Lancet Oncol	 BACKGROUND: Malignant cells of classical Hodgkin's lymphoma are characterised by   genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1  ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a  PD-1-blocking antibody, produced a high response in patients with relapsed and  refractory classical Hodgkin's lymphoma, with an acceptable safety profile. We  aimed to assess the clinical benefit and safety of nivolumab monotherapy in  patients with classical Hodgkin's lymphoma after failure of both autologous  stem-cell transplantation and brentuximab vedotin. METHODS: In this ongoing,  single-arm phase 2 study, adult patients (aged >/=18 years) with recurrent  classical Hodgkin's lymphoma who had failed to respond to autologous stem-cell  transplantation and had either relapsed after or failed to respond to brentuximab  vedotin, and with an Eastern Cooperative Oncology Group performance status score   of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and  North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg  every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from  study. The primary endpoint was objective response following a prespecified  minimum follow-up period of 6 months, assessed by an independent radiological  review committee (IRRC). All patients who received at least one dose of nivolumab  were included in the primary and safety analyses. This trial is registered with  ClinicalTrials.gov, number NCT02181738. FINDINGS: Among 80 treated patients  recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous  therapies was four (IQR 4-7). At a median follow-up of 8.9 months (IQR 7.8-9.9),   53 (66.3%, 95% CI 54.8-76.4) of 80 patients achieved an IRRC-assessed objective  response. The most common drug-related adverse events (those that occurred in  >/=15% of patients) included fatigue (20 [25%] patients), infusion-related  reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or  4 adverse events were neutropenia (four [5%] patients) and increased lipase  concentrations (four [5%]). The most common serious adverse event (any grade) was  pyrexia (three [4%] patients). Three patients died during the study; none of  these deaths were judged to be treatment related. INTERPRETATION: Nivolumab  resulted in frequent responses with an acceptable safety profile in patients with  classical Hodgkin's lymphoma who progressed after autologous stem-cell  transplantation and brentuximab vedotin. Therefore, nivolumab might be a new  treatment option for a patient population with a high unmet need. Ongoing  follow-up will help to assess the durability of response. FUNDING: Bristol-Myers   Squibb.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000686	27458307	Clinical research	Extensive-stage small-cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus etoposide and platinum	Placebo plus etoposide and platinum	Immune checkpoint therapy plus Chemotherapy	Platinum (DB12257); etoposide (DB00773); ipilimumab (DB06186); 	478	476	A randomized, double-blind phase III	Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.	Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. 	N/A	N/A	N/A	N/A	N/A	 2016 Nov 1	 Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus  Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer.	 J Clin Oncol	 Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have   poor survival outcomes despite first-line chemotherapy with etoposide and  platinum. This randomized, double-blind phase III study evaluated the efficacy  and safety of ipilimumab or placebo plus etoposide and platinum in patients with   newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were   randomly assigned at a ratio of one to one to receive chemotherapy with etoposide  and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every  3 weeks for a total of four doses each in a phased induction schedule  (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle  three up to cycle six), followed by ipilimumab or placebo maintenance every 12  weeks. Primary end point was overall survival (OS) among patients receiving at  least one dose of blinded study therapy. Results Of 1,132 patients randomly  assigned, 954 received at least one dose of study therapy (chemotherapy plus  ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0  months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus   placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median  progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus   4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to  0.97). Rates and severity of treatment-related adverse events were similar  between arms, except for diarrhea, rash, and colitis, which were more frequent  with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was   higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus  placebo). Five treatment-related deaths occurred with chemotherapy plus  ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of  ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in  patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected   adverse events were observed with chemotherapy plus ipilimumab. Several ongoing  studies are evaluating ipilimumab in combination with programmed death-1  inhibitors in SCLC.
CANIT0000687	27473193	Case report	Relapsed anaplastic large cell lymphoma after allogeneic haematopoietic stem cell transplantation	Anaplastic large cell lymphoma	EFO:0003032	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Low-dose pembrolizumab resulted in CR without provoking undue side effects. Hence, it remains to be defined if the dose of anti-PD1 antibodies could be adjusted so as to restore anti-tumour immunity without provoking GVHD.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Oct	 Pembrolizumab for relapsed anaplastic large cell lymphoma after allogeneic  haematopoietic stem cell transplantation: efficacy and safety.	 Ann Hematol	Unable to provide
CANIT0000688	27485076	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	86	N/A	A retrospective cohort study	Autoimmune side effects correlate with response to therapy and survival.	A lactate dehydrogenase (LDH) value within the normal range before the start of therapy was significantly correlated with better OS (p  0.009). An increase in LDH level after two cycles was indicative of a poor outcome, and was significantly negatively correlated with treatment response and overall survival and progression-free survival. 42% of all patients suffered from autoimmune toxicity (CTCAE grades 2-4). The occurrence of autoimmune toxicity clearly correlated with clinical benefit.	N/A	N/A	Autoimmune side effects (EFO:0005140); 	Autoimmune side effects	Adverse events	 2016 Sep	 Use of LDH and autoimmune side effects to predict response to ipilimumab  treatment.	 Immunotherapy	 BACKGROUND: Ipilimumab is a cytotoxic T-lymphocyte antigen-4 antibody that  enhances T-cell activity and proliferation. METHODS: In a retrospective analysis   of 86 patients the clinical benefits of ipilimumab treatment were correlated with  laboratory and clinical data. RESULTS: A lactate dehydrogenase (LDH) value within  the normal range before the start of therapy was significantly correlated with  better OS (p </= 0.009). An increase in LDH level after two cycles was indicative  of a poor outcome, and was significantly negatively correlated with treatment  response and overall survival and progression-free survival. 42% of all patients   suffered from autoimmune toxicity (CTCAE grades 2-4). The occurrence of  autoimmune toxicity clearly correlated with clinical benefit. CONCLUSION: Changes  in LDH level and side effects correlate with response to therapy and survival.
CANIT0000689	27485076	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	86	N/A	A retrospective cohort study	Changes in lactate dehydrogenase (LDH) level correlate with response to therapy and survival.	A lactate dehydrogenase (LDH) value within the normal range before the start of therapy was significantly correlated with better OS (p  0.009). An increase in LDH level after two cycles was indicative of a poor outcome, and was significantly negatively correlated with treatment response and overall survival and progression-free survival. 42% of all patients suffered from autoimmune toxicity (CTCAE grades 2-4). The occurrence of autoimmune toxicity clearly correlated with clinical benefit.	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Sep	 Use of LDH and autoimmune side effects to predict response to ipilimumab  treatment.	 Immunotherapy	 BACKGROUND: Ipilimumab is a cytotoxic T-lymphocyte antigen-4 antibody that  enhances T-cell activity and proliferation. METHODS: In a retrospective analysis   of 86 patients the clinical benefits of ipilimumab treatment were correlated with  laboratory and clinical data. RESULTS: A lactate dehydrogenase (LDH) value within  the normal range before the start of therapy was significantly correlated with  better OS (p </= 0.009). An increase in LDH level after two cycles was indicative  of a poor outcome, and was significantly negatively correlated with treatment  response and overall survival and progression-free survival. 42% of all patients   suffered from autoimmune toxicity (CTCAE grades 2-4). The occurrence of  autoimmune toxicity clearly correlated with clinical benefit. CONCLUSION: Changes  in LDH level and side effects correlate with response to therapy and survival.
CANIT0000690	27486176	Clinical research	Chemotherapy-Resistant Polymerase  (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	N/A	Anti-PD-1 inhibitors represent a novel treatment option for recurrent/metastatic, ultra/hyper-mutated human tumors refractory to salvage treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec 1	 Regression of Chemotherapy-Resistant Polymerase epsilon (POLE) Ultra-Mutated and   MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab.	 Clin Cancer Res	 PURPOSE: The management of endometrial carcinoma no longer amenable to treatment   with surgery or radiotherapy has not improved significantly with modern  chemotherapy. Alternative therapeutic options are desperately needed.  EXPERIMENTAL DESIGN: We describe 2 heavily pretreated patients with recurrent  disease refractory to surgery, radiotherapy, and chemotherapy who were treated  with the anti-PD-1 immune checkpoint inhibitor nivolumab. RESULTS: Patient #1  harbored an ultra-mutated tumor (mutation load/MB = 117.3, total mutations =  4,660) driven by mutation in the exonuclease domain of the DNA polymerase epsilon  gene. Patient #2 harbored a hyper-mutated tumor (mutation load/MB = 33.5, total  mutations = 1,037) due to a germinal MSH6 gene mutation. Both patients  demonstrated a remarkable clinical response to the anti-PD-1 immune checkpoint  inhibitor nivolumab. Patients' clinical responses remain unchanged at the time of  the writing of this report, with no grade 3 or higher side effects reported to  date. CONCLUSIONS: Anti-PD-1 inhibitors represent a novel treatment option for  recurrent/metastatic, ultra/hyper-mutated human tumors refractory to salvage  treatment. Clin Cancer Res; 22(23); 5682-7. (c)2016 AACRSee related commentary by  Piulats and Matias-Guiu, p. 5623.CI  - (c)2016 American Association for Cancer Research.
CANIT0000691	27490976	Case report	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Posterior uveitis	N/A	N/A	N/A	N/A	N/A	 2017 Fall	 PEMBROLIZUMAB ADMINISTRATION ASSOCIATED WITH POSTERIOR UVEITIS.	 Retin Cases Brief Rep	 PURPOSE: To describe the development of uveitis and retinal vasculitis in  association with pembrolizumab treatment for metastatic uveal melanoma. METHODS:   A case report and a brief review of the literature are presented. Information  collected and reported include the patient's clinical course, physical  examination findings, fluorescein angiogram images, retinal photographs, and her   response to treatment. RESULTS: A 54-year-old woman was diagnosed with a large  choroidal malignant melanoma and had the affected eye enucleated. Pathology  confirmed a mixed cell choroidal melanoma, and gene expression profiling was  Class 2. Seventeen months after enucleation, the patient was diagnosed with  metastatic uveal melanoma to the liver. Disease progression was observed during  ipilimumab treatment. Pembrolizumab treatment was initiated, and after four  infusions, she presented to clinic complaining of floaters and blurred vision.  Examination revealed a nongranulomatous panuveitis characterized by perivascular   retinal pigment epithelium pigmentary changes, retinal venous sheathing, 1+  anterior chamber and vitreous cellular reaction, 2+ vitreous haze, and optic disk  edema. A dexamethasone sustained-release implant was administered and the uveitis  regressed. A relapse in symptoms occurred but quickly subsided with a repeat  injection. CONCLUSION: Pembrolizumab may induce a uveitic reaction. There is  mounting evidence that patients using prembrolizumab should be educated and  monitored for signs of uveitis.
CANIT0000692	27510892	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	35	N/A	A multicentre, retrospective cohort study	The occurrence of vitiligo during nivolumab treatment may be correlated with  favorable clinical outcome.	25.7% (9/35) developed vitiligo during treatment.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Vitiligo 	Adverse events	 2017 Feb	 Correlation between vitiligo occurrence and clinical benefit in advanced melanoma  patients treated with nivolumab: A multi-institutional retrospective study.	 J Dermatol	 Vitiligo is occasionally seen in melanoma patients. Although several studies  indicate a correlation between vitiligo occurrence and clinical response in  melanoma patients receiving immunotherapy, most studies have included  heterogeneous patient and treatment settings. The aim of this study is to  investigate the correlation between the occurrence of vitiligo and clinical  benefit of nivolumab treatment in advanced melanoma patients. We retrospectively   reviewed unresectable stage III or IV melanoma patients treated with nivolumab.  Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo  during treatment. The time from the start of nivolumab treatment to occurrence of  vitiligo ranged 2-9 months (mean, 5.2). Of nine patients who developed vitiligo,   two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial  response. The objective response rate was significantly higher in patients with  vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P =  0.027). The mean time to vitiligo occurrence in patients achieving an objective  response was significantly less than that in patients who showed no response (3.1  vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with   prolonged progression-free and overall survival (hazard ratio, 0.24 and 0.16; 95%  confidence interval, 0.11-0.55 and 0.03-0.79; P = 0.005, and 0.047,  respectively). At the 20-week landmark analysis, however, vitiligo was not  associated with a statistically significant overall survival benefit (P = 0.28).   The occurrence of vitiligo during nivolumab treatment may be correlated with  favorable clinical outcome.CI  - (c) 2016 Japanese Dermatological Association.
CANIT0000693	27511215	Case report	Metastatic myxoid liposarcoma	Myxoid liposarcoma	EFO:0000613	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Sustained clinico-radiologic response to anti-cytotoxic T lymphocyte antigen 4  antibody therapy in metastatic myxoid liposarcoma.	 J Oncol Pharm Pract	 Rarity and heterogeneity of sarcomas pose significant challenges in terms of  developing new therapies. Therefore, efforts towards studying immunotherapy in  sarcomas may provide hope for effective control of this group of devastating  cancers. A sustained clinico-radiologic response to the anti-cytotoxic T  lymphocyte antigen 4 antibody ipilimumab in a patient with metastatic myxoid  liposarcoma is reported. Although the patient was treated with this agent for  metastatic melanoma, both his metastatic cancers - melanoma and sarcoma -  meaningfully responded to this agent. Consideration of enrolling patients in  immunotherapy trials using various immune checkpoint inhibitors, where available,  is of paramount importance, especially when facing advanced and/or refractory  sarcoma situation.
CANIT0000694	27521552	Case report	Metastatic breast carcinoma	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); HER2 (P04626); 	PD-1; HER2	Pembrolizumab plus trastuzumab	N/A	Immune checkpoint therapy plus Target therapy	Trastuzumab (DB00072); pembrolizumab (DB09037); 	1	N/A	Case	N/A	Apical takotsubo syndrome	N/A	N/A	N/A	N/A	N/A	 2016 Nov 1	 Apical takotsubo syndrome in a patient with metastatic breast carcinoma on novel   immunotherapy.	 Int J Cardiol	Unable to provide
CANIT0000695	27533633	Clinical research	Acral and mucosal melanoma	Acral lentiginous melanoma	MONDO:0003865	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	60	N/A	A multicentre, retrospective cohort study	Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice.	Only 2 patients (3%) discontinued treatment because of toxicity.	N/A	N/A	N/A	N/A	N/A	 2016 Nov 15	 The efficacy of anti-PD-1 agents in acral and mucosal melanoma.	 Cancer	 BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1  (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of   PD-1 blockade for patients with biologically distinct melanomas arising from  acral and mucosal surfaces has not been well described. METHODS: A  multi-institutional, retrospective cohort analysis identified adults with  advanced acral and mucosal melanoma who received treatment with nivolumab or  pembrolizumab as standard clinical practice through expanded access programs or  published prospective trials. Objective responses were determined using  investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST)  version 1.1. Progression-free survival and overall survival were assessed using  the Kaplan-Meier method. RESULTS: Sixty individuals were identified, including 25  (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients   (85%) had received previous therapy, including 77% who had previously received  ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or  10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg  every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval,  15%-54%) in patients with acral melanoma and 23% (95% confidence interval,  10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in  the acral melanoma group and 10.6 months in the mucosal melanoma group, the  median progression-free survival was 4.1 months and 3.9 months, respectively.  Only 2 patients (3%) discontinued treatment because of toxicity. CONCLUSIONS:  Response rates to PD-1 blockade in patients with acral and mucosal melanomas were  comparable to the published rates in patients with cutaneous melanoma and support  the routine use of PD-1 blockade in clinical practice. Further investigation is  needed to identify the mechanisms of response and resistance to therapy in these   subtypes. Cancer 2016;122:3354-3362. (c) 2016 American Cancer Society.CI  - (c) 2016 American Cancer Society.
CANIT0000696	27533633	Clinical research	Acral and mucosal melanoma	Acral lentiginous melanoma	MONDO:0003865	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	60	N/A	A multicentre, retrospective cohort study	Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice.	Only 2 patients (3%) discontinued treatment because of toxicity.	N/A	N/A	N/A	N/A	N/A	 2016 Nov 15	 The efficacy of anti-PD-1 agents in acral and mucosal melanoma.	 Cancer	 BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1  (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of   PD-1 blockade for patients with biologically distinct melanomas arising from  acral and mucosal surfaces has not been well described. METHODS: A  multi-institutional, retrospective cohort analysis identified adults with  advanced acral and mucosal melanoma who received treatment with nivolumab or  pembrolizumab as standard clinical practice through expanded access programs or  published prospective trials. Objective responses were determined using  investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST)  version 1.1. Progression-free survival and overall survival were assessed using  the Kaplan-Meier method. RESULTS: Sixty individuals were identified, including 25  (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients   (85%) had received previous therapy, including 77% who had previously received  ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or  10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg  every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval,  15%-54%) in patients with acral melanoma and 23% (95% confidence interval,  10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in  the acral melanoma group and 10.6 months in the mucosal melanoma group, the  median progression-free survival was 4.1 months and 3.9 months, respectively.  Only 2 patients (3%) discontinued treatment because of toxicity. CONCLUSIONS:  Response rates to PD-1 blockade in patients with acral and mucosal melanomas were  comparable to the published rates in patients with cutaneous melanoma and support  the routine use of PD-1 blockade in clinical practice. Further investigation is  needed to identify the mechanisms of response and resistance to therapy in these   subtypes. Cancer 2016;122:3354-3362. (c) 2016 American Cancer Society.CI  - (c) 2016 American Cancer Society.
CANIT0000697	27533633	Clinical research	Acral and mucosal melanoma	Mucosal melanoma	MONDO:0000544	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	60	N/A	A multicentre, retrospective cohort study	Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice.	Only 2 patients (3%) discontinued treatment because of toxicity.	N/A	N/A	N/A	N/A	N/A	 2016 Nov 15	 The efficacy of anti-PD-1 agents in acral and mucosal melanoma.	 Cancer	 BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1  (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of   PD-1 blockade for patients with biologically distinct melanomas arising from  acral and mucosal surfaces has not been well described. METHODS: A  multi-institutional, retrospective cohort analysis identified adults with  advanced acral and mucosal melanoma who received treatment with nivolumab or  pembrolizumab as standard clinical practice through expanded access programs or  published prospective trials. Objective responses were determined using  investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST)  version 1.1. Progression-free survival and overall survival were assessed using  the Kaplan-Meier method. RESULTS: Sixty individuals were identified, including 25  (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients   (85%) had received previous therapy, including 77% who had previously received  ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or  10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg  every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval,  15%-54%) in patients with acral melanoma and 23% (95% confidence interval,  10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in  the acral melanoma group and 10.6 months in the mucosal melanoma group, the  median progression-free survival was 4.1 months and 3.9 months, respectively.  Only 2 patients (3%) discontinued treatment because of toxicity. CONCLUSIONS:  Response rates to PD-1 blockade in patients with acral and mucosal melanomas were  comparable to the published rates in patients with cutaneous melanoma and support  the routine use of PD-1 blockade in clinical practice. Further investigation is  needed to identify the mechanisms of response and resistance to therapy in these   subtypes. Cancer 2016;122:3354-3362. (c) 2016 American Cancer Society.CI  - (c) 2016 American Cancer Society.
CANIT0000698	27533633	Clinical research	Acral and mucosal melanoma	Mucosal melanoma	MONDO:0000544	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	60	N/A	A multicentre, retrospective cohort study	Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice.	Only 2 patients (3%) discontinued treatment because of toxicity.	N/A	N/A	N/A	N/A	N/A	 2016 Nov 15	 The efficacy of anti-PD-1 agents in acral and mucosal melanoma.	 Cancer	 BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1  (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of   PD-1 blockade for patients with biologically distinct melanomas arising from  acral and mucosal surfaces has not been well described. METHODS: A  multi-institutional, retrospective cohort analysis identified adults with  advanced acral and mucosal melanoma who received treatment with nivolumab or  pembrolizumab as standard clinical practice through expanded access programs or  published prospective trials. Objective responses were determined using  investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST)  version 1.1. Progression-free survival and overall survival were assessed using  the Kaplan-Meier method. RESULTS: Sixty individuals were identified, including 25  (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients   (85%) had received previous therapy, including 77% who had previously received  ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or  10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg  every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval,  15%-54%) in patients with acral melanoma and 23% (95% confidence interval,  10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in  the acral melanoma group and 10.6 months in the mucosal melanoma group, the  median progression-free survival was 4.1 months and 3.9 months, respectively.  Only 2 patients (3%) discontinued treatment because of toxicity. CONCLUSIONS:  Response rates to PD-1 blockade in patients with acral and mucosal melanomas were  comparable to the published rates in patients with cutaneous melanoma and support  the routine use of PD-1 blockade in clinical practice. Further investigation is  needed to identify the mechanisms of response and resistance to therapy in these   subtypes. Cancer 2016;122:3354-3362. (c) 2016 American Cancer Society.CI  - (c) 2016 American Cancer Society.
CANIT0000699	27535979	Clinical research	Patients with advanced melanoma, lung cancer, or lymphoma	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	170	N/A	N/A	PD-1 inhibitor-related pneumonitis showed a spectrum of  radiographic patterns, reflecting pneumonitis grades. COP was the most common  pattern across tumor types and therapeutic regimens. Most patients were  successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis   flare were noted in a few patients.	Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy, and 15 received combination therapy. The median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern was most common in all tumors and treatment regimens. Most patients (17/20; 85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment.	N/A	N/A	N/A	N/A	N/A	 2016 Dec 15	 PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic  Patterns and Clinical Course.	 Clin Cancer Res	 PURPOSE: Investigate the clinical characteristics, radiographic patterns, and  treatment course of PD-1 inhibitor-related pneumonitis in advanced cancer  patients. EXPERIMENTAL DESIGN: Among patients with advanced melanoma, lung  cancer, or lymphoma treated in trials of nivolumab, we identified those who  developed pneumonitis. Chest CT scans were reviewed to assess extent,  distribution, and radiographic patterns of pneumonitis. RESULTS: Among 170  patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6  lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received  nivolumab monotherapy, and 15 received combination therapy. The median time from   therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was  cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia   (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial  pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The  AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had   lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern   was most common in all tumors and treatment regimens. Most patients (17/20; 85%)   received corticosteroids, and 3 (15%) also required infliximab. Seven patients  restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were  successfully retreated with corticosteroids. One of the patients experienced a  pneumonitis flare after completion of corticosteroid taper without nivolumab  retreatment. CONCLUSIONS: PD-1 inhibitor-related pneumonitis showed a spectrum of  radiographic patterns, reflecting pneumonitis grades. COP was the most common  pattern across tumor types and therapeutic regimens. Most patients were  successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis   flare were noted in a few patients. Clin Cancer Res; 22(24); 6051-60. (c)2016  AACRSee related commentary by Castanon, p. 5956.CI  - (c)2016 American Association for Cancer Research.
CANIT0000700	27535979	Clinical research	Patients with advanced melanoma, lung cancer, or lymphoma	Lymphoma	EFO:0000574	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	170	N/A	N/A	PD-1 inhibitor-related pneumonitis showed a spectrum of  radiographic patterns, reflecting pneumonitis grades. COP was the most common  pattern across tumor types and therapeutic regimens. Most patients were  successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis   flare were noted in a few patients.	Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy, and 15 received combination therapy. The median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern was most common in all tumors and treatment regimens. Most patients (17/20; 85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment.	N/A	N/A	N/A	N/A	N/A	 2016 Dec 15	 PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic  Patterns and Clinical Course.	 Clin Cancer Res	 PURPOSE: Investigate the clinical characteristics, radiographic patterns, and  treatment course of PD-1 inhibitor-related pneumonitis in advanced cancer  patients. EXPERIMENTAL DESIGN: Among patients with advanced melanoma, lung  cancer, or lymphoma treated in trials of nivolumab, we identified those who  developed pneumonitis. Chest CT scans were reviewed to assess extent,  distribution, and radiographic patterns of pneumonitis. RESULTS: Among 170  patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6  lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received  nivolumab monotherapy, and 15 received combination therapy. The median time from   therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was  cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia   (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial  pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The  AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had   lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern   was most common in all tumors and treatment regimens. Most patients (17/20; 85%)   received corticosteroids, and 3 (15%) also required infliximab. Seven patients  restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were  successfully retreated with corticosteroids. One of the patients experienced a  pneumonitis flare after completion of corticosteroid taper without nivolumab  retreatment. CONCLUSIONS: PD-1 inhibitor-related pneumonitis showed a spectrum of  radiographic patterns, reflecting pneumonitis grades. COP was the most common  pattern across tumor types and therapeutic regimens. Most patients were  successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis   flare were noted in a few patients. Clin Cancer Res; 22(24); 6051-60. (c)2016  AACRSee related commentary by Castanon, p. 5956.CI  - (c)2016 American Association for Cancer Research.
CANIT0000701	27535979	Clinical research	Patients with advanced melanoma, lung cancer, or lymphoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	170	N/A	N/A	PD-1 inhibitor-related pneumonitis showed a spectrum of  radiographic patterns, reflecting pneumonitis grades. COP was the most common  pattern across tumor types and therapeutic regimens. Most patients were  successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis   flare were noted in a few patients.	Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy, and 15 received combination therapy. The median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern was most common in all tumors and treatment regimens. Most patients (17/20; 85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment.	N/A	N/A	N/A	N/A	N/A	 2016 Dec 15	 PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic  Patterns and Clinical Course.	 Clin Cancer Res	 PURPOSE: Investigate the clinical characteristics, radiographic patterns, and  treatment course of PD-1 inhibitor-related pneumonitis in advanced cancer  patients. EXPERIMENTAL DESIGN: Among patients with advanced melanoma, lung  cancer, or lymphoma treated in trials of nivolumab, we identified those who  developed pneumonitis. Chest CT scans were reviewed to assess extent,  distribution, and radiographic patterns of pneumonitis. RESULTS: Among 170  patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6  lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received  nivolumab monotherapy, and 15 received combination therapy. The median time from   therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was  cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia   (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial  pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The  AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had   lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern   was most common in all tumors and treatment regimens. Most patients (17/20; 85%)   received corticosteroids, and 3 (15%) also required infliximab. Seven patients  restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were  successfully retreated with corticosteroids. One of the patients experienced a  pneumonitis flare after completion of corticosteroid taper without nivolumab  retreatment. CONCLUSIONS: PD-1 inhibitor-related pneumonitis showed a spectrum of  radiographic patterns, reflecting pneumonitis grades. COP was the most common  pattern across tumor types and therapeutic regimens. Most patients were  successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis   flare were noted in a few patients. Clin Cancer Res; 22(24); 6051-60. (c)2016  AACRSee related commentary by Castanon, p. 5956.CI  - (c)2016 American Association for Cancer Research.
CANIT0000702	27538576	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	54	N/A	N/A	Mutational load did not correlate with MSKCC risk prognostic classification	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor nonsynonymous mutational burden	Mutational status	 2016 Oct	 Tumor Mutational Load and Immune Parameters across Metastatic Renal Cell  Carcinoma Risk Groups.	 Cancer Immunol Res	 Patients with metastatic renal cell carcinoma (mRCC) have better overall survival  when treated with nivolumab, a cancer immunotherapy that targets the immune  checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a  chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients  treated with nivolumab seemed to experience the greatest overall survival  benefit, compared with patients with favorable or intermediate risk, in an  analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering  Cancer Center (MSKCC) prognostic risk groups. Here, we explore whether tumor  mutational load and RNA expression of specific immune parameters could be  segregated by prognostic MSKCC risk strata and explain the survival seen in the  poor-risk group. We queried whole-exome transcriptome data in renal cell  carcinoma patients (n = 54) included in The Cancer Genome Atlas who ultimately  developed metastatic disease or were diagnosed with metastatic disease at  presentation and did not receive immune checkpoint inhibitors. Nonsynonymous  mutational load did not differ significantly by the MSKCC risk group, nor was the  expression of cytolytic genes-granzyme A and perforin-or selected immune  checkpoint molecules different across MSKCC risk groups. In conclusion, this  analysis revealed that mutational load and expression of markers of an active  tumor microenvironment did not correlate with MSKCC risk prognostic  classification in mRCC. Cancer Immunol Res; 4(10); 820-2. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000703	27538576	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	54	N/A	N/A	Expression of markers of an active tumor microenvironment did not correlate with MSKCC risk prognostic classification	N/A	N/A	N/A	Active tumor microenvironment (NCIT:C94498); 	Gene expression signatures of an active tumor microenvironment	Gene expression signature on/in immune cell	 2016 Oct	 Tumor Mutational Load and Immune Parameters across Metastatic Renal Cell  Carcinoma Risk Groups.	 Cancer Immunol Res	 Patients with metastatic renal cell carcinoma (mRCC) have better overall survival  when treated with nivolumab, a cancer immunotherapy that targets the immune  checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a  chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients  treated with nivolumab seemed to experience the greatest overall survival  benefit, compared with patients with favorable or intermediate risk, in an  analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering  Cancer Center (MSKCC) prognostic risk groups. Here, we explore whether tumor  mutational load and RNA expression of specific immune parameters could be  segregated by prognostic MSKCC risk strata and explain the survival seen in the  poor-risk group. We queried whole-exome transcriptome data in renal cell  carcinoma patients (n = 54) included in The Cancer Genome Atlas who ultimately  developed metastatic disease or were diagnosed with metastatic disease at  presentation and did not receive immune checkpoint inhibitors. Nonsynonymous  mutational load did not differ significantly by the MSKCC risk group, nor was the  expression of cytolytic genes-granzyme A and perforin-or selected immune  checkpoint molecules different across MSKCC risk groups. In conclusion, this  analysis revealed that mutational load and expression of markers of an active  tumor microenvironment did not correlate with MSKCC risk prognostic  classification in mRCC. Cancer Immunol Res; 4(10); 820-2. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000704	27539158	Case report	Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Autoimmune hemolytic anemia is not an absolute contraindication to drug continuation.	Autoimmune hemolytic anemia	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Autoimmune hemolytic anemia after nivolumab treatment in Hodgkin lymphoma  responsive to immunosuppressive treatment. A case report.	 Hematol Oncol	 The patients with refractory Hodgkin lymphoma have a poor prognosis. The  nivolumab, an IgG4 monoclonal antibody inhibiting the program death 1 pathway has  recently demonstrated its efficacy and its safety in patients with heavily  pretreated refractory Hodgkin lymphoma. The side effects of this immunotherapy  include autoimmune-like syndromes. A 75-year-old woman with no significant  comorbidities was treated by nivolumab (3 mg/kg every 2 wk) as a third-line  treatment for refractory Hodgkin lymphoma. A clinical response was observed with   the first injection of nivolumab, with a reduction in superficial lymph nodes.  After the second injection, the patient presented an authentic autoimmune  hemolytic anemia with a profound anemia at 64 g/L and biologic characteristics of  hemolysis (elevated unconjugated bilirubin, lactate dehydrogenase, and  reticulocytes). The direct antiglobulin test was strongly positive for IgG  antibodies, and the indirect antiglobulin test became positive with a very high  level of autoantibodies. After 2 injections of nivolumab, the patient underwent a  fluodeoxyglucose F 18 positron emission tomography-computed tomography, showing a  partial response according to modified Cheson criteria. A treatment with  prednisone (2 mg/kg), initiated after transfusion of 2 units of red blood cells,   permitted the complete resolution of this autoimmune reaction after 3 months of  corticotherapy. The fluodeoxyglucose F 18 positron emission tomography-computed  tomography performed at the end of the corticotherapy showed a clear disease  progression. Considering the very good response achieved after only 2 injections   of nivolumab, the limited therapeutic resources for this old woman, and the  complete resolution of the autoimmune hemolytic anemia, nivolumab was  reintroduced at the same dose, with close clinical and biological monitoring. She  received 6 more injections of nivolumab without recurrence of hemolysis.CI  - Copyright (c) 2016 John Wiley & Sons, Ltd.
CANIT0000705	27543082	Case report	Malignant pleural mesothelioma	Pleural mesothelioma	EFO:1000485	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Minimal change disease 	N/A	N/A	N/A	N/A	N/A	 2016 Aug 19	 Pembrolizumab-associated minimal change disease in a patient with malignant  pleural mesothelioma.	 BMC Cancer	 BACKGROUND: Pembrolizumab is an anti- Programmed Death 1 (PD-1) antibody approved  in melanoma, non-small cell lung cancer and investigated in malignant pleural  mesothelioma. The most frequent immunotherapy related autoimmune reactions  include dermatitis, pneumonitis, colitis, hypophysitis, uveitis, hypothyreodism,   hepatitis and interstitial nephritis. CASE PRESENTATION: We describe a 62-year  old patient diagnosed with malignant pleural mesothelioma who experienced ten  days after the second dose of third line therapy with pembrolizumab sudden onset   of generalized edema including legs and eyelids and weight gain of 15 kg  resulting from nephrotic syndrome and acute renal failure. Pembrolizumab was  discontinued and prednisone, diuretics and angiotensin II receptor blocker were  initiated with full recovery of symptoms and renal function.  Pembrolizumab-associated minimal change disease (MCD) was confirmed by electron  microscopy in the renal biopsy. CONCLUSION: We are the first to describe  pembrolizumab-related minimal change disease (MCD). Physicians should be aware of  this side effect in patients presenting with edema and weight gain and initiate  prompt renal function testing, serum albumin and urinalysis followed by steroid  treatment if pembrolizumab-related MCD is suspected.
CANIT0000706	27544928	Case report	Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Abscopal effect	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Oct	 Abscopal effect in a Hodgkin lymphoma patient treated by an anti-programmed death  1 antibody.	 Eur J Cancer	Unable to provide
CANIT0000707	27549123	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); VEGF (P15692); 	CTLA-4; VEGF	Ipilimumab plus bevacizumab	N/A	Immune checkpoint therapy plus Target therapy	Ipilimumab (DB06186); bevacizumab (DB00112); 	46	N/A	A phase II clinical trial	Our findings suggest that Ipi-Bev therapy augments immune recognition in the tumor microenvironment through enhancing lymphocyte infiltration and antibody responses. IL1, TNF, and CXCL10, together with VEGF neutralization, contribute to Ipi-Bev-induced melanoma immune recognition.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2016 Oct	 VEGF Neutralization Plus CTLA-4 Blockade Alters Soluble and Cellular Factors  Associated with Enhancing Lymphocyte Infiltration and Humoral Recognition in  Melanoma.	 Cancer Immunol Res	 Immune recognition of tumor targets by specific cytotoxic lymphocytes is  essential for the effective rejection of tumors. A phase I clinical trial of  ipilimumab (an antibody that blocks CTLA-4 function) in combination with  bevacizumab (an antibody that inhibits angiogenesis) in patients with metastatic   melanoma found favorable clinical outcomes were associated with increased tumor  endothelial activation and lymphocyte infiltration. To better understand the  underlying mechanisms, we sought features and factors that changed as a function   of treatment in patients. Ipilimumab plus bevacizumab (Ipi-Bev) increased tumor  vascular expression of ICAM1 and VCAM1. Treatment also altered concentrations of   many circulating cytokines and chemokines, including increases of CXCL10,  IL1alpha, TNFalpha, CXCL1, IFNalpha2, and IL8, with decreases in VEGF-A in most  patients. IL1alpha and TNFalpha induced expression of E-selectin, CXCL1, and  VCAM1 on melanoma tumor-associated endothelial cells (TEC) in vitro and promoted   adhesion of activated T cells onto TEC. VEGFA inhibited TNFalpha-induced  expression of ICAM1 and VCAM1 and T-cell adhesion, which was blocked by  bevacizumab. CXCL10 promoted T-cell migration across TEC in vitro, was frequently  expressed by melanoma cells, and was upregulated in a subset of tumors in treated  patients. Robust upregulation of CXCL10 in tumors was accompanied by increased  T-cell infiltration. Ipi-Bev also augmented humoral immune responses recognizing   targets in melanoma, tumor endothelial, and tumor mesenchymal stem cells. Our  findings suggest that Ipi-Bev therapy augments immune recognition in the tumor  microenvironment through enhancing lymphocyte infiltration and antibody  responses. IL1alpha, TNFalpha, and CXCL10, together with VEGF neutralization,  contribute to Ipi-Bev-induced melanoma immune recognition. Cancer Immunol Res;  4(10); 858-68. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000708	27554283	Clinical research	Non-melanoma solid tumours (6 Mesothelioma, 9 Sarcoma, 1 urothelial carcinoma, 1 nasopharynx squamous cell carcinoma, 1 anal squamous cell carcinoma etc.)	Anal squamous cell carcinoma	EFO:1000081	Anus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	21	N/A	A retrospective cohort study	Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose.	Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed.	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Outcomes of patients with non-melanoma solid tumours receiving self-funded  pembrolizumab at Chris O'Brien Lifehouse.	 Intern Med J	 BACKGROUND: Immunotherapy agents show anti-cancer activity in several solid  cancers. Efficacy in non-melanoma solid tumours for non-approved indications is  unknown. AIM: To evaluate patient and disease characteristics, rate and duration   of response, and toxicity of self-funded pembrolizumab in patients with  non-melanoma solid cancers. METHOD: Retrospective review describing outcomes and   toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers  treated at Chris O'Brien Lifehouse. RESULTS: From April 2015 to December 2015, 21  patients received or were planned to receive self-funded pembrolizumab. The  median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology  Group performance status of 2, and 3-4 respectively. Sixty-two percent received  at least two to four lines of prior drug treatment. Median follow-up was 3.0  months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab.  Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested   pembrolizumab had worse outcomes. Three patients died before receiving  pembrolizumab. Of the 18 patients that received at least one dose, a partial  response was observed in 3 (17%). Progressive disease occurred in 83%. Four  patients received only one cycle of pembrolizumab and died after a median of 27  days (range 13-43). Immune-related adverse events of any grade occurred in 33%.  No grade 3-4 events were observed. CONCLUSION: Pembrolizumab was well tolerated.   Meaningful responses were observed in 17% of treated patients. Response continues  after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other  responding patient. Financial impact to the patient can be substantial. Outcomes   for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose. This highlights issues regarding the  careful selection of patients, futility of anti-cancer therapy at the end-of-life  and patients' perceived benefit of receiving this therapy.CI  - (c) 2016 Royal Australasian College of Physicians.
CANIT0000709	27554283	Clinical research	Non-melanoma solid tumours (6 Mesothelioma, 9 Sarcoma, 1 urothelial carcinoma, 1 nasopharynx squamous cell carcinoma, 1 anal squamous cell carcinoma etc.)	Mesothelioma	EFO:0000588	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	21	N/A	A retrospective cohort study	Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose.	Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed.	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Outcomes of patients with non-melanoma solid tumours receiving self-funded  pembrolizumab at Chris O'Brien Lifehouse.	 Intern Med J	 BACKGROUND: Immunotherapy agents show anti-cancer activity in several solid  cancers. Efficacy in non-melanoma solid tumours for non-approved indications is  unknown. AIM: To evaluate patient and disease characteristics, rate and duration   of response, and toxicity of self-funded pembrolizumab in patients with  non-melanoma solid cancers. METHOD: Retrospective review describing outcomes and   toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers  treated at Chris O'Brien Lifehouse. RESULTS: From April 2015 to December 2015, 21  patients received or were planned to receive self-funded pembrolizumab. The  median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology  Group performance status of 2, and 3-4 respectively. Sixty-two percent received  at least two to four lines of prior drug treatment. Median follow-up was 3.0  months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab.  Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested   pembrolizumab had worse outcomes. Three patients died before receiving  pembrolizumab. Of the 18 patients that received at least one dose, a partial  response was observed in 3 (17%). Progressive disease occurred in 83%. Four  patients received only one cycle of pembrolizumab and died after a median of 27  days (range 13-43). Immune-related adverse events of any grade occurred in 33%.  No grade 3-4 events were observed. CONCLUSION: Pembrolizumab was well tolerated.   Meaningful responses were observed in 17% of treated patients. Response continues  after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other  responding patient. Financial impact to the patient can be substantial. Outcomes   for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose. This highlights issues regarding the  careful selection of patients, futility of anti-cancer therapy at the end-of-life  and patients' perceived benefit of receiving this therapy.CI  - (c) 2016 Royal Australasian College of Physicians.
CANIT0000710	27554283	Clinical research	Non-melanoma solid tumours (6 Mesothelioma, 9 Sarcoma, 1 urothelial carcinoma, 1 nasopharynx squamous cell carcinoma, 1 anal squamous cell carcinoma etc.)	Nasopharyngeal squamous cell carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	21	N/A	A retrospective cohort study	Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose.	Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed.	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Outcomes of patients with non-melanoma solid tumours receiving self-funded  pembrolizumab at Chris O'Brien Lifehouse.	 Intern Med J	 BACKGROUND: Immunotherapy agents show anti-cancer activity in several solid  cancers. Efficacy in non-melanoma solid tumours for non-approved indications is  unknown. AIM: To evaluate patient and disease characteristics, rate and duration   of response, and toxicity of self-funded pembrolizumab in patients with  non-melanoma solid cancers. METHOD: Retrospective review describing outcomes and   toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers  treated at Chris O'Brien Lifehouse. RESULTS: From April 2015 to December 2015, 21  patients received or were planned to receive self-funded pembrolizumab. The  median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology  Group performance status of 2, and 3-4 respectively. Sixty-two percent received  at least two to four lines of prior drug treatment. Median follow-up was 3.0  months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab.  Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested   pembrolizumab had worse outcomes. Three patients died before receiving  pembrolizumab. Of the 18 patients that received at least one dose, a partial  response was observed in 3 (17%). Progressive disease occurred in 83%. Four  patients received only one cycle of pembrolizumab and died after a median of 27  days (range 13-43). Immune-related adverse events of any grade occurred in 33%.  No grade 3-4 events were observed. CONCLUSION: Pembrolizumab was well tolerated.   Meaningful responses were observed in 17% of treated patients. Response continues  after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other  responding patient. Financial impact to the patient can be substantial. Outcomes   for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose. This highlights issues regarding the  careful selection of patients, futility of anti-cancer therapy at the end-of-life  and patients' perceived benefit of receiving this therapy.CI  - (c) 2016 Royal Australasian College of Physicians.
CANIT0000711	27554283	Clinical research	Non-melanoma solid tumours (6 Mesothelioma, 9 Sarcoma, 1 urothelial carcinoma, 1 nasopharynx squamous cell carcinoma, 1 anal squamous cell carcinoma etc.)	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	21	N/A	A retrospective cohort study	Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose.	Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed.	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Outcomes of patients with non-melanoma solid tumours receiving self-funded  pembrolizumab at Chris O'Brien Lifehouse.	 Intern Med J	 BACKGROUND: Immunotherapy agents show anti-cancer activity in several solid  cancers. Efficacy in non-melanoma solid tumours for non-approved indications is  unknown. AIM: To evaluate patient and disease characteristics, rate and duration   of response, and toxicity of self-funded pembrolizumab in patients with  non-melanoma solid cancers. METHOD: Retrospective review describing outcomes and   toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers  treated at Chris O'Brien Lifehouse. RESULTS: From April 2015 to December 2015, 21  patients received or were planned to receive self-funded pembrolizumab. The  median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology  Group performance status of 2, and 3-4 respectively. Sixty-two percent received  at least two to four lines of prior drug treatment. Median follow-up was 3.0  months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab.  Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested   pembrolizumab had worse outcomes. Three patients died before receiving  pembrolizumab. Of the 18 patients that received at least one dose, a partial  response was observed in 3 (17%). Progressive disease occurred in 83%. Four  patients received only one cycle of pembrolizumab and died after a median of 27  days (range 13-43). Immune-related adverse events of any grade occurred in 33%.  No grade 3-4 events were observed. CONCLUSION: Pembrolizumab was well tolerated.   Meaningful responses were observed in 17% of treated patients. Response continues  after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other  responding patient. Financial impact to the patient can be substantial. Outcomes   for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose. This highlights issues regarding the  careful selection of patients, futility of anti-cancer therapy at the end-of-life  and patients' perceived benefit of receiving this therapy.CI  - (c) 2016 Royal Australasian College of Physicians.
CANIT0000712	27554283	Clinical research	Non-melanoma solid tumours (6 Mesothelioma, 9 Sarcoma, 1 urothelial carcinoma, 1 nasopharynx squamous cell carcinoma, 1 anal squamous cell carcinoma etc.)	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	21	N/A	A retrospective cohort study	Pembrolizumab was well tolerated. Meaningful responses were observed in 17% of treated patients. Response continues after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other responding patient. Financial impact to the patient can be substantial. Outcomes for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose.	Immune-related adverse events of any grade occurred in 33%. No grade 3-4 events were observed.	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Outcomes of patients with non-melanoma solid tumours receiving self-funded  pembrolizumab at Chris O'Brien Lifehouse.	 Intern Med J	 BACKGROUND: Immunotherapy agents show anti-cancer activity in several solid  cancers. Efficacy in non-melanoma solid tumours for non-approved indications is  unknown. AIM: To evaluate patient and disease characteristics, rate and duration   of response, and toxicity of self-funded pembrolizumab in patients with  non-melanoma solid cancers. METHOD: Retrospective review describing outcomes and   toxicity of self-funded pembrolizumab in patients with non-melanoma solid cancers  treated at Chris O'Brien Lifehouse. RESULTS: From April 2015 to December 2015, 21  patients received or were planned to receive self-funded pembrolizumab. The  median age was 50 years (16-76), 28 and 10% had an Eastern Cooperative Oncology  Group performance status of 2, and 3-4 respectively. Sixty-two percent received  at least two to four lines of prior drug treatment. Median follow-up was 3.0  months (range, 0.4-9.6). Fourteen (67%) patients requested pembrolizumab.  Pembrolizumab was clinician offered for 7 (33%) patients. Patients who requested   pembrolizumab had worse outcomes. Three patients died before receiving  pembrolizumab. Of the 18 patients that received at least one dose, a partial  response was observed in 3 (17%). Progressive disease occurred in 83%. Four  patients received only one cycle of pembrolizumab and died after a median of 27  days (range 13-43). Immune-related adverse events of any grade occurred in 33%.  No grade 3-4 events were observed. CONCLUSION: Pembrolizumab was well tolerated.   Meaningful responses were observed in 17% of treated patients. Response continues  after 5-6.5 months follow-up in 11% and >8 months of follow-up for the other  responding patient. Financial impact to the patient can be substantial. Outcomes   for 33% were poor with three patients dying prior to receiving therapy and four  dying within weeks of receiving one dose. This highlights issues regarding the  careful selection of patients, futility of anti-cancer therapy at the end-of-life  and patients' perceived benefit of receiving this therapy.CI  - (c) 2016 Royal Australasian College of Physicians.
CANIT0000713	27554835	Case report	Metastatic squamous cell carcinoma of the lung	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Pericardial Tamponade	N/A	N/A	N/A	N/A	N/A	2017	 Nivolumab-Induced Pericardial Tamponade: A Case Report and Discussion.	 Cardiology	 Nivolumab, a programmed death 1 (PD1) inhibitor, belongs to a family of drugs  known as immune checkpoint inhibitors that share a similar toxicity profile,  which includes rash, pruritus, colitis, hepatitis, pneumonitis and thyroid  dysfunction. Nivolumab has a proven efficacy in the treatment of malignant  melanoma, non-small cell lung cancer and renal cell carcinoma. We present the  case of a 67-year-old male patient with metastatic squamous cell carcinoma of the  lung who suffered from a massive pericardial effusion secondary to treatment with  nivolumab, which he began in June 2015. After five cycles the patient was  hospitalized due to acute respiratory failure requiring mechanical ventilation.  An echocardiogram revealed a massive pericardial effusion with tamponade. After  pericardiocentesis and corticosteroid treatment, the patient's condition improved  rapidly. A CT scan revealed a response of the tumor. Although anti-PD1 treatment   is usually regarded as less toxic than chemotherapy, a wide spectrum of  life-threatening immune-related side effects may still occur and clinical  vigilance is required.CI  - (c) 2016 S. Karger AG, Basel.
CANIT0000714	27565924	Case report	Squamous cell carcinoma of the lung	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Drug-induced myocarditis	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Drug-induced myocarditis after nivolumab treatment in a patient with PDL1-  negative squamous cell carcinoma of the lung.	 Lung Cancer	 Immunotherapy such as nivolumab is a new promising therapeutic option for  advanced stage non small cell lung cancer (NSCLC). Due to the interference with  the immune system previously unknown side effects are observed both in clinical  studies and experience. Autoimmune phenomena effecting skin, gastrointestinal  tract, endocrine glands, kidney and lung have been described. Up to now there is   only limited information regarding potential cardiac side effects. We present a  case of symptomatic drug induced myocarditis after nine cycles of nivolumab in a   patient with efficient anticancer response.CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
CANIT0000715	27565926	Case report	Metastatic non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Severe agranulocytosis	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Severe agranulocytosis in a patient with metastatic non-small-cell lung cancer  treated with nivolumab.	 Lung Cancer	 Immune checkpoint inhibitors are novel agents in the process of revolutionising  cancer care. These agents have become a very appealing therapeutic alternative  since they are much better tolerated than cytotoxic therapy, due to their  relatively favorable toxicity profile. However, adverse events associated with  these agents usually involve the immune system and can have serious implications   jeopardising survival. Herein we report the first case of immune-mediated  agranulocytosis due to Nivolumab therapy. The patient suffered from  Staphylococcus infection during her agranulocytosis which only responded to high   dose corticosteroid therapy.CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
CANIT0000716	27565931	Case report	Recurrent lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Pancreatitis	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Immune-related pancreatitis secondary to nivolumab in a patient with recurrent  lung adenocarcinoma: A case report.	 Lung Cancer	 Immune checkpoint inhibitor is a verified standard of care as a second-line  chemotherapy for non-small cell lung cancer. Management of immune-related adverse  effects (irAEs) is crucial for ensuring patient safety. However, less frequent  irAEs may result in complications. Here, we report a patient with recurrent lung   adenocarcinoma who was treated with nivolumab and developed immune-related  pancreatitis. A 66-year-old Japanese female with recurrent lung adenocarcinoma  and metastatic lymph nodes presented with anorexia, vomiting, and back pain on  day 18 of two cycles of nivolumab. Laboratory data demonstrated a grade 3  elevation of serum amylase and lipase levels. Initially, no abnormality could be   detected on computed tomography (CT), magnetic resonance cholangiopancreatography  (MRCP), or the Gallium scan. The patient was treated with high-dose prednisone,  resulting in gradual improvement of symptoms and laboratory data. A follow-up  MRCP revealed a swollen pancreas and pancreatic inflammation. Immune-related  pancreatitis is a rare type of nivolumab-induced irAE that shows no significant  changes on radiologic imaging, except for a swollen pancreas on CT, and can be  suppressed using high-dose prednisone.CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
CANIT0000717	27565934	Case report	Lung sarcomatoid carcinoma	Lung sarcomatoid carcinoma	EFO:1000336	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Organizing pneumonitis	N/A	N/A	N/A	N/A	N/A	 2016 Sep	 Nivolumab-induced organizing pneumonitis in a patient with lung sarcomatoid  carcinoma.	 Lung Cancer	 Immune checkpoint inhibitors are known to induce 'immune pneumonitis' in 3-6% of   patients treated for lung cancer. However, their dramatic efficacy in as much as   20% of patients led to recent registrations in squamous, and then non-squamous  lung carcinoma, in second line setting after failure of first-line chemotherapy,   while large phase 3 trials are on-going, to assess first-line immunotherapy,  either alone or in combination with chemotherapy. Pulmonary Sarcomatoid  carcinomas consist of a rare subset of highly aggressive and poorly  differentiated non-small-cell lung carcinomas (NSCLC), with poor prognosis and  chemo-resistance. Although exhibiting high expression of programmed death  ligand-1 (PD-L1), their sensitivity to inhibitors of PD-1/PD-L1 axis is still  unknown. Here we report a case of lung sarcomatoid carcinoma with Nivolumab  dramatic and long-lasting efficacy, but occurrence of a very specific pattern of   lung toxicity, the so-called 'organizing bronchiolitis syndrome'. As more and  more NSCLC patients are promised to receive PD-1 inhibitors as part of their  treatment, we feel that specific features of such Nivolumab-induced organizing  pneumonitis should be known. Although corticosteroid sensitivity is high,  recurrence is frequent because of premature steroid tapering, as for all other  causes of organizing pneumonias, and probably because of the Nivolumab long  tissue half-life.CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
CANIT0000718	27566765	Clinical research	Operable breast cancer	Breast cancer	MONDO:0007254	Breast	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Cryoablation	Immune checkpoint therapy	Ipilimumab (DB06186); cryoablation (NCIT:C15215); 	6	7	A pilot study	Preoperative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intratumoral and systemic immunologic effects  were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy.	Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab).	N/A	N/A	N/A	N/A	N/A	 2016 Dec 1	 A Pilot Study of Preoperative Single-Dose Ipilimumab and/or Cryoablation in Women  with Early-Stage Breast Cancer with Comprehensive Immune Profiling.	 Clin Cancer Res	 PURPOSE: To assess the safety and tolerability of preoperative  cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated  immune modulation in women with operable breast cancer. EXPERIMENTAL DESIGN: In  this pilot study, 19 women with breast cancer for whom mastectomy was planned  were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab  at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study  was safety/tolerability as defined as freedom from delays in pre-planned,  curative-intent mastectomy. Exploratory studies of immune activation were  performed on peripheral blood and tumor. RESULTS: Preoperative cryoablation  and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery.  Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab).  Combination therapy was associated with sustained peripheral elevations in:  Th1-type cytokines, activated (ICOS(+)) and proliferating (Ki67(+)) CD4(+) and  CD8(+) T cells, and posttreatment proliferative T-effector cells relative to  T-regulatory cells within tumor. CONCLUSIONS: Preoperative cryoablation and  single-dose ipilimumab are safe alone or in combination with no surgical delays  incurred. Potentially favorable intratumoral and systemic immunologic effects  were observed with the combination, suggesting the possibility for induced and  synergistic antitumor immunity with this strategy. Clin Cancer Res; 22(23);  5729-37. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000719	27566765	Clinical research	Operable breast cancer	Breast cancer	MONDO:0007254	Breast	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus cryoablation	Cryoablation	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); cryoablation (NCIT:C15215); 	6	7	A pilot study	Preoperative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intratumoral and systemic immunologic effects  were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy.	Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab).	N/A	N/A	N/A	N/A	N/A	 2016 Dec 1	 A Pilot Study of Preoperative Single-Dose Ipilimumab and/or Cryoablation in Women  with Early-Stage Breast Cancer with Comprehensive Immune Profiling.	 Clin Cancer Res	 PURPOSE: To assess the safety and tolerability of preoperative  cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated  immune modulation in women with operable breast cancer. EXPERIMENTAL DESIGN: In  this pilot study, 19 women with breast cancer for whom mastectomy was planned  were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab  at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study  was safety/tolerability as defined as freedom from delays in pre-planned,  curative-intent mastectomy. Exploratory studies of immune activation were  performed on peripheral blood and tumor. RESULTS: Preoperative cryoablation  and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery.  Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab).  Combination therapy was associated with sustained peripheral elevations in:  Th1-type cytokines, activated (ICOS(+)) and proliferating (Ki67(+)) CD4(+) and  CD8(+) T cells, and posttreatment proliferative T-effector cells relative to  T-regulatory cells within tumor. CONCLUSIONS: Preoperative cryoablation and  single-dose ipilimumab are safe alone or in combination with no surgical delays  incurred. Potentially favorable intratumoral and systemic immunologic effects  were observed with the combination, suggesting the possibility for induced and  synergistic antitumor immunity with this strategy. Clin Cancer Res; 22(23);  5729-37. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000720	27571927	Basic research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab	N/A	Immune checkpoint therapy followed by Target therapy	Atezolizumab (DB11595); bevacizumab (DB00112); 	Cell lines	N/A	Basic research	These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2016 Aug 30	 Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell  migration in metastatic renal cell carcinoma.	 Nat Commun	 Anti-tumour immune activation by checkpoint inhibitors leads to durable responses  in a variety of cancers, but combination approaches are required to extend this  benefit beyond a subset of patients. In preclinical models tumour-derived VEGF  limits immune cell activity while anti-VEGF augments intra-tumoral T-cell  infiltration, potentially through vascular normalization and endothelial cell  activation. This study investigates how VEGF blockade with bevacizumab could  potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue  collections are before treatment, after bevacizumab and after the addition of  atezolizumab. We discover that intra-tumoral CD8(+) T cells increase following  combination treatment. A related increase is found in intra-tumoral MHC-I, Th1  and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We  also discover that the fractalkine receptor increases on peripheral CD8(+) T  cells with treatment. Furthermore, trafficking lymphocyte increases are observed   in tumors following bevacizumab and combination treatment. These data suggest  that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell  migration.
CANIT0000721	27573705	Clinical research	Malignant glioma patients	Glioma	EFO:0005543	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	6	N/A	N/A	These results indicate that specific cellular immunological mechanisms are partly responsible for the antitumor effect exhibited by the anti-PD-1 antibody against advanced cancers in clinical trials.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2016 Sep	 Immunological effects of the anti-programmed death-1 antibody on human peripheral  blood mononuclear cells.	 Int J Oncol	 Immune checkpoint antibody-mediated blockade has gained attention as a new cancer  immunotherapy strategy. Accumulating evidence suggests that this therapy imparts   a survival benefit to metastatic melanoma and non-small cell lung cancer  patients. A substantial amount of data on immune checkpoint antibodies has been  collected from clinical trials; however, the direct effect of the antibodies on  human peripheral blood mononuclear cells (PBMCs) has not been exclusively  investigated. In this study, we developed an anti-programmed death-1 (PD-1)  antibody (with biosimilarity to nivolumab) and examined the effects of the  antibody on PBMCs derived from cancer patients. Specifically, we investigated the  effects of the anti-PD-1 antibody on proliferation, cytokine production,  cytotoxic T lymphocytes (CTL) and regulatory T cells. These investigations  yielded several important results. First, the anti-PD-1 antibody had no obvious  effect on resting PBMCs; however, high levels of the anti-PD-1 antibody partly  stimulated PBMC proliferation when accompanied by an anti-CD3 antibody. Second,  the anti-PD-1 antibody restored the growth inhibition of anti-CD3 Ab-stimulated  PBMCs mediated by PD-L1. Third, the anti-PD-1 antibody exhibited a moderate  inhibitory effect on the induction of myeloid-derived suppressor cells (MDSCs) by  anti-CD3 antibody stimulation. Additionally, the presence of the anti-PD-1  antibody promoted antigen-specific CTL induction, which suggests that combining  anti-PD-1 antibody and conventional immunotherapy treatments may have beneficial   effects. These results indicate that specific cellular immunological mechanisms  are partly responsible for the antitumor effect exhibited by the anti-PD-1  antibody against advanced cancers in clinical trials.
CANIT0000722	27581765	Clinical research	Anti-PD-1 treated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	A retrospective cohort study	In this small retrospective series of cases, the efficacy of ipilimumab post-anti-PD-1 was similar to that described in the previous reports on ipilimumab.	Five (5/9; 55.6%) patients experienced grade 3 immune-related adverse events. No grade 4 or 5 adverse events were reported.	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Ipilimumab after progression on anti-PD-1 treatment in advanced melanoma.	 Future Oncol	 AIM: While both efficacy and safety of anti-PD-1 agents seem to be independent of  previous treatment with anti-CTLA-4, limited data exist of efficacy and toxicity   of ipilimumab after progression on anti-PD-1 therapy. This retrospective analysis  describes the efficacy and safety of sequential therapy with ipilimumab in  patients with metastatic melanoma who progressed on anti-PD-1 antibody. METHODS:   Nine patients who progressed on anti-PD-1 therapy received four cycles of  ipilimumab 3 mg/kg every 3 weeks. RESULTS: Two out of nine patients (2/9; 22.2%)   showed a partial response, and seven patients (7/9; 77.8%) experienced disease  progression. Median progression-free survival was 3.14 months (95% CI:  2.56-3.71), and the median overall survival since the start of anti-PD-1 therapy   was 16.8 months (95% CI: 8.1-25.4). Five (5/9; 55.6%) patients experienced grade   3 immune-related adverse events. No grade 4 or 5 adverse events were reported.  CONCLUSION: In this small retrospective series of cases, the efficacy of  ipilimumab post-anti-PD-1 was similar to that described in the previous reports  on ipilimumab.
CANIT0000723	27587469	Clinical research	Early-stage breast cancer	Breast cancer	MONDO:0007254	Breast	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	18	N/A	N/A	TCR sequencing correlates with H&E lymphocyte scoring and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T-cell responses to therapy and for the study of cryoimmunotherapy in early-stage breast cancer.	N/A	N/A	N/A	T-cell receptor (NCIT:C12476); 	T-cell receptor	Gene expression signature on/in immune cell	 2016 Oct	 Deep Sequencing of T-cell Receptor DNA as a Biomarker of Clonally Expanded TILs  in Breast Cancer after Immunotherapy.	 Cancer Immunol Res	 In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL)   predicts response to chemotherapy and overall survival. Combination immunotherapy  with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic  infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA  sequencing to evaluate both the effect of cryoimmunotherapy in humans and the  feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical  trial, 18 women with early-stage breast cancer were treated preoperatively with  cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab.  TCRs within serially collected peripheral blood and tumor tissue were sequenced.   In baseline tumor tissues, T-cell density as measured by TCR sequencing  correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining.  However, tumors with little or no lymphocytes by H&E contained up to 3.6 x 10(6)   TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In  this dataset, ipilimumab increased intratumoral T-cell density over time, whereas  cryoablation +/- ipilimumab diversified and remodeled the intratumoral T-cell  clonal repertoire. Compared with monotherapy, cryoablation plus ipilimumab was  associated with numerically greater numbers of peripheral blood and intratumoral   T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing  correlates with H&E lymphocyte scoring and provides additional information on  clonal diversity. These findings support further study of the use of TCR  sequencing as a biomarker for T-cell responses to therapy and for the study of  cryoimmunotherapy in early-stage breast cancer. Cancer Immunol Res; 4(10);  835-44. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000724	27590328	Case report	Stage III surgically resected melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	2	N/A	Case	N/A	Sarcoidosis-like syndrome and lymphadenopathy	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Sarcoidosis-like syndrome and lymphadenopathy due to checkpoint inhibitors.	 J Oncol Pharm Pract	 Immunotherapy with checkpoint inhibitors has revolutionized the management of  metastatic melanoma. These checkpoints, namely the cytotoxic T lymphocyte antigen  4 and the programmed T cell death 1 receptor, possess an inhibitory effect on the  T cell function. Pharmacologic inhibition of cytotoxic T lymphocyte antigen 4  with ipilimumab and programmed T cell death 1 with either pembrolizumab or  nivolumab has resulted in long-term sustained responses among patients with  metastatic melanoma. The adverse events of these medications are predominantly  immune related. Sarcoidosis-like syndrome/lymphadenopathy represents a  challenging adverse event to the oncologist as it can be mistaken for progressive  disease. Hence, awareness of such adverse event and obtaining a biopsy of the  enlarged lymph nodes will confirm the diagnosis and avoid the unnecessary change   of current therapies for those with stage IV disease or adding new ones for those  with stage III disease. We report three cases of immunotherapy-related  sarcoidosis-like syndrome/lymphadenopathy; two cases occurred during adjuvant  ipilimumab for stage III surgically resected melanoma and one case during  pemprolizumab for stage IV metastatic melanoma.
CANIT0000725	27590328	Case report	Stage IV metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Sarcoidosis-like syndrome and lymphadenopathy	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Sarcoidosis-like syndrome and lymphadenopathy due to checkpoint inhibitors.	 J Oncol Pharm Pract	 Immunotherapy with checkpoint inhibitors has revolutionized the management of  metastatic melanoma. These checkpoints, namely the cytotoxic T lymphocyte antigen  4 and the programmed T cell death 1 receptor, possess an inhibitory effect on the  T cell function. Pharmacologic inhibition of cytotoxic T lymphocyte antigen 4  with ipilimumab and programmed T cell death 1 with either pembrolizumab or  nivolumab has resulted in long-term sustained responses among patients with  metastatic melanoma. The adverse events of these medications are predominantly  immune related. Sarcoidosis-like syndrome/lymphadenopathy represents a  challenging adverse event to the oncologist as it can be mistaken for progressive  disease. Hence, awareness of such adverse event and obtaining a biopsy of the  enlarged lymph nodes will confirm the diagnosis and avoid the unnecessary change   of current therapies for those with stage IV disease or adding new ones for those  with stage III disease. We report three cases of immunotherapy-related  sarcoidosis-like syndrome/lymphadenopathy; two cases occurred during adjuvant  ipilimumab for stage III surgically resected melanoma and one case during  pemprolizumab for stage IV metastatic melanoma.
CANIT0000726	27595932	Case report	Advanced melanoma and refractory Crohn's disease	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); IL6R (P08887); 	PD-1; IL6R	Pembrolizumab plus tocilizumab	N/A	Immune checkpoint therapy plus Target therapy	Tocilizumab (DB06273); pembrolizumab (DB09037); 	1	N/A	Case	Marked, durable antitumor responses	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Sep 5	 Selective inhibition of autoimmune exacerbation while preserving the anti-tumor  clinical benefit using IL-6 blockade in a patient with advanced melanoma and  Crohn's disease: a case report.	 J Hematol Oncol	 BACKGROUND: Novel immunotherapies, or checkpoint inhibitors, targeting programmed  cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4  (CTLA-4) have significantly improved outcomes for patients with numerous  different cancer types. However, owing to their exclusion from clinical trials  and risk for autoimmune exacerbation on these treatments, the impact on safety  and degree of toxicity of these potentially life-prolonging therapies is not well  characterized in patients with an underlying autoimmune disease or previous organ  transplant. CASE PRESENTATION: We report a case of a patient with advanced  melanoma and refractory Crohn's disease who was treated concurrently with  pembrolizumab (anti-PD-1 antibody) and tocilizumab (anti-interluekin-6 receptor  antibody). This novel treatment strategy was well tolerated and did not result in  Crohn's disease exacerbation for at least 16 weeks. Importantly, this treatment  resulted in marked, durable antitumor responses. CONCLUSIONS: This outcome  suggests that targeted immunosuppression combined with checkpoint inhibitors may   hold promise as a treatment strategy for this unique patient population and may  warrant additional study.
CANIT0000727	27599705	Case report	Stage IV lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by osimertinib	N/A	Immune checkpoint therapy followed by Target therapy	Osimertinib (DB09330); nivolumab (DB09035); 	1	N/A	Case	N/A	Interstitial lung disease	N/A	N/A	N/A	N/A	N/A	 2017 Feb	 Osimertinib-induced interstitial lung disease after treatment with anti-PD1  antibody.	 Invest New Drugs	 We report a case of a 38-year-old woman who was diagnosed with stage IV lung  adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) L858R  mutation on exon 21 and a T790 M mutation on exon 20. The patient was treated  with osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI)  following treatment with nivolumab, an anti-Programmed Cell Death 1 (anti-PD1)  antibody. After initiating osimertinib treatment, the patient began to complain  of low-grade fever and shortness of breath without hypoxemia, and her chest  radiograph and a CT scan revealed a remarkable antitumor response, although faint  infiltrations were observed in the bilateral lung field. Bronchoalveolar lavage  fluid mainly contained lymphocytes (CD4+/CD8+ ratio of 0.3), and a transbronchial  lung biopsy specimen showed lymphocytic alveolitis with partial organization in  several alveolar spaces. Therefore we diagnosed the patient with  osimertinib-induced interstitial lung disease (ILD) after treatment with anti-PD1  antibody. We considered anti-PD1 therapies may be the risk factor of  EGFR-TKI-induced ILD.
CANIT0000728	27604993	Case report	Advanced mucosal melanoma	Mucosal melanoma	MONDO:0000544	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov	 Complete response to nivolumab monotherapy in a treatment-naive, BRAF wild-type  patient with advanced mucosal melanoma and elevated lactate dehydrogenase: a case  report from a phase III trial.	 Cancer Immunol Immunother	 The anti-PD-1 agent, nivolumab, has been approved both as monotherapy and in  combination with ipilimumab for the treatment of unresectable or metastatic  melanoma in the USA and European Union. Here we present the case of a patient  with treatment-naive, metastatic mucosal melanoma and baseline LDH approximately   seven times the upper limit of normal. The patient was enrolled in a clinical  trial (CheckMate 066) and achieved a partial response, followed by a durable  complete response with nivolumab treatment. The patient's LDH levels were  documented in each cycle and dropped markedly within 2 months, when partial  response to treatment was already evident. LDH levels remained low for the rest  of follow-up, consistent with the ongoing complete response to treatment. The  patient experienced only mild immune-related adverse events (grade 1-2), which  included vitiligo and rash. This exceptional response suggests that patients with  high LDH levels at baseline should be considered for nivolumab treatment. LDH  levels, however, should not serve as a predictive marker of response to  nivolumab. Moreover, this case suggests the need to identify patients who will  achieve the greatest benefit from nivolumab monotherapy.
CANIT0000729	27614165	Clinical research	Metastatic melanoma and impaired kidney function	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab followed by nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	4	N/A	N/A	These cases show that checkpoint inhibitors can be a safe therapeutic option in patients with impaired kidney function. Furthermore, we report the first organ transplant patient with malignant melanoma who received ipilimumab followed by nivolumab without experiencing a kidney allograft rejection.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov	 Checkpoint inhibitors in chronic kidney failure and an organ transplant  recipient.	 Eur J Cancer	 BACKGROUND: Immune-checkpoint inhibitors have been approved for the treatment of   metastatic melanoma based on several phase III trials. Patients after organ  transplantation and patients with impaired renal function were excluded from  these studies. Recently, allograft rejections were reported in organ transplant  recipients receiving PD-1 blocking antibodies. PATIENTS AND FINDINGS: Four  patients with metastatic melanoma and impaired kidney function (baseline serum  creatinine 1.79-2.59 mg/dl) were treated with immune-checkpoint blockers, of  which one was a kidney-transplant recipient receiving immunosuppressive therapy  with tacrolimus and prednisolone. The patient was initially treated with the  anti-CTLA-4 antibody ipilimumab after detailed explanation of the potential risk   of allograft rejection. Upon disease progression, therapy was switched to the  anti-PD-1 antibody nivolumab. The other three patients were treated with  nivolumab or pembrolizumab, two of them after previous therapy with ipilimumab.  RESULTS: The patients received a median of six doses (range 3-21) of anti-PD-1  antibodies and 3-4 doses of ipilimumab. Kidney function tests remained stable  throughout the course of checkpoint blockade. In the kidney transplant recipient,  neither ipilimumab nor nivolumab led to an allograft rejection. Responses to  anti-PD-1 treatment were divergent with two patients showing disease progression,  one achieving a mixed response and one experiencing a complete response.  CONCLUSION: These cases show that checkpoint inhibitors can be a safe therapeutic  option in patients with impaired kidney function. Furthermore, we report the  first organ transplant patient with malignant melanoma who received ipilimumab  followed by nivolumab without experiencing a kidney allograft rejection.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000730	27614165	Clinical research	Metastatic melanoma and impaired kidney function	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab followed by pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); ipilimumab (DB06186); 	4	N/A	N/A	These cases show that checkpoint inhibitors can be a safe therapeutic option in patients with impaired kidney function. Furthermore, we report the first organ transplant patient with malignant melanoma who received ipilimumab followed by nivolumab without experiencing a kidney allograft rejection.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov	 Checkpoint inhibitors in chronic kidney failure and an organ transplant  recipient.	 Eur J Cancer	 BACKGROUND: Immune-checkpoint inhibitors have been approved for the treatment of   metastatic melanoma based on several phase III trials. Patients after organ  transplantation and patients with impaired renal function were excluded from  these studies. Recently, allograft rejections were reported in organ transplant  recipients receiving PD-1 blocking antibodies. PATIENTS AND FINDINGS: Four  patients with metastatic melanoma and impaired kidney function (baseline serum  creatinine 1.79-2.59 mg/dl) were treated with immune-checkpoint blockers, of  which one was a kidney-transplant recipient receiving immunosuppressive therapy  with tacrolimus and prednisolone. The patient was initially treated with the  anti-CTLA-4 antibody ipilimumab after detailed explanation of the potential risk   of allograft rejection. Upon disease progression, therapy was switched to the  anti-PD-1 antibody nivolumab. The other three patients were treated with  nivolumab or pembrolizumab, two of them after previous therapy with ipilimumab.  RESULTS: The patients received a median of six doses (range 3-21) of anti-PD-1  antibodies and 3-4 doses of ipilimumab. Kidney function tests remained stable  throughout the course of checkpoint blockade. In the kidney transplant recipient,  neither ipilimumab nor nivolumab led to an allograft rejection. Responses to  anti-PD-1 treatment were divergent with two patients showing disease progression,  one achieving a mixed response and one experiencing a complete response.  CONCLUSION: These cases show that checkpoint inhibitors can be a safe therapeutic  option in patients with impaired kidney function. Furthermore, we report the  first organ transplant patient with malignant melanoma who received ipilimumab  followed by nivolumab without experiencing a kidney allograft rejection.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000731	27624447	Case report	Primary pelvic retroperitoneal melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Stable disease	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Sep 13	 Immunotherapy in a rare case of primary pelvic retroperitoneal melanoma.	 BMJ Case Rep	 Recent advances in novel immunotherapeutic and targeted therapeutic agents have  increased treatment options in patients with advanced metastatic melanoma.  However, evidence in the literature on whether or not extracutaneous melanoma  will acquire an equivalent advantage from these therapies is very scarce. In  general, extracutaneous melanomas are rare and aggressive melanomas, which are  clinically and biologically unique, with higher incidence of metastatic disease  and poor prognosis. In this case report, we present a very rare case of a  54-year-old woman with primary pelvic retroperitoneal melanoma treated with an  anti-PD-1 antibody, pembrolizumab. Furthermore, we explore the role of novel  immunotherapies in the treatment of advanced melanoma.CI  - 2016 BMJ Publishing Group Ltd.
CANIT0000732	27624914	Clinical research	Recurrent high-grade gliomas	Glioma	EFO:0005543	Brain	EPHA2 (P29317); IL13RA2 (Q14627); SURVIVIN (O15392); 	EPHA2 ;  IL13RA2 ;  SURVIVIN 	Vaccination with glioma-associated antigen peptides	N/A	Tumor vaccine	Glioma-associated antigen peptides vaccine (NCIT:C82661); 	12	N/A	N/A	GAA peptide vaccination in children with recurrent malignant gliomas is generally well tolerated, and has preliminary evidence of immunological and modest clinical activity.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Antigen-specific immunoreactivity and clinical outcome following vaccination with  glioma-associated antigen peptides in children with recurrent high-grade gliomas:  results of a pilot study.	 J Neurooncol	 Recurrent high-grade gliomas (HGGs) of childhood have an exceedingly poor  prognosis with current therapies. Accordingly, new treatment approaches are  needed. We initiated a pilot trial of vaccinations with peptide epitopes derived   from glioma-associated antigens (GAAs) overexpressed in these tumors in HLA-A2+  children with recurrent HGG that had progressed after prior treatments. Peptide  epitopes for three GAAs (EphA2, IL13Ralpha2, survivin), emulsified in  Montanide-ISA-51, were administered subcutaneously adjacent to intramuscular  injections of poly-ICLC every 3 weeks for 8 courses, followed by booster vaccines  every 6 weeks. Primary endpoints were safety and T-cell responses against the GAA  epitopes, assessed by enzyme-linked immunosorbent spot (ELISPOT) analysis.  Treatment response was evaluated clinically and by magnetic resonance imaging.  Twelve children were enrolled, 6 with glioblastoma, 5 with anaplastic  astrocytoma, and one with malignant gliomatosis cerebri. No dose-limiting non-CNS  toxicity was encountered. ELISPOT analysis, in ten children, showed GAA responses  in 9: to IL13Ralpha2 in 4, EphA2 in 9, and survivin in 3. One child had presumed   symptomatic pseudoprogression, discontinued vaccine therapy, and responded to  subsequent treatment. One other child had a partial response that persisted  throughout 2 years of vaccine therapy, and continues at >39 months. Median  progression-free survival (PFS) from the start of vaccination was 4.1 months and   median overall survival (OS) was 12.9 months. 6-month PFS and OS were 33 and 73  %, respectively. GAA peptide vaccination in children with recurrent malignant  gliomas is generally well tolerated, and has preliminary evidence of  immunological and modest clinical activity.
CANIT0000733	27646946	Clinical research	Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	132	N/A	A phase Ib, multicenter, nonrandomized, multicohort study	Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1-positive versus -negative patients (22% v 4%; P = .021).	Treatment-related adverse events of any grade and grade  3 events occurred in 62% and 9% of patients, respectively.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on immune cells	Gene expression signature on/in immune cell	 2016 Nov 10	 Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With  Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From  the Phase Ib KEYNOTE-012 Expansion Cohort.	 J Clin Oncol	 Purpose Treatment with pembrolizumab, an anti-programmed death-1 antibody, at 10   mg/kg administered once every 2 weeks, displayed durable antitumor activity in  programmed death-ligand 1 (PD-L1) -positive recurrent and/or metastatic (R/M)  head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results  from the expansion cohort, in which patients with HNSCC, irrespective of  biomarker status, received a fixed dose of pembrolizumab at a less frequent  dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC,  irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200   mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary  end points were overall response rate (ORR) per central imaging vendor (Response   Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points  included progression-free survival, overall survival, and association of response  and PD-L1 expression. Patients who received one or more doses of pembrolizumab  were included in analyses. Results Of 132 patients enrolled, median age was 60  years (range, 25 to 84 years), 83% were male, and 57% received two or more lines   of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging  vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of  response was not reached (range, >/= 2 to >/= 11 months). Six-month  progression-free survival and overall survival rates were 23% and 59%,  respectively. By using tumor and immune cells, a statistically significant  increase in ORR was observed for PD-L1-positive versus -negative patients (22% v   4%; P = .021). Treatment-related adverse events of any grade and grade >/= 3  events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose  pembrolizumab 200 mg administered once every 3 weeks was well tolerated and  yielded a clinically meaningful ORR with evidence of durable responses, which  supports further development of this regimen in patients with advanced HNSCC.
CANIT0000734	27646946	Clinical research	Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	132	N/A	A phase Ib, multicenter, nonrandomized, multicohort study	Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1-positive versus -negative patients (22% v 4%; P = .021).	Treatment-related adverse events of any grade and grade  3 events occurred in 62% and 9% of patients, respectively.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2016 Nov 10	 Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With  Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From  the Phase Ib KEYNOTE-012 Expansion Cohort.	 J Clin Oncol	 Purpose Treatment with pembrolizumab, an anti-programmed death-1 antibody, at 10   mg/kg administered once every 2 weeks, displayed durable antitumor activity in  programmed death-ligand 1 (PD-L1) -positive recurrent and/or metastatic (R/M)  head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results  from the expansion cohort, in which patients with HNSCC, irrespective of  biomarker status, received a fixed dose of pembrolizumab at a less frequent  dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC,  irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200   mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary  end points were overall response rate (ORR) per central imaging vendor (Response   Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points  included progression-free survival, overall survival, and association of response  and PD-L1 expression. Patients who received one or more doses of pembrolizumab  were included in analyses. Results Of 132 patients enrolled, median age was 60  years (range, 25 to 84 years), 83% were male, and 57% received two or more lines   of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging  vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of  response was not reached (range, >/= 2 to >/= 11 months). Six-month  progression-free survival and overall survival rates were 23% and 59%,  respectively. By using tumor and immune cells, a statistically significant  increase in ORR was observed for PD-L1-positive versus -negative patients (22% v   4%; P = .021). Treatment-related adverse events of any grade and grade >/= 3  events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose  pembrolizumab 200 mg administered once every 3 weeks was well tolerated and  yielded a clinically meaningful ORR with evidence of durable responses, which  supports further development of this regimen in patients with advanced HNSCC.
CANIT0000735	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in peripheral CD8+ T cells.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Peripheral CD8(+) T-cell counts	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000736	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in CD8+/CD4+ T-cell ratio.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD8(+)-to-CD4(+) T-cell ratios	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000737	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in proportion of CD8+ T cells expressing 4-1BB and PD1.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	Treg cells (CL:0000815); CTLA-4 (P16410); T-Lymphocyte (NCIT:C12476); 	CTLA-4(NEG) regulatory T-cell 	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000738	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in peripheral CD8+ T cells.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Peripheral CD8(+) T-cell counts	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000739	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in CD8+/CD4+ T-cell ratio.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD8(+)-to-CD4(+) T-cell ratios	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000740	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in proportion of CD8+ T cells expressing 4-1BB and PD1.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	Treg cells (CL:0000815); CTLA-4 (P16410); T-Lymphocyte (NCIT:C12476); 	CTLA-4(NEG) regulatory T-cell 	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000741	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in peripheral CD8+ T cells.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Peripheral CD8(+) T-cell counts	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000742	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in CD8+/CD4+ T-cell ratio.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD8(+)-to-CD4(+) T-cell ratios	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000743	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in proportion of CD8+ T cells expressing 4-1BB and PD1.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	Treg cells (CL:0000815); CTLA-4 (P16410); T-Lymphocyte (NCIT:C12476); 	CTLA-4(NEG) regulatory T-cell 	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000744	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Sarcoma	EFO:0000691	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in peripheral CD8+ T cells.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Peripheral CD8(+) T-cell counts	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000745	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Sarcoma	EFO:0000691	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in CD8+/CD4+ T-cell ratio.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD8(+)-to-CD4(+) T-cell ratios	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000746	27649551	Clinical research	Cancer (NSCLC (8), Colorectal (4), Sarcoma (3), RCC (3), Other (17))	Sarcoma	EFO:0000691	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic ablative radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	35	N/A	A phase I clinical trial 	Clinical benefit was associated with increases in proportion of CD8+ T cells expressing 4-1BB and PD1.	Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity.	N/A	N/A	Treg cells (CL:0000815); CTLA-4 (P16410); T-Lymphocyte (NCIT:C12476); 	CTLA-4(NEG) regulatory T-cell 	Gene expression signature on/in immune cell	 2017 Mar 15	 Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and  Immunologic Correlates from Peripheral T Cells.	 Clin Cancer Res	 Purpose: Little prospective data are available on clinical outcomes and immune  correlates from combination radiation and immunotherapy. We conducted a phase I  trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with  ipilimumab.Experimental Design: SABR was given either concurrently (1 day after  the first dose) or sequentially (1 week after the second dose) with ipilimumab (3  mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4  fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy  (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and  sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3   + 3 dose de-escalation design. Immune marker expression was assessed by flow  cytometry.Results: Among 35 patients who initiated ipilimumab, 2 experienced  dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the  radiation field was assessable in 31 patients. Three patients (10%) exhibited  partial response and 7 (23%) experienced clinical benefit (defined as partial  response or stable disease lasting >/=6 months). Clinical benefit was associated   with increases in peripheral CD8(+) T cells, CD8(+)/CD4(+) T-cell ratio, and  proportion of CD8(+) T cells expressing 4-1BB and PD1. Liver (vs. lung)  irradiation produced greater T-cell activation, reflected as increases in the  proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB.Conclusions:  Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell   markers may predict clinical benefit, and systemic immune activation was greater   after liver irradiation. Clin Cancer Res; 23(6); 1388-96. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000747	27650418	Case report	Choroidal malignant melanoma with liver and bone metastases	Choroidal melanoma	EFO:0009093	Eye	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Acute lymphocytic myocarditis	N/A	N/A	N/A	N/A	N/A	2016 Oct	Acute Lymphocytic Myocarditis With Anti-PD-1 Antibody Nivolumab.	Circ Heart Fail	Unable to provide
CANIT0000748	27650634	Case report	Multiple-relapsed Hodgkin lymphoma after pediatric T-cell replete, haploidentical, bone marrow transplantation	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Anti-PD-1 therapy with nivolumab resulted in significant objective disease response and clinical improvement without notable side effects, including the absence of a graft-versus-host disease (GVHD).	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Mar	 Tolerance and effectiveness of nivolumab after pediatric T-cell replete,  haploidentical, bone marrow transplantation: A case report.	 Pediatr Blood Cancer	 To date, there has been a lack of pediatric experience regarding the efficacy and  tolerability of immune checkpoint inhibitors after haploidentical hematopoietic  stem cell transplant (HSCT). We present the case of a 22-year-old female with  multiple-relapsed Hodgkin lymphoma (HL) who presented with a new relapse after  haploidentical (post-haplo) HSCT. Anti-PD-1 therapy with nivolumab resulted in  significant objective disease response and clinical improvement without notable  side effects, including the absence of a graft-versus-host disease (GVHD). This  case report suggests that immune checkpoint inhibition may be safely tolerated  even in the setting of haploidentical HSCT, without triggering overt GVHD.CI  - (c) 2016 Wiley Periodicals, Inc.
CANIT0000749	27662198	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Case	The authors herein describe the use of PD-1 inhibitors as a new  alternative in the treatment of metastatic melanoma to the orbit or metastatic  ocular adnexal melanomas in these clinical settings.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul/Aug	 Immune Checkpoint Inhibitors for Treatment of Metastatic Melanoma of the Orbit  and Ocular Adnexa.	 Ophthalmic Plast Reconstr Surg	 Programmed cell death 1 (PD-1) inhibitors are members of a new class of drugs  known as immune checkpoint inhibitors and have proven efficacy in the treatment  of metastatic melanoma. Herein, the authors report the use of nivolumab and  pembrolizumab, 2 recently Food and Drug Administration-approved PD-1 inhibitors,   in 3 patients: 1 with metastatic conjunctival melanoma and 2 with metastatic  cutaneous melanoma and orbital involvement. The patients' metastatic disease  responded well to drug treatment. As of this writing, 2 patients have completed  therapy and remain disease free at least 1 year after treatment completion; the  other patient is still receiving treatment, and his orbital disease is  responding. The authors herein describe the use of PD-1 inhibitors as a new  alternative in the treatment of metastatic melanoma to the orbit or metastatic  ocular adnexal melanomas in these clinical settings.
CANIT0000750	27662198	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Case	The authors herein describe the use of PD-1 inhibitors as a new  alternative in the treatment of metastatic melanoma to the orbit or metastatic  ocular adnexal melanomas in these clinical settings.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul/Aug	 Immune Checkpoint Inhibitors for Treatment of Metastatic Melanoma of the Orbit  and Ocular Adnexa.	 Ophthalmic Plast Reconstr Surg	 Programmed cell death 1 (PD-1) inhibitors are members of a new class of drugs  known as immune checkpoint inhibitors and have proven efficacy in the treatment  of metastatic melanoma. Herein, the authors report the use of nivolumab and  pembrolizumab, 2 recently Food and Drug Administration-approved PD-1 inhibitors,   in 3 patients: 1 with metastatic conjunctival melanoma and 2 with metastatic  cutaneous melanoma and orbital involvement. The patients' metastatic disease  responded well to drug treatment. As of this writing, 2 patients have completed  therapy and remain disease free at least 1 year after treatment completion; the  other patient is still receiving treatment, and his orbital disease is  responding. The authors herein describe the use of PD-1 inhibitors as a new  alternative in the treatment of metastatic melanoma to the orbit or metastatic  ocular adnexal melanomas in these clinical settings.
CANIT0000751	27667683	Basic research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines/ animal models	N/A	Basic research	Our findings demonstrate the importance of tumor genomic data, especially IFNG related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	IFNG (P01579); 	IFNG-response gene expression signatures	Gene expression signature on/in tumor cell	 2016 Oct 6	 Loss of IFN-gamma Pathway Genes in Tumor Cells as a Mechanism of Resistance to  Anti-CTLA-4 Therapy.	 Cell	 Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in  a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell  responses, including production of IFN-gamma, which is a critical cytokine for  host immune responses. However, the role of IFNG signaling in tumor cells in  the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that  patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors  with genomic defects in IFNG pathway genes. Furthermore, mice bearing  melanoma tumors with knockdown of IFNG receptor 1 (IFNGR1) have impaired  tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the  IFNG signaling pathway is associated with primary resistance to anti-CTLA-4   therapy. Our findings demonstrate the importance of tumor genomic data,  especially IFNG related genes, as prognostic information for patients  selected to receive treatment with immune checkpoint therapy.CI  - Published by Elsevier Inc.
CANIT0000752	27681753	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); radiotherapy (NCIT:C15313); 	22	N/A	N/A	The results from the present trial demonstrate that a subset of patients  may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response.	Combination therapy was well-tolerated without unexpected toxicities.	N/A	N/A	N/A	Elevated CD8-activated T-cell 	Cell percentage/counts in blood	 2016 Nov 1	 A Prospective Clinical Trial Combining Radiation Therapy With Systemic  Immunotherapy in Metastatic Melanoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: Local radiation therapy (RT) combined with systemic anti-cytotoxic  T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic  antimelanoma immune responses. The primary objective of the present trial was to   assess the safety and efficacy of combining ipilimumab with RT in patients with  stage IV melanoma. The secondary objectives included laboratory assessment of  induction of antimelanoma immune responses. METHODS AND MATERIALS: In our  prospective clinical trial, 22 patients with stage IV melanoma were treated with   palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was  initiated within 5 days after starting ipilimumab. Patients had >/=1  nonirradiated metastasis measuring >/=1.5 cm available for response assessment.  Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of  ipilimumab, and every 3 months until progression. Laboratory immune response  parameters were measured before and during treatment. RESULTS: Combination  therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%)  experienced clinical benefit from therapy, including complete and partial  responses and stable disease at median follow-up of 55 weeks. Three patients  (27.3%) achieved an ongoing systemic complete response at a median follow-up of  55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a  median of 40 weeks. Analysis of immune response data suggested a relationship  between elevated CD8-activated T-cells and response. CONCLUSION: This is the  second prospective clinical trial of treatment of metastatic melanoma using the  combination of RT and systemic immunotherapy and the first using this sequence of  therapy. The results from the present trial demonstrate that a subset of patients  may benefit from combination therapy, arguing for continued clinical  investigation of the use of RT combined with immunotherapy, including programmed   cell death 1 inhibitors, which might have the potential to be even more effective  in combination with RT.CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
CANIT0000753	27683208	Clinical research	Cutaneous metastatic melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	183	N/A	N/A	Better outcome with low baseline lactate dehydrogenase	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Oct	 The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated  cutaneous metastatic melanoma.	 Cancer Med	 Ipilimumab produces durable responses in some metastatic melanoma patients.  Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may  be associated with the immune response in cancer thereby acting as biomarkers of   toxicity and efficacy in ipilimumab-treated patients. Data were collected on  clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at  baseline, post cycle 2 and at the end of treatment for 183 patients treated with   ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre.  Associations between clinical characteristics, LDH, NLR, PLR, and ELR with  toxicity or survival outcomes of progression-free (PFS) and overall survival (OS)  were assessed using univariable and multivariable analysis. Prognostic models of   outcome at each time point were determined. Of the 183 patients included, the  median age was 58, 85% had M1c disease, 58% were performance status 1, and 64%  received ipilimumab as second line therapy. Median follow up was 7.5 months  (range: 0.3-49.5), median PFS was 2.8 months (95% confidence intervals (CI):  2.8-3.2), and median OS was 9.6 months (95% CI: 7.9-13.2). Prognostic factors for  OS by multivariable analysis were LDH and NLR at all-time points. Prognostic  models using LDH (x 2 upper limit of normal) and NLR 4) differentiated patients  into high, moderate, and low risk of death prior to or on ipilimumab treatment (P  < 0.0001 for each model). No factors were associated with toxicity. Prognostic  models based on NLR and LDH values at baseline and on treatment differentiate  patients into good, intermediate, and poor prognostic groups and may be relevant   in patient management.CI  - (c) 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0000754	27683208	Clinical research	Cutaneous metastatic melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	183	N/A	N/A	Better outcome with low baseline neutrophil lymphocyte ratios	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Baseline neutrophil lymphocyte ratios	Cell percentage/counts in blood	 2016 Oct	 The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated  cutaneous metastatic melanoma.	 Cancer Med	 Ipilimumab produces durable responses in some metastatic melanoma patients.  Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may  be associated with the immune response in cancer thereby acting as biomarkers of   toxicity and efficacy in ipilimumab-treated patients. Data were collected on  clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at  baseline, post cycle 2 and at the end of treatment for 183 patients treated with   ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre.  Associations between clinical characteristics, LDH, NLR, PLR, and ELR with  toxicity or survival outcomes of progression-free (PFS) and overall survival (OS)  were assessed using univariable and multivariable analysis. Prognostic models of   outcome at each time point were determined. Of the 183 patients included, the  median age was 58, 85% had M1c disease, 58% were performance status 1, and 64%  received ipilimumab as second line therapy. Median follow up was 7.5 months  (range: 0.3-49.5), median PFS was 2.8 months (95% confidence intervals (CI):  2.8-3.2), and median OS was 9.6 months (95% CI: 7.9-13.2). Prognostic factors for  OS by multivariable analysis were LDH and NLR at all-time points. Prognostic  models using LDH (x 2 upper limit of normal) and NLR 4) differentiated patients  into high, moderate, and low risk of death prior to or on ipilimumab treatment (P  < 0.0001 for each model). No factors were associated with toxicity. Prognostic  models based on NLR and LDH values at baseline and on treatment differentiate  patients into good, intermediate, and poor prognostic groups and may be relevant   in patient management.CI  - (c) 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0000755	27683208	Clinical research	Cutaneous metastatic melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	183	N/A	N/A	Better outcome with low baseline platelet lymphocyte ratios	N/A	N/A	N/A	Platelet-to-lymphocyte ratios (EFO:0008446); 	Platelet-to-lymphocyte ratios	Cell percentage/counts in blood	 2016 Oct	 The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated  cutaneous metastatic melanoma.	 Cancer Med	 Ipilimumab produces durable responses in some metastatic melanoma patients.  Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may  be associated with the immune response in cancer thereby acting as biomarkers of   toxicity and efficacy in ipilimumab-treated patients. Data were collected on  clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at  baseline, post cycle 2 and at the end of treatment for 183 patients treated with   ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre.  Associations between clinical characteristics, LDH, NLR, PLR, and ELR with  toxicity or survival outcomes of progression-free (PFS) and overall survival (OS)  were assessed using univariable and multivariable analysis. Prognostic models of   outcome at each time point were determined. Of the 183 patients included, the  median age was 58, 85% had M1c disease, 58% were performance status 1, and 64%  received ipilimumab as second line therapy. Median follow up was 7.5 months  (range: 0.3-49.5), median PFS was 2.8 months (95% confidence intervals (CI):  2.8-3.2), and median OS was 9.6 months (95% CI: 7.9-13.2). Prognostic factors for  OS by multivariable analysis were LDH and NLR at all-time points. Prognostic  models using LDH (x 2 upper limit of normal) and NLR 4) differentiated patients  into high, moderate, and low risk of death prior to or on ipilimumab treatment (P  < 0.0001 for each model). No factors were associated with toxicity. Prognostic  models based on NLR and LDH values at baseline and on treatment differentiate  patients into good, intermediate, and poor prognostic groups and may be relevant   in patient management.CI  - (c) 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0000756	27683208	Clinical research	Cutaneous metastatic melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	183	N/A	N/A	Better outcome with low lactate dehydrogenase after C2	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Oct	 The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated  cutaneous metastatic melanoma.	 Cancer Med	 Ipilimumab produces durable responses in some metastatic melanoma patients.  Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may  be associated with the immune response in cancer thereby acting as biomarkers of   toxicity and efficacy in ipilimumab-treated patients. Data were collected on  clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at  baseline, post cycle 2 and at the end of treatment for 183 patients treated with   ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre.  Associations between clinical characteristics, LDH, NLR, PLR, and ELR with  toxicity or survival outcomes of progression-free (PFS) and overall survival (OS)  were assessed using univariable and multivariable analysis. Prognostic models of   outcome at each time point were determined. Of the 183 patients included, the  median age was 58, 85% had M1c disease, 58% were performance status 1, and 64%  received ipilimumab as second line therapy. Median follow up was 7.5 months  (range: 0.3-49.5), median PFS was 2.8 months (95% confidence intervals (CI):  2.8-3.2), and median OS was 9.6 months (95% CI: 7.9-13.2). Prognostic factors for  OS by multivariable analysis were LDH and NLR at all-time points. Prognostic  models using LDH (x 2 upper limit of normal) and NLR 4) differentiated patients  into high, moderate, and low risk of death prior to or on ipilimumab treatment (P  < 0.0001 for each model). No factors were associated with toxicity. Prognostic  models based on NLR and LDH values at baseline and on treatment differentiate  patients into good, intermediate, and poor prognostic groups and may be relevant   in patient management.CI  - (c) 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0000757	27683208	Clinical research	Cutaneous metastatic melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	183	N/A	N/A	Better outcome with low lactate dehydrogenase at end of treatment	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Oct	 The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated  cutaneous metastatic melanoma.	 Cancer Med	 Ipilimumab produces durable responses in some metastatic melanoma patients.  Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may  be associated with the immune response in cancer thereby acting as biomarkers of   toxicity and efficacy in ipilimumab-treated patients. Data were collected on  clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at  baseline, post cycle 2 and at the end of treatment for 183 patients treated with   ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre.  Associations between clinical characteristics, LDH, NLR, PLR, and ELR with  toxicity or survival outcomes of progression-free (PFS) and overall survival (OS)  were assessed using univariable and multivariable analysis. Prognostic models of   outcome at each time point were determined. Of the 183 patients included, the  median age was 58, 85% had M1c disease, 58% were performance status 1, and 64%  received ipilimumab as second line therapy. Median follow up was 7.5 months  (range: 0.3-49.5), median PFS was 2.8 months (95% confidence intervals (CI):  2.8-3.2), and median OS was 9.6 months (95% CI: 7.9-13.2). Prognostic factors for  OS by multivariable analysis were LDH and NLR at all-time points. Prognostic  models using LDH (x 2 upper limit of normal) and NLR 4) differentiated patients  into high, moderate, and low risk of death prior to or on ipilimumab treatment (P  < 0.0001 for each model). No factors were associated with toxicity. Prognostic  models based on NLR and LDH values at baseline and on treatment differentiate  patients into good, intermediate, and poor prognostic groups and may be relevant   in patient management.CI  - (c) 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0000758	27683208	Clinical research	Cutaneous metastatic melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	183	N/A	N/A	Better outcome with low performance status	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2016 Oct	 The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated  cutaneous metastatic melanoma.	 Cancer Med	 Ipilimumab produces durable responses in some metastatic melanoma patients.  Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may  be associated with the immune response in cancer thereby acting as biomarkers of   toxicity and efficacy in ipilimumab-treated patients. Data were collected on  clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at  baseline, post cycle 2 and at the end of treatment for 183 patients treated with   ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre.  Associations between clinical characteristics, LDH, NLR, PLR, and ELR with  toxicity or survival outcomes of progression-free (PFS) and overall survival (OS)  were assessed using univariable and multivariable analysis. Prognostic models of   outcome at each time point were determined. Of the 183 patients included, the  median age was 58, 85% had M1c disease, 58% were performance status 1, and 64%  received ipilimumab as second line therapy. Median follow up was 7.5 months  (range: 0.3-49.5), median PFS was 2.8 months (95% confidence intervals (CI):  2.8-3.2), and median OS was 9.6 months (95% CI: 7.9-13.2). Prognostic factors for  OS by multivariable analysis were LDH and NLR at all-time points. Prognostic  models using LDH (x 2 upper limit of normal) and NLR 4) differentiated patients  into high, moderate, and low risk of death prior to or on ipilimumab treatment (P  < 0.0001 for each model). No factors were associated with toxicity. Prognostic  models based on NLR and LDH values at baseline and on treatment differentiate  patients into good, intermediate, and poor prognostic groups and may be relevant   in patient management.CI  - (c) 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0000759	27683208	Clinical research	Cutaneous metastatic melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	183	N/A	N/A	Better outcome with low platelet lymphocyte ratios at end of treatment	N/A	N/A	N/A	Platelet-to-lymphocyte ratios (EFO:0008446); 	Platelet-to-lymphocyte ratios	Cell percentage/counts in blood	 2016 Oct	 The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated  cutaneous metastatic melanoma.	 Cancer Med	 Ipilimumab produces durable responses in some metastatic melanoma patients.  Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may  be associated with the immune response in cancer thereby acting as biomarkers of   toxicity and efficacy in ipilimumab-treated patients. Data were collected on  clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at  baseline, post cycle 2 and at the end of treatment for 183 patients treated with   ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre.  Associations between clinical characteristics, LDH, NLR, PLR, and ELR with  toxicity or survival outcomes of progression-free (PFS) and overall survival (OS)  were assessed using univariable and multivariable analysis. Prognostic models of   outcome at each time point were determined. Of the 183 patients included, the  median age was 58, 85% had M1c disease, 58% were performance status 1, and 64%  received ipilimumab as second line therapy. Median follow up was 7.5 months  (range: 0.3-49.5), median PFS was 2.8 months (95% confidence intervals (CI):  2.8-3.2), and median OS was 9.6 months (95% CI: 7.9-13.2). Prognostic factors for  OS by multivariable analysis were LDH and NLR at all-time points. Prognostic  models using LDH (x 2 upper limit of normal) and NLR 4) differentiated patients  into high, moderate, and low risk of death prior to or on ipilimumab treatment (P  < 0.0001 for each model). No factors were associated with toxicity. Prognostic  models based on NLR and LDH values at baseline and on treatment differentiate  patients into good, intermediate, and poor prognostic groups and may be relevant   in patient management.CI  - (c) 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0000760	27683208	Clinical research	Cutaneous metastatic melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	183	N/A	N/A	Better outcome with neutrophil lymphocyte ratios at end of treatment	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2016 Oct	 The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated  cutaneous metastatic melanoma.	 Cancer Med	 Ipilimumab produces durable responses in some metastatic melanoma patients.  Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may  be associated with the immune response in cancer thereby acting as biomarkers of   toxicity and efficacy in ipilimumab-treated patients. Data were collected on  clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at  baseline, post cycle 2 and at the end of treatment for 183 patients treated with   ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre.  Associations between clinical characteristics, LDH, NLR, PLR, and ELR with  toxicity or survival outcomes of progression-free (PFS) and overall survival (OS)  were assessed using univariable and multivariable analysis. Prognostic models of   outcome at each time point were determined. Of the 183 patients included, the  median age was 58, 85% had M1c disease, 58% were performance status 1, and 64%  received ipilimumab as second line therapy. Median follow up was 7.5 months  (range: 0.3-49.5), median PFS was 2.8 months (95% confidence intervals (CI):  2.8-3.2), and median OS was 9.6 months (95% CI: 7.9-13.2). Prognostic factors for  OS by multivariable analysis were LDH and NLR at all-time points. Prognostic  models using LDH (x 2 upper limit of normal) and NLR 4) differentiated patients  into high, moderate, and low risk of death prior to or on ipilimumab treatment (P  < 0.0001 for each model). No factors were associated with toxicity. Prognostic  models based on NLR and LDH values at baseline and on treatment differentiate  patients into good, intermediate, and poor prognostic groups and may be relevant   in patient management.CI  - (c) 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0000761	27683556	Case report	Hypermutated glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Herein, we provide proof of principle that glioblastomas with DNA-repair defects treated with checkpoint blockade may result in CNS immune activation, leading to clinically and immunologically significant responses.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov	 Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE  Deficiency Treated with Checkpoint Blockade Immunotherapy.	 Cancer Discov	 We present the case of a patient with a left frontal glioblastoma with primitive   neuroectodermal tumor features and hypermutated genotype in the setting of a POLE  germline alteration. During standard-of-care chemoradiation, the patient  developed a cervical spine metastasis and was subsequently treated with  pembrolizumab. Shortly thereafter, the patient developed an additional metastatic  spinal lesion. Using whole-exome DNA sequencing and clonal analysis, we report  changes in the subclonal architecture throughout treatment. Furthermore, a  persistently high neoantigen load was observed within all tumors. Interestingly,   following initiation of pembrolizumab, brisk lymphocyte infiltration was observed  in the subsequently resected metastatic spinal lesion and an objective  radiographic response was noted in a progressive intracranial lesion, suggestive   of active central nervous system (CNS) immunosurveillance following checkpoint  blockade therapy. SIGNIFICANCE: It is unclear whether hypermutated glioblastomas   are susceptible to checkpoint blockade in adults. Herein, we provide proof of  principle that glioblastomas with DNA-repair defects treated with checkpoint  blockade may result in CNS immune activation, leading to clinically and  immunologically significant responses. These patients may represent a genomically  stratified group for whom immunotherapy could be considered. Cancer Discov;  6(11); 1230-6. (c)2016 AACR.See related commentary by Snyder and Wolchok, p.  1210This article is highlighted in the In This Issue feature, p. 1197.CI  - (c)2016 American Association for Cancer Research.
CANIT0000762	27687237	Case report	Relapsed/refractory Hodgkins lymphoma after both autologous and allogeneic stem cell transplantation	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Mar	 Successful treatment of relapsed/refractory Hodgkins lymphoma with nivolumab in a  heavily pretreated patient with progressive disease after both autologous and  allogeneic stem cell transplantation.	 Leuk Lymphoma	Unable to provide
CANIT0000763	27687304	Clinical research	Advanced melanoma and major toxicity with ipilimumab	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	67	N/A	A retrospective cohort study	In melanoma patients with preexisting ADs or major immune-related adverse events with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major immune-related adverse events with ipilimumab.	Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Feb 1	 Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune  disorders or major toxicity with ipilimumab.	 Ann Oncol	 Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number  of malignancies. All clinical trials have excluded patients with significant  preexisting autoimmune disorders (ADs) and only one has included patients with  immune-related adverse events (irAEs) with ipilimumab. We sought to explore the  safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients  with advanced melanoma and preexisting ADs and/or major immune-related adverse  events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were  treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were  retrospectively identified. Results: One hundred and nineteen patients from 13  academic tertiary referral centers were treated with anti-PD-1. In patients with   preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare  of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3   with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune  thrombocytopaenic purpura and 3/8 with psoriasis. No patients with  gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%)  patients discontinued treatment due to flare, but 15 (29%) developed other irAEs   and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs  requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients  had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs  (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no  treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs   or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune  toxicities, but these were often mild, easily managed and did not necessitate  discontinuation of therapy, and a significant proportion of patients achieved  clinical responses. The results support that anti-PD-1 can be administered safely  and can achieve clinical benefit in patients with preexisting ADs or prior major   irAEs with ipilimumab.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000764	27687304	Clinical research	Advanced melanoma and major toxicity with ipilimumab	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	67	N/A	A retrospective cohort study	In melanoma patients with preexisting ADs or major immune-related adverse events with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major immune-related adverse events with ipilimumab.	Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Feb 1	 Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune  disorders or major toxicity with ipilimumab.	 Ann Oncol	 Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number  of malignancies. All clinical trials have excluded patients with significant  preexisting autoimmune disorders (ADs) and only one has included patients with  immune-related adverse events (irAEs) with ipilimumab. We sought to explore the  safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients  with advanced melanoma and preexisting ADs and/or major immune-related adverse  events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were  treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were  retrospectively identified. Results: One hundred and nineteen patients from 13  academic tertiary referral centers were treated with anti-PD-1. In patients with   preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare  of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3   with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune  thrombocytopaenic purpura and 3/8 with psoriasis. No patients with  gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%)  patients discontinued treatment due to flare, but 15 (29%) developed other irAEs   and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs  requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients  had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs  (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no  treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs   or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune  toxicities, but these were often mild, easily managed and did not necessitate  discontinuation of therapy, and a significant proportion of patients achieved  clinical responses. The results support that anti-PD-1 can be administered safely  and can achieve clinical benefit in patients with preexisting ADs or prior major   irAEs with ipilimumab.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000765	27687304	Clinical research	Advanced melanoma and preexisting autoimmune disorders	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	52	N/A	A retrospective cohort study	In melanoma patients with preexisting ADs or major immune-related adverse events with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major immune-related adverse events with ipilimumab.	20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment.	N/A	N/A	Preexisting autoimmune disorders (NCIT:C27351); 	Preexisting autoimmune disorders	Disease status	 2017 Feb 1	 Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune  disorders or major toxicity with ipilimumab.	 Ann Oncol	 Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number  of malignancies. All clinical trials have excluded patients with significant  preexisting autoimmune disorders (ADs) and only one has included patients with  immune-related adverse events (irAEs) with ipilimumab. We sought to explore the  safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients  with advanced melanoma and preexisting ADs and/or major immune-related adverse  events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were  treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were  retrospectively identified. Results: One hundred and nineteen patients from 13  academic tertiary referral centers were treated with anti-PD-1. In patients with   preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare  of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3   with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune  thrombocytopaenic purpura and 3/8 with psoriasis. No patients with  gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%)  patients discontinued treatment due to flare, but 15 (29%) developed other irAEs   and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs  requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients  had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs  (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no  treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs   or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune  toxicities, but these were often mild, easily managed and did not necessitate  discontinuation of therapy, and a significant proportion of patients achieved  clinical responses. The results support that anti-PD-1 can be administered safely  and can achieve clinical benefit in patients with preexisting ADs or prior major   irAEs with ipilimumab.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000766	27687304	Clinical research	Advanced melanoma and preexisting autoimmune disorders	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	52	N/A	A retrospective cohort study	In melanoma patients with preexisting ADs or major immune-related adverse events with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major immune-related adverse events with ipilimumab.	20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment.	N/A	N/A	Preexisting autoimmune disorders (NCIT:C27351); 	Preexisting autoimmune disorders	Disease status	 2017 Feb 1	 Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune  disorders or major toxicity with ipilimumab.	 Ann Oncol	 Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number  of malignancies. All clinical trials have excluded patients with significant  preexisting autoimmune disorders (ADs) and only one has included patients with  immune-related adverse events (irAEs) with ipilimumab. We sought to explore the  safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients  with advanced melanoma and preexisting ADs and/or major immune-related adverse  events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were  treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were  retrospectively identified. Results: One hundred and nineteen patients from 13  academic tertiary referral centers were treated with anti-PD-1. In patients with   preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare  of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3   with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune  thrombocytopaenic purpura and 3/8 with psoriasis. No patients with  gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%)  patients discontinued treatment due to flare, but 15 (29%) developed other irAEs   and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs  requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients  had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs  (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no  treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs   or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune  toxicities, but these were often mild, easily managed and did not necessitate  discontinuation of therapy, and a significant proportion of patients achieved  clinical responses. The results support that anti-PD-1 can be administered safely  and can achieve clinical benefit in patients with preexisting ADs or prior major   irAEs with ipilimumab.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000767	27688162	Clinical research	Glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immunotherapy with fusions of dendritic and glioma cells plus temozolomide chemotherapy	N/A	Cell immunotherapy	Immunotherapy with fusions of dendritic and glioma cells (NCIT:C74036); temozolomide (DB00853); 	32	N/A	A phase I/II clinical trial 	The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor  effects in patients with GBM.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy  with fusions of dendritic and glioma cells in patients with glioblastoma.	 Cancer Immunol Immunother	 BACKGROUND: This trial was designed to evaluate the safety and clinical responses  to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with  fusions of DCs and glioma cells in patients with glioblastoma (GBM). METHOD: GBM   patients were assigned to two groups: a group of recurrent GBMs after failing  TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of  newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from  surgical specimens were fused with autologous DCs using polyethylene glycol. The   fusion cells (FC) were inoculated intradermally in the cervical region. Toxicity,  progression-free survival (PFS), and overall survival (OS) of this trial were  evaluated. Expressions of WT-1, gp-100, and MAGE-A3, recognized as  chemoresistance-associated peptides (CAP), were confirmed by immunohistochemistry  of paraffin-embedded tumor samples. Patient's PBMCs of pre- and post-vaccination   were evaluated by tetramer and ELISPOT assays. RESULTS: FC-immunotherapy was well  tolerated in all patients. Medians of PFS and OS of Group-R (n = 10) were 10.3  and 18.0 months, and those of Group-N (n = 22) were 18.3 and 30.5 months,  respectively. Up-regulation and/or cytoplasmic accumulation of CAPs was observed   in the recurrent tumors of Group-R patients compared with their initially excised  tumors. Specific immune responses against CAPs were observed in the tetramer and   ELISPOT assays. CONCLUSIONS: The combination of TMZ-treatment leading to  up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a  means of producing specific immunity against CAPs, may safely induce anti-tumor  effects in patients with GBM.
CANIT0000768	27696192	Case report	Relapsed classical Hodgkin lymphoma	Classic hodgkin lymphoma	MONDO:0009348	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Fulminant type I diabetes mellitus	N/A	N/A	N/A	N/A	N/A	 2017 Mar	 Fulminant type I diabetes mellitus associated with nivolumab in a patient with  relapsed classical Hodgkin lymphoma.	 Int J Hematol	 We report the case of a patient with relapsed classical Hodgkin lymphoma who  developed fulminant type I diabetes mellitus as a severe adverse event of  treatment with the anti-programmed cell death-1 (PD-1) antibody, nivolumab. On  the first day of the sixth cycle, the blood glucose level was markedly elevated  (375 mg/dL). Although neither ketoacidosis nor ketonuria was detected, the  markedly acute onset of the hyperglycemia was consistent with the typical  clinical course of fulminant type I diabetes mellitus, and this diagnosis was  supported by clinical data. All autoantibodies associated with type I diabetes  mellitus were negative. The endogenous insulin secretion ceased completely within  2 weeks. After the blood glucose level was brought under control, nivolumab was  resumed and continued without other major adverse events. Human leukocyte antigen  (HLA) analysis revealed that the patient carried the HLA-B*4002 haplotype, a  susceptibility allele for this type of diabetes mellitus. This case suggests that  fulminant type I diabetes mellitus may be triggered by nivolumab in patients with  a genetic background associated with the condition, warranting careful future  consideration of this particular adverse event.
CANIT0000769	27698113	Clinical research	Metastatic prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus androgen deprivation therapy	N/A	Immune checkpoint therapy plus Hormone therapy	Ipilimumab (DB06186); androgen deprivation therapy (NCIT:C15481); 	27	N/A	A phase II clinical trial	We propose that CD8 T-cell clonal expansion may be a correlative biomarker to enable close monitoring and early intervention for patients receiving ipilimumab.	We observed grade 3 toxicities in >40% of treated patients, which led to early closure of the study. Because ipilimumab enhances T-cell responses, we hypothesized that increased clonal T-cell responses in the systemic circulation may contribute to irAEs. Sequencing of the T-cell receptor -chains in purified T cells revealed clonal expansion of CD8 T cells, which occurred in blood samples collected before the onset of grade 2-3 irAEs. These initial results suggested that expansion of 55 CD8 T-cell clones preceded the development of severe irAEs. We further evaluated available blood samples from a second trial and determined that patients who experienced grade 2-3 irAEs also had expansion of 55 CD8 T-cell clones in blood samples collected before the onset of irAEs. 	N/A	N/A	Effector-memory type 1 T-cells (NCIT:C126419); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Percentage of CD8(+) effector-memory type 1 T-cell 	Gene expression signature on/in immune cell	 2016 Oct 18	 Clonal expansion of CD8 T cells in the systemic circulation precedes development   of ipilimumab-induced toxicities.	 Proc Natl Acad Sci U S A	 Immune checkpoint therapies, such as ipilimumab, induce dramatic antitumor  responses in a subset of patients with advanced malignancies, but they may also  induce inflammatory responses and toxicities termed immune-related adverse events  (irAEs). These irAEs are often low grade and manageable, but severe irAEs may  lead to prolonged hospitalizations or fatalities. Early intervention is necessary  to minimize morbidities that occur with severe irAEs. However, correlative  biomarkers are currently lacking. In a phase II clinical trial that treated 27  patients with metastatic prostate cancer, we aimed to test the safety and  efficacy of androgen deprivation therapy plus ipilimumab. In this study, we  observed grade 3 toxicities in >40% of treated patients, which led to early  closure of the study. Because ipilimumab enhances T-cell responses, we  hypothesized that increased clonal T-cell responses in the systemic circulation  may contribute to irAEs. Sequencing of the T-cell receptor beta-chains in  purified T cells revealed clonal expansion of CD8 T cells, which occurred in  blood samples collected before the onset of grade 2-3 irAEs. These initial  results suggested that expansion of >/=55 CD8 T-cell clones preceded the  development of severe irAEs. We further evaluated available blood samples from a   second trial and determined that patients who experienced grade 2-3 irAEs also  had expansion of >/=55 CD8 T-cell clones in blood samples collected before the  onset of irAEs. We propose that CD8 T-cell clonal expansion may be a correlative   biomarker to enable close monitoring and early intervention for patients  receiving ipilimumab.
CANIT0000770	27701388	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	37	N/A	N/A	Response by any criterion was prognostic. Novel patterns of response and changes on treatment in tumour density suggest complex anti-tumour responses to immunotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov 8	 Patterns of response to anti-PD-1 treatment: an exploratory comparison of four  radiological response criteria and associations with overall survival in  metastatic melanoma patients.	 Br J Cancer	 BACKGROUND: Radiological assessment of response to checkpoint inhibitors remains   imperfect. We evaluated individual lesion and inter-patient response by response   evaluation (RECIST) 1.1, immune-related response criteria (irRC), CHOI and  modified CHOI (mCHOI) and correlated response with overall survival (OS).  METHODS: Thirty-seven patients with 567 measurable lesions treated with  pembrolizumab in the Keynote 001 trial were studied. Association of response with  OS was determined. RESULTS: Response varied according to site; lung lesions had  the highest rate of complete response (69 out of 163 (42%) vs other sites 71 out   of 404 (18%), P<0.0001). Delayed response post first scan was seen in 2 out of 37  (5%) deemed progressive (PD) by RECIST and 2 out of 14 (14%) deemed PD by irRC.  Modified CHOI criteria showed response of 38% (14 out of 37). Change in tumour  size and density on first follow-up assessment was associated with OS with each  1000 mm(2) increase in tumour size from baseline increasing the hazard of dying  by 25.9% (HR=1.259, (95% CI=1.116-1.420), P=0.0002). Similarly, each 20HU  increase in density increased the HR by 15% (HR=1.15, (95% CI 1.045-1.260),  P=0.004). Response defined by any criteria had superior OS (CHOI P=0.0084; mCHOI   P=0.0183; irRC P<0.0001 and RECIST P=0.0003). CONCLUSIONS: Response by any  criterion was prognostic. Novel patterns of response and changes on treatment in   tumour density suggest complex anti-tumour responses to immunotherapy.
CANIT0000771	27718784	Clinical research	Recurrent or metastatic squamous-cell carcinoma of the head and neck	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	Standard or single-agent systemic therapy	Immune checkpoint therapy	Nivolumab (DB09035); 	240	121	A randomized, open-label, phase III trial,	Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy.	Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.	N/A	N/A	N/A	N/A	N/A	 2016 Nov 10	 Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.	 N Engl J Med	 BACKGROUND: Patients with recurrent or metastatic squamous-cell carcinoma of the   head and neck after platinum chemotherapy have a very poor prognosis and limited   therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal  antibody, was assessed as treatment for this condition. METHODS: In this  randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients   with recurrent squamous-cell carcinoma of the head and neck whose disease had  progressed within 6 months after platinum-based chemotherapy to receive nivolumab  (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard,  single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The  primary end point was overall survival. Additional end points included  progression-free survival, rate of objective response, safety, and  patient-reported quality of life. RESULTS: The median overall survival was 7.5  months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus  5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy.  Overall survival was significantly longer with nivolumab than with standard  therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the   estimates of the 1-year survival rate were approximately 19 percentage points  higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median  progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab  versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for  disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of  progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with  standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8%   in the standard-therapy group. Treatment-related adverse events of grade 3 or 4  occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in  the standard-therapy group. Physical, role, and social functioning was stable in   the nivolumab group, whereas it was meaningfully worse in the standard-therapy  group. CONCLUSIONS: Among patients with platinum-refractory, recurrent  squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted  in longer overall survival than treatment with standard, single-agent therapy.  (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number,  NCT02105636 .).
CANIT0000772	27720718	Basic research	Metastatic colon carcinoma cell line (CT26) and mouse T cells line (CTLL-2), emale BALB/c mice.	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	BIPI	N/A	Immune checkpoint therapy	Fusing hIL-2 to the C-Term of atezolizumab (NCIT:C106250); 	Cell lines/ animal models	N/A	Basic research	Our data evidenced the enhanced antitumor potency of BIPI, suggesting its potential use for cancers with a low response to the anti-PD-L1 or IL-2 treatment.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2016 Nov 11	 Therapeutic efficacy of an anti-PD-L1 antibody based immunocytokine in a  metastatic mouse model of colorectal cancer.	 Biochem Biophys Res Commun	 Immunocytokines (antibody-cytokine fusions) have been proved to be a promising  class of therapeutic agents for tumors. Anti-PD-L1 antibodies or IL-2 have been  used to treat a variety of cancers. Here, in order to remove T cell inhibition  and increasing the IL-2 concentration in the tumor microenvironment, we  engineered a novel anti-PD-L1 antibody based immunocytokine by fusing hIL-2 to  the C-Term of atezolizumab, denoted as BIPI. Our results revealed that BIPI was  effective in stimulating T cell activation in vitro and could selectively  localize to the tumor. Furthermore, tumor regression and prolonged survival were   also observed in the metastatic colorectal cancer mouse model. The obviously  longer survival mice in BIPI treatment group turned out depending on the function  of CD8(+) T cells. The IFN- secreted from CD8(+) T cells in the spleen also  contributed to the better tumor inhibition profile in BIPI treatment group than  in anti-PD-L1 or IL-2 treatment alone. Taken together, our data evidenced the  enhanced antitumor potency of BIPI, suggesting its potential use for cancers with  a low response to the anti-PD-L1 or IL-2 treatment.CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
CANIT0000773	27728898	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	77	N/A	N/A	Higher sMICA serum levels at baseline were associated with less frequency of immune-related adverse events.	N/A	N/A	N/A	MICA (Q29983); 	Serum MICA levels	Gene expression signature in serum	 2016 Nov	 Relevance of serum biomarkers associated with melanoma during follow-up of  anti-CTLA-4 immunotherapy.	 Int Immunopharmacol	 Metastatic melanoma is a rapidly spreading cancer whose prognosis remains poor  although important therapy advances in recent years. Ipilimumab, an anti-CTLA-4  immunotherapy used in advanced melanoma, is an effective immunotherapy alone or  combined with other agents but with few predictive biomarkers of response. Here,   we sought to analyze the potential of S100B, MIA, soluble MICA, anti-MICA  antibodies and LDH as serum biomarkers of response and survival in a cohort of 77  advanced melanoma patients subjected to ipilimumab. Lower levels of S100B, and  LDH at baseline and at weeks 3 and 6 correlated to a better response and  survival. After multivariate analysis LDH maintained its independence at baseline  and week 6, whereas S100B might be a useful tool for anti-CTLA-4 treatment  monitoring after the first two doses of ipilimumab (W6). In addition, higher  sMICA serum levels at baseline were associated with less frequency of irAEs.CI  - Copyright (c) 2016 Elsevier B.V. All rights reserved.
CANIT0000774	27728898	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	77	N/A	N/A	Lower levels of LDH at baseline and at weeks 3 and 6 correlated to a better response and survival.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2016 Nov	 Relevance of serum biomarkers associated with melanoma during follow-up of  anti-CTLA-4 immunotherapy.	 Int Immunopharmacol	 Metastatic melanoma is a rapidly spreading cancer whose prognosis remains poor  although important therapy advances in recent years. Ipilimumab, an anti-CTLA-4  immunotherapy used in advanced melanoma, is an effective immunotherapy alone or  combined with other agents but with few predictive biomarkers of response. Here,   we sought to analyze the potential of S100B, MIA, soluble MICA, anti-MICA  antibodies and LDH as serum biomarkers of response and survival in a cohort of 77  advanced melanoma patients subjected to ipilimumab. Lower levels of S100B, and  LDH at baseline and at weeks 3 and 6 correlated to a better response and  survival. After multivariate analysis LDH maintained its independence at baseline  and week 6, whereas S100B might be a useful tool for anti-CTLA-4 treatment  monitoring after the first two doses of ipilimumab (W6). In addition, higher  sMICA serum levels at baseline were associated with less frequency of irAEs.CI  - Copyright (c) 2016 Elsevier B.V. All rights reserved.
CANIT0000775	27728898	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	77	N/A	N/A	Lower levels of S100B at baseline and at weeks 3 and 6 correlated to a better response and survival.	N/A	N/A	N/A	S100B (P04271); 	Serum S100B levels	Gene expression signature in serum	 2016 Nov	 Relevance of serum biomarkers associated with melanoma during follow-up of  anti-CTLA-4 immunotherapy.	 Int Immunopharmacol	 Metastatic melanoma is a rapidly spreading cancer whose prognosis remains poor  although important therapy advances in recent years. Ipilimumab, an anti-CTLA-4  immunotherapy used in advanced melanoma, is an effective immunotherapy alone or  combined with other agents but with few predictive biomarkers of response. Here,   we sought to analyze the potential of S100B, MIA, soluble MICA, anti-MICA  antibodies and LDH as serum biomarkers of response and survival in a cohort of 77  advanced melanoma patients subjected to ipilimumab. Lower levels of S100B, and  LDH at baseline and at weeks 3 and 6 correlated to a better response and  survival. After multivariate analysis LDH maintained its independence at baseline  and week 6, whereas S100B might be a useful tool for anti-CTLA-4 treatment  monitoring after the first two doses of ipilimumab (W6). In addition, higher  sMICA serum levels at baseline were associated with less frequency of irAEs.CI  - Copyright (c) 2016 Elsevier B.V. All rights reserved.
CANIT0000776	27733243	Clinical research	Recurrent metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	86	N/A	A multicentre, open-label, two-stage, multi-arm, phase I/II	Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma.	Grade 3-4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four [5%]), elevated amylase (three [4%]), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two [3%] each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died.	N/A	N/A	N/A	N/A	N/A	 2016 Nov	 Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate  032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.	 Lancet Oncol	 BACKGROUND: Few effective treatments exist for patients with advanced urothelial   carcinoma that has progressed after platinum-based chemotherapy. We assessed the   activity and safety of nivolumab in patients with locally advanced or metastatic   urothelial carcinoma whose disease progressed after previous platinum-based  chemotherapy. METHODS: In this phase 1/2, multicentre, open-label study, we  enrolled patients (age >/=18 years) with urothelial carcinoma of the renal  pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the  UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1  membrane expression was assessed retrospectively. Patients received nivolumab 3  mg/kg intravenously every 2 weeks until disease progression or treatment  discontinuation because of unacceptable toxicity or other protocol-defined  reasons, whichever occurred later. The primary endpoint was objective response by  investigator assessment. All patients who received at least one dose of the study  drug were included in the analyses. We report an interim analysis of this ongoing  trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394.  FINDINGS: Between June 5, 2014, and April 24, 2015, 86 patients with metastatic  urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78  received at least one dose of treatment. At data cutoff (March 24, 2016), the  minimum follow-up was 9 months (median 15.2 months, IQR 12.9-16.8). A confirmed  investigator-assessed objective response was achieved in 19 (24.4%, 95% CI  15.3-35.4) of 78 patients. Grade 3-4 treatment-related adverse events occurred in  17 (22%) of 78 patients; the most common were elevated lipase (four [5%]),  elevated amylase (three [4%]), and fatigue, maculopapular rash, dyspnoea,  decreased lymphocyte count, and decreased neutrophil count (two [3%] each).  Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%)  had a serious adverse event judged to be treatment related. Two (3%) of 78  patients discontinued because of treatment-related adverse events (grade 4  pneumonitis and grade 4 thrombocytopenia) and subsequently died. INTERPRETATION:   Nivolumab monotherapy was associated with a substantial and durable clinical  response and a manageable safety profile in previously treated patients with  locally advanced or metastatic urothelial carcinoma. These data support further  investigation of nivolumab monotherapy in advanced urothelial carcinoma. FUNDING:  Bristol-Myers Squibb.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000777	27741091	Clinical research	12 metastatic melanoma, 2 NSCLC (both adenocarcinoma) and 2 metastatic clear cell carcinoma of the kidneys.	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	16	N/A	A retrospective cohort study	No patients with NSCLC or renal cancer showed abscopal effect, but 25% of patients with melanoma showed regression of nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site that had progressed on anti-PD1 monotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov/Dec	 Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic  Solid Tumors.	 J Immunother	 Abscopal effect is a rare phenomenon characterized by tumor regression of  untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied  the probability of abscopal effect with radiotherapy associated with  anti-programmed death cell 1 (PD1) therapy after progression on anti-PD1. This  study is a retrospective analysis of patients treated with nivolumab or  pembrolizumab for melanoma, non-small cell lung cancer (NSCLC) and renal cancer  at Antonio Ermirio de Moraes Oncology Center, Brazil. To be eligible for this  analysis, patients must have had unequivocal evidence of disease progression on  anti-PD1 therapy and subsequent radiotherapy for any tumor site while still  receiving anti-PD1. The abscopal effect was characterized as a response outside  the irradiated field after radiotherapy plus anti-PD1. Sixteen patients were  evaluated, including 12 metastatic melanoma, 2 metastatic NSCLC, and 2 metastatic  renal cell carcinoma. The median time to disease progression on anti-PD1 was 3  months. The radiotherapy field included lung, lymph nodes, and bones, with a  median total dose of 24 Gy (1-40 Gy), usually in 3 fractions (1-10 fractions).  Three patients with melanoma developed an abscopal effect at a rate of 18.7% (25%  among melanoma patients). Of note, one of them achieved a remarkable complete  response lasting >6 months. Three patients with melanoma obtained a significant  local response after radiotherapy, despite no response in distant metastases.  Eleven patients presented disease progression after radiotherapy. No increased  toxicity was observed. In conclusion, no patients with NSCLC or renal cancer  showed abscopal effect, but 25% of patients with melanoma showed regression of  nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site  that had progressed on anti-PD1 monotherapy.
CANIT0000778	27741091	Clinical research	12 metastatic melanoma, 2 NSCLC (both adenocarcinoma) and 2 metastatic clear cell carcinoma of the kidneys.	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); radiotherapy (NCIT:C15313); 	16	N/A	A retrospective cohort study	No patients with NSCLC or renal cancer showed abscopal effect, but 25% of patients with melanoma showed regression of nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site that had progressed on anti-PD1 monotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov/Dec	 Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic  Solid Tumors.	 J Immunother	 Abscopal effect is a rare phenomenon characterized by tumor regression of  untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied  the probability of abscopal effect with radiotherapy associated with  anti-programmed death cell 1 (PD1) therapy after progression on anti-PD1. This  study is a retrospective analysis of patients treated with nivolumab or  pembrolizumab for melanoma, non-small cell lung cancer (NSCLC) and renal cancer  at Antonio Ermirio de Moraes Oncology Center, Brazil. To be eligible for this  analysis, patients must have had unequivocal evidence of disease progression on  anti-PD1 therapy and subsequent radiotherapy for any tumor site while still  receiving anti-PD1. The abscopal effect was characterized as a response outside  the irradiated field after radiotherapy plus anti-PD1. Sixteen patients were  evaluated, including 12 metastatic melanoma, 2 metastatic NSCLC, and 2 metastatic  renal cell carcinoma. The median time to disease progression on anti-PD1 was 3  months. The radiotherapy field included lung, lymph nodes, and bones, with a  median total dose of 24 Gy (1-40 Gy), usually in 3 fractions (1-10 fractions).  Three patients with melanoma developed an abscopal effect at a rate of 18.7% (25%  among melanoma patients). Of note, one of them achieved a remarkable complete  response lasting >6 months. Three patients with melanoma obtained a significant  local response after radiotherapy, despite no response in distant metastases.  Eleven patients presented disease progression after radiotherapy. No increased  toxicity was observed. In conclusion, no patients with NSCLC or renal cancer  showed abscopal effect, but 25% of patients with melanoma showed regression of  nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site  that had progressed on anti-PD1 monotherapy.
CANIT0000779	27741091	Clinical research	12 metastatic melanoma, 2 NSCLC (both adenocarcinoma) and 2 metastatic clear cell carcinoma of the kidneys.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	16	N/A	A retrospective cohort study	No patients with NSCLC or renal cancer showed abscopal effect, but 25% of patients with melanoma showed regression of nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site that had progressed on anti-PD1 monotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov/Dec	 Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic  Solid Tumors.	 J Immunother	 Abscopal effect is a rare phenomenon characterized by tumor regression of  untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied  the probability of abscopal effect with radiotherapy associated with  anti-programmed death cell 1 (PD1) therapy after progression on anti-PD1. This  study is a retrospective analysis of patients treated with nivolumab or  pembrolizumab for melanoma, non-small cell lung cancer (NSCLC) and renal cancer  at Antonio Ermirio de Moraes Oncology Center, Brazil. To be eligible for this  analysis, patients must have had unequivocal evidence of disease progression on  anti-PD1 therapy and subsequent radiotherapy for any tumor site while still  receiving anti-PD1. The abscopal effect was characterized as a response outside  the irradiated field after radiotherapy plus anti-PD1. Sixteen patients were  evaluated, including 12 metastatic melanoma, 2 metastatic NSCLC, and 2 metastatic  renal cell carcinoma. The median time to disease progression on anti-PD1 was 3  months. The radiotherapy field included lung, lymph nodes, and bones, with a  median total dose of 24 Gy (1-40 Gy), usually in 3 fractions (1-10 fractions).  Three patients with melanoma developed an abscopal effect at a rate of 18.7% (25%  among melanoma patients). Of note, one of them achieved a remarkable complete  response lasting >6 months. Three patients with melanoma obtained a significant  local response after radiotherapy, despite no response in distant metastases.  Eleven patients presented disease progression after radiotherapy. No increased  toxicity was observed. In conclusion, no patients with NSCLC or renal cancer  showed abscopal effect, but 25% of patients with melanoma showed regression of  nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site  that had progressed on anti-PD1 monotherapy.
CANIT0000780	27741091	Clinical research	12 metastatic melanoma, 2 NSCLC (both adenocarcinoma) and 2 metastatic clear cell carcinoma of the kidneys.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); radiotherapy (NCIT:C15313); 	16	N/A	A retrospective cohort study	No patients with NSCLC or renal cancer showed abscopal effect, but 25% of patients with melanoma showed regression of nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site that had progressed on anti-PD1 monotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov/Dec	 Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic  Solid Tumors.	 J Immunother	 Abscopal effect is a rare phenomenon characterized by tumor regression of  untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied  the probability of abscopal effect with radiotherapy associated with  anti-programmed death cell 1 (PD1) therapy after progression on anti-PD1. This  study is a retrospective analysis of patients treated with nivolumab or  pembrolizumab for melanoma, non-small cell lung cancer (NSCLC) and renal cancer  at Antonio Ermirio de Moraes Oncology Center, Brazil. To be eligible for this  analysis, patients must have had unequivocal evidence of disease progression on  anti-PD1 therapy and subsequent radiotherapy for any tumor site while still  receiving anti-PD1. The abscopal effect was characterized as a response outside  the irradiated field after radiotherapy plus anti-PD1. Sixteen patients were  evaluated, including 12 metastatic melanoma, 2 metastatic NSCLC, and 2 metastatic  renal cell carcinoma. The median time to disease progression on anti-PD1 was 3  months. The radiotherapy field included lung, lymph nodes, and bones, with a  median total dose of 24 Gy (1-40 Gy), usually in 3 fractions (1-10 fractions).  Three patients with melanoma developed an abscopal effect at a rate of 18.7% (25%  among melanoma patients). Of note, one of them achieved a remarkable complete  response lasting >6 months. Three patients with melanoma obtained a significant  local response after radiotherapy, despite no response in distant metastases.  Eleven patients presented disease progression after radiotherapy. No increased  toxicity was observed. In conclusion, no patients with NSCLC or renal cancer  showed abscopal effect, but 25% of patients with melanoma showed regression of  nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site  that had progressed on anti-PD1 monotherapy.
CANIT0000781	27741091	Clinical research	12 metastatic melanoma, 2 NSCLC (both adenocarcinoma) and 2 metastatic clear cell carcinoma of the kidneys.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	16	N/A	A retrospective cohort study	No patients with NSCLC or renal cancer showed abscopal effect, but 25% of patients with melanoma showed regression of nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site that had progressed on anti-PD1 monotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov/Dec	 Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic  Solid Tumors.	 J Immunother	 Abscopal effect is a rare phenomenon characterized by tumor regression of  untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied  the probability of abscopal effect with radiotherapy associated with  anti-programmed death cell 1 (PD1) therapy after progression on anti-PD1. This  study is a retrospective analysis of patients treated with nivolumab or  pembrolizumab for melanoma, non-small cell lung cancer (NSCLC) and renal cancer  at Antonio Ermirio de Moraes Oncology Center, Brazil. To be eligible for this  analysis, patients must have had unequivocal evidence of disease progression on  anti-PD1 therapy and subsequent radiotherapy for any tumor site while still  receiving anti-PD1. The abscopal effect was characterized as a response outside  the irradiated field after radiotherapy plus anti-PD1. Sixteen patients were  evaluated, including 12 metastatic melanoma, 2 metastatic NSCLC, and 2 metastatic  renal cell carcinoma. The median time to disease progression on anti-PD1 was 3  months. The radiotherapy field included lung, lymph nodes, and bones, with a  median total dose of 24 Gy (1-40 Gy), usually in 3 fractions (1-10 fractions).  Three patients with melanoma developed an abscopal effect at a rate of 18.7% (25%  among melanoma patients). Of note, one of them achieved a remarkable complete  response lasting >6 months. Three patients with melanoma obtained a significant  local response after radiotherapy, despite no response in distant metastases.  Eleven patients presented disease progression after radiotherapy. No increased  toxicity was observed. In conclusion, no patients with NSCLC or renal cancer  showed abscopal effect, but 25% of patients with melanoma showed regression of  nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site  that had progressed on anti-PD1 monotherapy.
CANIT0000782	27741091	Clinical research	12 metastatic melanoma, 2 NSCLC (both adenocarcinoma) and 2 metastatic clear cell carcinoma of the kidneys.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); radiotherapy (NCIT:C15313); 	16	N/A	A retrospective cohort study	No patients with NSCLC or renal cancer showed abscopal effect, but 25% of patients with melanoma showed regression of nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site that had progressed on anti-PD1 monotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov/Dec	 Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic  Solid Tumors.	 J Immunother	 Abscopal effect is a rare phenomenon characterized by tumor regression of  untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied  the probability of abscopal effect with radiotherapy associated with  anti-programmed death cell 1 (PD1) therapy after progression on anti-PD1. This  study is a retrospective analysis of patients treated with nivolumab or  pembrolizumab for melanoma, non-small cell lung cancer (NSCLC) and renal cancer  at Antonio Ermirio de Moraes Oncology Center, Brazil. To be eligible for this  analysis, patients must have had unequivocal evidence of disease progression on  anti-PD1 therapy and subsequent radiotherapy for any tumor site while still  receiving anti-PD1. The abscopal effect was characterized as a response outside  the irradiated field after radiotherapy plus anti-PD1. Sixteen patients were  evaluated, including 12 metastatic melanoma, 2 metastatic NSCLC, and 2 metastatic  renal cell carcinoma. The median time to disease progression on anti-PD1 was 3  months. The radiotherapy field included lung, lymph nodes, and bones, with a  median total dose of 24 Gy (1-40 Gy), usually in 3 fractions (1-10 fractions).  Three patients with melanoma developed an abscopal effect at a rate of 18.7% (25%  among melanoma patients). Of note, one of them achieved a remarkable complete  response lasting >6 months. Three patients with melanoma obtained a significant  local response after radiotherapy, despite no response in distant metastases.  Eleven patients presented disease progression after radiotherapy. No increased  toxicity was observed. In conclusion, no patients with NSCLC or renal cancer  showed abscopal effect, but 25% of patients with melanoma showed regression of  nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site  that had progressed on anti-PD1 monotherapy.
CANIT0000783	27743938	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Squamous cell carcinoma associated with chronic graft versus host disease-like/lichen planus-like lesion of the oral cavity	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Squamous cell carcinoma associated with chronic graft versus host  disease-like/lichen planus-like lesion of the oral cavity in a patient managed  for metastatic melanoma with a PD-1 inhibitor pembrolizumab.	 Oral Oncol	Unable to provide
CANIT0000784	27745820	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	60	63	A randomised, open-label, phase II	Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC.	The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia.	N/A	N/A	N/A	N/A	N/A	 2016 Nov	 Carboplatin and pemetrexed with or without pembrolizumab for advanced,  non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the  open-label KEYNOTE-021 study.	 Lancet Oncol	 BACKGROUND: Limited evidence exists to show that adding a third agent to  platinum-doublet chemotherapy improves efficacy in the first-line advanced  non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab   has shown efficacy as monotherapy in patients with advanced NSCLC and has a  non-overlapping toxicity profile with chemotherapy. We assessed whether the  addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in  patients with advanced non-squamous NSCLC. METHODS: In this randomised,  open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were  enrolled at 26 medical centres in the USA and Taiwan. Patients with  chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR   or ALK genetic aberrations were randomly assigned (1:1) in blocks of four  stratified by PD-L1 tumour proportion score (<1% vs >/=1%) using an interactive  voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area  under curve 5 mg/mL per min and pemetrexed 500 mg/m(2) every 3 weeks followed by   pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4  cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed  maintenance therapy. The primary endpoint was the proportion of patients who  achieved an objective response, defined as the percentage of patients with  radiologically confirmed complete or partial response according to Response  Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent  central review, in the intention-to-treat population, defined as all patients who  were allocated to study treatment. Significance threshold was p<0.025 (one  sided). Safety was assessed in the as-treated population, defined as all patients  who received at least one dose of the assigned study treatment. This trial, which  is closed for enrolment but continuing for follow-up, is registered with  ClinicalTrials.gov, number NCT02039674. FINDINGS: Between Nov 25, 2014, and Jan  25, 2016, 123 patients were enrolled; 60 were randomly assigned to the  pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33   (55%; 95% CI 42-68) of 60 patients in the pembrolizumab plus chemotherapy group  achieved an objective response compared with 18 (29%; 18-41) of 63 patients in  the chemotherapy alone group (estimated treatment difference 26% [95% CI 9-42%];   p=0.0016). The incidence of grade 3 or worse treatment-related adverse events was  similar between groups (23 [39%] of 59 patients in the pembrolizumab plus  chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most   common grade 3 or worse treatment-related adverse events in the pembrolizumab  plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil  count (three [5%]); an additional six events each occurred in two (3%) for acute   kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and   thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or  worse events were anaemia (nine [15%] of 62) and decreased neutrophil count,  pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in  the pembrolizumab plus chemotherapy group experienced treatment-related death  because of sepsis compared with two (3%) of 62 patients in the chemotherapy  group: one because of sepsis and one because of pancytopenia. INTERPRETATION:  Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective  and tolerable first-line treatment option for patients with advanced non-squamous  NSCLC. This finding is being further explored in an ongoing international,  randomised, double-blind, phase 3 study. FUNDING: Merck & Co.CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
CANIT0000785	27749580	Case report	Relapsed advanced-stage lung squamous cell carcinoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Excellent response	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Oct	 Efficacy of short-term nivolumab treatment in a Chinese patient with relapsed  advanced-stage lung squamous cell carcinoma: A case report.	 Medicine (Baltimore)	 INTRODUCTION: Currently, the options are limited for the treatment of patients  who have failed 2 lines of chemotherapy for advanced lung squamous cell carcinoma  (SCC). Recently, nivolumab, a fully human IgG4 programmed death 1 immune  checkpoint inhibitor antibody, was approved to treat patients with advanced  stage, relapsed/refractory lung SCC. Although nivolumab has demonstrated  antitumor activity with survival benefit in Caucasian patients, its efficacy in  Asian patients is unknown. CASE REPORT: In this report, we describe a Chinese  patient with relapsed advanced stage lung SCC who had an excellent response to  nivolumab after only 2 doses without any adverse effects. Immunohistochemical  analysis indicated the tumor was stained positive for programmed death-ligand 1.   CONCLUSION: To our knowledge, this is the first report of satisfactory efficacy  of short-term nivolumab treatment in a Chinese patient with relapsed  advanced-stage lung SCC. Further clinical trials in Asian countries are needed to  test whether nivolumab immunotherapy is a safe and effective treatment for Asian   patients with lung SCC.
CANIT0000786	27760736	Case report	After small cell lung cancer transformation of mutant EGFR non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 A case treated with nivolumab after small cell lung cancer transformation of  mutant EGFR non-small cell lung cancer.	 Ann Oncol	Unable to provide
CANIT0000787	27761609	Case report	Metastatic lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Effectivity	Type 1 diabetes mellitus	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune  checkpoint inhibitor-induced type 1 diabetes.	 Cancer Immunol Immunother	 Immune checkpoint inhibitors such as pembrolizumab, ipilimumab, and nivolumab,  now FDA-approved for use in treating several types of cancer, have been  associated with immune-related adverse effects. Specifically, the antibodies  targeting the programmed-cell death-1 immune checkpoint, pembrolizumab and  nivolumab, have been rarely reported to induce the development of type 1 diabetes  mellitus. Here we describe a case of a patient who developed antibody-positive  type 1 diabetes mellitus following treatment with pembrolizumab in combination  with systemic chemotherapy for metastatic adenocarcinoma of the lung. We will  also provide a brief literature review of other rarely reported cases of type 1  diabetes presenting after treatment with pembrolizumab and nivolumab, as well as   discussion regarding potential mechanisms of this adverse effect and its  importance as these drugs continue to become even more widespread.
CANIT0000788	27765535	Clinical research	EGFR-mutant advanced NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Docetaxel	Immune checkpoint therapy	Nivolumab (DB09035); 	292	776	A meta-analysis	In the three included studies that compared immune  checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and  atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors   significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68,  95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR =  0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n =  186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81; treatment-mutation interaction p =  0.03). CONCLUSION: In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do  not improve OS over that with docetaxel. Mechanisms of acquired resistance to  first-line tyrosine kinase inhibitor therapy should be elucidated to guide  selection of second-line treatment for these patients.CI  - Copyright (c) 2016 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2017 Feb	 Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A  Meta-Analysis.	 J Thorac Oncol	 INTRODUCTION: We performed a meta-analysis to assess the role of immune  checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC.  METHODS: Randomized trials comparing immune checkpoint inhibitors against  chemotherapy were identified. We retrieved the hazard ratio (HR) and 95%  confidence interval (CI) for overall survival (OS) of the intention-to-treat  population and EGFR mutation-defined subgroups. We used the fixed-effects inverse  variance-weighted method to pool estimates of treatment efficacy. Statistical  tests were two sided. RESULTS: In the three included studies that compared immune  checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and  atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors   significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68,  95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR =  0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n =  186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81; treatment-mutation interaction p =  0.03). CONCLUSION: In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do  not improve OS over that with docetaxel. Mechanisms of acquired resistance to  first-line tyrosine kinase inhibitor therapy should be elucidated to guide  selection of second-line treatment for these patients.CI  - Copyright (c) 2016 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0000789	27765535	Clinical research	EGFR-mutant advanced NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Docetaxel	Immune checkpoint therapy	Pembrolizumab (DB09037); 	691	776	A meta-analysis	In the three included studies that compared immune  checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and  atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors   significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68,  95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR =  0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n =  186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81; treatment-mutation interaction p =  0.03). CONCLUSION: In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do  not improve OS over that with docetaxel. Mechanisms of acquired resistance to  first-line tyrosine kinase inhibitor therapy should be elucidated to guide  selection of second-line treatment for these patients.CI  - Copyright (c) 2016 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2017 Feb	 Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A  Meta-Analysis.	 J Thorac Oncol	 INTRODUCTION: We performed a meta-analysis to assess the role of immune  checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC.  METHODS: Randomized trials comparing immune checkpoint inhibitors against  chemotherapy were identified. We retrieved the hazard ratio (HR) and 95%  confidence interval (CI) for overall survival (OS) of the intention-to-treat  population and EGFR mutation-defined subgroups. We used the fixed-effects inverse  variance-weighted method to pool estimates of treatment efficacy. Statistical  tests were two sided. RESULTS: In the three included studies that compared immune  checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and  atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors   significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68,  95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR =  0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n =  186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81; treatment-mutation interaction p =  0.03). CONCLUSION: In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do  not improve OS over that with docetaxel. Mechanisms of acquired resistance to  first-line tyrosine kinase inhibitor therapy should be elucidated to guide  selection of second-line treatment for these patients.CI  - Copyright (c) 2016 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0000790	27765535	Clinical research	EGFR-mutant advanced NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Docetaxel	Immune checkpoint therapy	Atezolizumab (DB11595); 	144	776	A meta-analysis	In the three included studies that compared immune  checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and  atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors   significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68,  95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR =  0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n =  186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81; treatment-mutation interaction p =  0.03). CONCLUSION: In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do  not improve OS over that with docetaxel. Mechanisms of acquired resistance to  first-line tyrosine kinase inhibitor therapy should be elucidated to guide  selection of second-line treatment for these patients.CI  - Copyright (c) 2016 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2017 Feb	 Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A  Meta-Analysis.	 J Thorac Oncol	 INTRODUCTION: We performed a meta-analysis to assess the role of immune  checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC.  METHODS: Randomized trials comparing immune checkpoint inhibitors against  chemotherapy were identified. We retrieved the hazard ratio (HR) and 95%  confidence interval (CI) for overall survival (OS) of the intention-to-treat  population and EGFR mutation-defined subgroups. We used the fixed-effects inverse  variance-weighted method to pool estimates of treatment efficacy. Statistical  tests were two sided. RESULTS: In the three included studies that compared immune  checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and  atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors   significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68,  95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR =  0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n =  186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81; treatment-mutation interaction p =  0.03). CONCLUSION: In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do  not improve OS over that with docetaxel. Mechanisms of acquired resistance to  first-line tyrosine kinase inhibitor therapy should be elucidated to guide  selection of second-line treatment for these patients.CI  - Copyright (c) 2016 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0000791	27765756	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus gemcitabine or cisplatin	Pemetrexed or cisplatin or paclitaxel or carboplatin or bevacizumab or docetaxel (arm D)	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); docetaxel (DB01248); bevacizumab (DB00112); carboplatin (DB00958); paclitaxel (DB01229); pemetrexed (DB00642); cisplatin (DB00515); gemcitabine (DB00441); 	6	6,6,6	A four arms single-center phase Ib study	Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Safety and efficacy of nivolumab and standard chemotherapy drug combination in  patients with advanced non-small-cell lung cancer: a four arms phase Ib study.	 Ann Oncol	 BACKGROUND: The human IgG4 monoclonal antibody nivolumab targets programmed cell   death-1 (PD-1) and promotes antitumor response by blocking the interaction of  PD-1 with its ligands. This single-center phase Ib study investigated the  tolerability, safety, and pharmacokinetics of nivolumab combined with standard  chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).  PATIENTS AND METHODS: Patients who had stage IIIB without indication for  definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens  were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin  (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D).  Regimens A, B, and D were repeated every 3 weeks for up to four cycles and  regimen C was repeated for up to six cycles; nivolumab alone (arm A), with  pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every  3 weeks as maintenance therapy until disease progression or unacceptable  toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment  cycle. RESULTS: As of March 2014, six patients were enrolled in each arm. The  combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was  observed in only one patient in arm A (alanine aminotransferase increased).  Select adverse events (those with a potential immunologic cause) of any grade  were observed in six, four, six, and five patients in arms A, B, C, and D,  respectively. Three, three, six, and one patient achieved partial response while   median progression-free survival was 6.28, 9.63 months, not reached, and 3.15  months in arms A, B, C, and D, respectively. CONCLUSIONS: Combination of  nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and  encouraging antitumor activity in patients with advanced NSCLC. CLINICAL TRIALS  NUMBER: Japanese Pharmaceutical Information Center Clinical Trials Information  (JapicCTI)-132071.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology.
CANIT0000792	27768639	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	81	N/A	N/A	Feasible treatment option and poor outcome with high CTLA-4 protein expression levels	N/A	N/A	N/A	CTLA-4 (P16410); 	CTLA-4 expression levels in peritumoral lymphocytes	Gene expression signature on/in immune cell	 2017 Feb	 High cytotoxic T-lymphocyte-associated antigen 4 and phospho-Akt expression in  tumor samples predicts poor clinical outcomes in ipilimumab-treated melanoma  patients.	 Melanoma Res	 Ipilimumab, a fully human monoclonal antibody against cytotoxic  T-lymphocyte-associated antigen 4 (CTLA-4), is the first immune checkpoint  inhibitor approved for the treatment of unresectable melanoma on the basis of its  overall survival (OS) benefit. However, ipilimumab is associated with significant  immune-related adverse events. We hypothesized that biomarker exploration of  pretreatment tumor samples and correlation with clinical outcome would enable  patient selection with an increased benefit/risk ratio for ipilimumab therapy. At  the University of Texas MD Anderson Cancer Center, a total of 81 advanced  melanoma patients were treated on the Ipilimumab Expanded Access Program from  2007 to 2008. Using immunohistochemistry, we analyzed the expression of immune  checkpoint (CTLA-4, PD-1, PD-L1) and Akt-pathway proteins in formalin-fixed tumor  tissue. Associations between these biomarkers and progression-free survival (PFS)  and OS were analyzed with univariate and multivariate Cox proportional-hazards  models. There was a significant correlation between high CTLA-4 protein  expression levels in tumor cells and risk of death (P=0.02) and decreased PFS  (P=0.023). In addition, high expression of CTLA-4 in peritumoral lymphocytes  correlated with poor OS (P=0.023). In multivariate analysis, patients with high  CTLA-4 and phospho-Akt (p-Akt) expression correlated with poor OS (log-rank test,  P=0.039) and PFS (log-rank test, P=0.014). High levels of CTLA-4 and p-Akt  expression in pretreatment tumor cells in melanoma patients were associated with   poor clinical outcomes. Immunohistochemistry analysis of CTLA-4 and p-Akt in  pretreatment tumor samples provides useful biomarkers that may enable improved  patient selection for ipilimumab therapy. Prospective clinical studies are  warranted to investigate the predictive value of these biomarkers.
CANIT0000793	27768639	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	81	N/A	N/A	Feasible treatment option and poor outcome with high CTLA-4 protein expression levels	N/A	N/A	N/A	CTLA-4 (P16410); 	CTLA-4 expression levels in tumor cells	Gene expression signature on/in tumor cell	 2017 Feb	 High cytotoxic T-lymphocyte-associated antigen 4 and phospho-Akt expression in  tumor samples predicts poor clinical outcomes in ipilimumab-treated melanoma  patients.	 Melanoma Res	 Ipilimumab, a fully human monoclonal antibody against cytotoxic  T-lymphocyte-associated antigen 4 (CTLA-4), is the first immune checkpoint  inhibitor approved for the treatment of unresectable melanoma on the basis of its  overall survival (OS) benefit. However, ipilimumab is associated with significant  immune-related adverse events. We hypothesized that biomarker exploration of  pretreatment tumor samples and correlation with clinical outcome would enable  patient selection with an increased benefit/risk ratio for ipilimumab therapy. At  the University of Texas MD Anderson Cancer Center, a total of 81 advanced  melanoma patients were treated on the Ipilimumab Expanded Access Program from  2007 to 2008. Using immunohistochemistry, we analyzed the expression of immune  checkpoint (CTLA-4, PD-1, PD-L1) and Akt-pathway proteins in formalin-fixed tumor  tissue. Associations between these biomarkers and progression-free survival (PFS)  and OS were analyzed with univariate and multivariate Cox proportional-hazards  models. There was a significant correlation between high CTLA-4 protein  expression levels in tumor cells and risk of death (P=0.02) and decreased PFS  (P=0.023). In addition, high expression of CTLA-4 in peritumoral lymphocytes  correlated with poor OS (P=0.023). In multivariate analysis, patients with high  CTLA-4 and phospho-Akt (p-Akt) expression correlated with poor OS (log-rank test,  P=0.039) and PFS (log-rank test, P=0.014). High levels of CTLA-4 and p-Akt  expression in pretreatment tumor cells in melanoma patients were associated with   poor clinical outcomes. Immunohistochemistry analysis of CTLA-4 and p-Akt in  pretreatment tumor samples provides useful biomarkers that may enable improved  patient selection for ipilimumab therapy. Prospective clinical studies are  warranted to investigate the predictive value of these biomarkers.
CANIT0000794	27768639	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	81	N/A	N/A	Feasible treatment option and poor outcome with high p-Akt protein expression levels	N/A	N/A	N/A	AKT (P31749); 	P-Akt expression levels on tumor cells	Gene expression signature on/in tumor cell	 2017 Feb	 High cytotoxic T-lymphocyte-associated antigen 4 and phospho-Akt expression in  tumor samples predicts poor clinical outcomes in ipilimumab-treated melanoma  patients.	 Melanoma Res	 Ipilimumab, a fully human monoclonal antibody against cytotoxic  T-lymphocyte-associated antigen 4 (CTLA-4), is the first immune checkpoint  inhibitor approved for the treatment of unresectable melanoma on the basis of its  overall survival (OS) benefit. However, ipilimumab is associated with significant  immune-related adverse events. We hypothesized that biomarker exploration of  pretreatment tumor samples and correlation with clinical outcome would enable  patient selection with an increased benefit/risk ratio for ipilimumab therapy. At  the University of Texas MD Anderson Cancer Center, a total of 81 advanced  melanoma patients were treated on the Ipilimumab Expanded Access Program from  2007 to 2008. Using immunohistochemistry, we analyzed the expression of immune  checkpoint (CTLA-4, PD-1, PD-L1) and Akt-pathway proteins in formalin-fixed tumor  tissue. Associations between these biomarkers and progression-free survival (PFS)  and OS were analyzed with univariate and multivariate Cox proportional-hazards  models. There was a significant correlation between high CTLA-4 protein  expression levels in tumor cells and risk of death (P=0.02) and decreased PFS  (P=0.023). In addition, high expression of CTLA-4 in peritumoral lymphocytes  correlated with poor OS (P=0.023). In multivariate analysis, patients with high  CTLA-4 and phospho-Akt (p-Akt) expression correlated with poor OS (log-rank test,  P=0.039) and PFS (log-rank test, P=0.014). High levels of CTLA-4 and p-Akt  expression in pretreatment tumor cells in melanoma patients were associated with   poor clinical outcomes. Immunohistochemistry analysis of CTLA-4 and p-Akt in  pretreatment tumor samples provides useful biomarkers that may enable improved  patient selection for ipilimumab therapy. Prospective clinical studies are  warranted to investigate the predictive value of these biomarkers.
CANIT0000795	27771741	Case report	Cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Immune checkpoint inhibitors should be avoided in allograft recipients but high-intensity immunosuppression is effective to salvage allograft rejection induced by these agents.	Cardiac allograft rejection	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for  cancer immunotherapy: a case report.	 Cancer Immunol Immunother	 INTRODUCTION: The increased availability of immunotherapeutic agents for the  treatment of a wide array of cancer in the general oncology practice setting will  reveal rare and unique toxicities. MATERIALS AND METHODS: The mechanism of  cardiac allograft rejection in the context of PD-1 antibody therapy was explored   in a patient with cutaneous squamous cell cancer complicating long-standing  cardiac allograft. Immune cell infiltrate in the myocardium and peripheral blood   lymphocyte repertoire were assessed using myocardial biopsy and temporal analysis  of peripheral blood samples. The efficacy of high-intensity immunosuppression to   reverse graft rejection was explored. RESULTS: Endomyocardial biopsy showed acute  moderate diffuse cellular rejection with a predominant population of CD3+, CD8+  and CD4+ infiltrating lymphocytes; peripheral blood circulating lymphocytes  showed a high frequency of proliferating and activated CD8+ T cells expressing  PD-1 compared to a normal control. There was no difference in the activation and   proliferation of CD4+ T cells compared to a normal control. Cardiac function  improved following high-intensity immunosuppression and patient survived for up  to 7 months after discontinuation of nivolumab. CONCLUSIONS: Immune checkpoint  inhibitors should be avoided in allograft recipients but high-intensity  immunosuppression is effective to salvage allograft rejection induced by these  agents.
CANIT0000796	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000797	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000798	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000799	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000800	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000801	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000802	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000803	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000804	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000805	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000806	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000807	27777770	Clinical research	Renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4)	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	A multicentre, retrospective cohort study	In our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable immune-related adverse events and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.	Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis).	N/A	N/A	Organ dysfunction (NCIT:C53526); 	Baseline organ dysfunction	Disease status	2016	 Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or  hepatic dysfunction.	 J Immunother Cancer	 BACKGROUND: Anti-PD-1 therapy is increasingly used in various advanced  malignancies. Patients with baseline organ dysfunction are largely excluded from   clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or  effective in this setting. Further, these patients are often not candidates for  other anti-cancer therapies, highlighting their need for active treatment  options. METHODS: We performed a retrospective analysis of patients from multiple  centers with advanced solid tumors and baseline organ dysfunction who received  anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular  ejection fraction </=45 %), renal (creatinine >/=2 mg/dL or GFR </=30 ml/min) or   hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin  >/=3x ULN). We assessed change in organ dysfunction, immune related adverse  events (irAEs), response rate, progression free survival (PFS) and overall  survival (OS). RESULTS: We identified 27 patients eligible for inclusion with the  following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell  lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4).  Baseline organ dysfunction included renal dysfunction (n = 17), hepatic  dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8).  Worsening organ dysfunction requiring hospitalization or dose delays occurred in   8 patients (30 %) although in most cases this was thought not-drug related and  resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis  and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective  response or stable disease) at data collection (48 %). Eleven patients had  primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial  responses (15 %), and one had a complete response (4 %). Overall, median PFS was   168 days. Median OS was not reached. CONCLUSIONS: In our experience, anti-PD-1  agents in this group of patients with cardiac, hepatic or renal dysfunction were   associated with tolerable irAEs and infrequent manageable worsening of organ  dysfunction. Further, objective responses and prolonged PFS were observed in a  number of patients. Thus, patients with baseline organ dysfunction may be  considered for anti-PD-1 therapy with appropriate clinical monitoring.
CANIT0000808	27777773	Clinical research	Pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	N/A	No patients with NSCLC or renal cancer showed abscopal effect, but 25% of patients with melanoma showed regression of nonirradiated lesions when anti-PD1 was continued after radiation to a tumor site that had progressed on anti-PD1 monotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	2016	 Antitumor activity of nivolumab on hemodialysis after renal allograft rejection.	 J Immunother Cancer	 BACKGROUND: Nivolumab (Opdivo) is a novel IgG4 subclass programmed death-1 (PD-1)  inhibiting antibody that has demonstrated breakthrough-designation anti-tumor  activity. To date, clinical trials of nivolumab and other checkpoint inhibitors  have generally excluded patients with solid organ transplantation and patients  with concurrent immunosuppression. However, organ transplant recipients are at  high-risk of development of malignancy as a result of suppressed immune  surveillance of cancer. CASE PRESENTATION: We illustrate the outcomes of a 63  year-old type I diabetic female patient who developed pulmonary metastatic, BRAF   wild-type cutaneous melanoma 10 years after renal transplantation. After downward  titration of the patient's immunosuppressive medications and extensive  multidisciplinary review, she was treated with nivolumab in the first-line  setting. Within 1 week of administration, the patient experienced acute renal  allograft rejection, renal failure and concurrent diabetic ketoacidosis due to  steroid therapy. Allograft function did not return, but patient made a full  clinical recovery after being placed on hemodialysis. Subsequently, the patient  had clinical disease progression off therapy and required re-challenge with  nivolumab on hemodialysis, resulting in ongoing clinical and radiographic  response. CONCLUSIONS: This case illustrates multiple practical challenges and  dangers of administering anti-PD1 immune checkpoint inhibitors to patients with  solid-organ transplantation including need for titration of immunosuppressive  medications, risks of allograft rejection, and treatment during hemodialysis.
CANIT0000809	27792061	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	2	N/A	Case	N/A	Hepatitis and fibrin ring granulomas	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Fibrin Ring Granulomas in Checkpoint Inhibitor-induced Hepatitis.	 Am J Surg Pathol	 Fibrin ring granulomas are an uncommon finding in liver biopsies although they  have been described in liver injury secondary to several infectious and  noninfectious entities, most notably Q fever. Immune checkpoint inhibitors are  recent advances in cancer therapy, and stimulate the immune system to cause  antitumoral effects but may also lead to adverse immune events such as hepatitis   and colitis. We report 2 patients on combination ipilimumab/nivolumab who  developed hepatitis and had fibrin ring granulomas in their liver biopsies.
CANIT0000810	27797838	Case report	Metastatic urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Systemic sarcoidosis first manifesting in a tattoo	N/A	N/A	N/A	N/A	N/A	 2016 Oct 26	 Systemic sarcoidosis first manifesting in a tattoo in the setting of immune  checkpoint inhibition.	 BMJ Case Rep	 The use of immune checkpoint inhibitors is revolutionising the treatment of  cancer. However, their unique toxicity profile is substantially different from  what has been observed with traditional chemotherapy, resulting in a novel  learning curve for medical oncologists. Early recognition of these toxicities can  make a substantial impact in ameliorating these side effects in the oncological  and medical-surgical fields. Here, we present a case of Lofgren syndrome  sarcoidosis, which first manifested in a tattoo in a patient with metastatic  urothelial cancer on therapy with anti-CTLA-4 (ipilimumab) and anti-PD1  (nivolumab).CI  - 2016 BMJ Publishing Group Ltd.
CANIT0000811	27806233	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	2	N/A	Case	N/A	Fulminant myocarditis	N/A	N/A	N/A	N/A	N/A	 2016 Nov 3	 Fulminant Myocarditis with Combination Immune Checkpoint Blockade.	 N Engl J Med	 Immune checkpoint inhibitors have improved clinical outcomes associated with  numerous cancers, but high-grade, immune-related adverse events can occur,  particularly with combination immunotherapy. We report the cases of two patients   with melanoma in whom fatal myocarditis developed after treatment with ipilimumab  and nivolumab. In both patients, there was development of myositis with  rhabdomyolysis, early progressive and refractory cardiac electrical instability,   and myocarditis with a robust presence of T-cell and macrophage infiltrates.  Selective clonal T-cell populations infiltrating the myocardium were identical to  those present in tumors and skeletal muscle. Pharmacovigilance studies show that   myocarditis occurred in 0.27% of patients treated with a combination of  ipilimumab and nivolumab, which suggests that our patients were having a rare,  potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram  Cancer Center Ambassadors and others.).
CANIT0000812	27824586	Case report	Metastatic squamous cell lung cancer	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Disease progressed four weeks later	Persistently curly hair phenotype	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Persistently curly hair phenotype with the use of nivolumab for squamous cell  lung cancer.	 J Oncol Pharm Pract	 Increasing use of programmed cell death protein 1/programmed cell death protein 1  ligand inhibition for the treatment of patients with various malignancies such as  advanced lung cancer, kidney cancer, and melanoma has resulted in valuable  clinical responses, along with the occurrence of new and often puzzling side  effects. Known cutaneous effects of CTLA4 and programmed cell death protein  1/programmed cell death protein 1 ligand inhibitors include generalized pruritus,  vitiligo, maculopapular lesions, and lichenoid skin eruptions. Alopecia has been   the only hair effect previously associated with this class of agents. We describe  herein the first case of a persistent curly hair phenotype with the use of  nivolumab in a patient with metastatic squamous cell lung cancer.
CANIT0000813	27828902	Case report	Bilateral metastatic cutaneous melanoma to the retina and vitreous	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Bilateral, sequential pars plana vitrectomy with pathomorphologic examination of the vitreous specimen demonstrated metastatic melanoma. Ocular radiotherapy followed by cataract surgery resulted in the regression of retinal lesions in both eyes and no recurrence of the vitreous metastases.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Summer	 BILATERAL METASTATIC CUTANEOUS MELANOMA TO RETINA AND VITREOUS AFTER IPILIMUMAB  TREATED WITH PARS PLANA VITRECTOMY AND RADIOTHERAPY.	 Retin Cases Brief Rep	 PURPOSE: To report a patient with bilateral metastatic cutaneous melanoma to the   retina and vitreous presenting as a right panuveitis. METHODS: A 63-year-old  woman with metastatic malignant cutaneous melanoma treated with ipilimumab and  prolonged high-dose steroids presented with a right panuveitis and right blurred   vision. Dilated fundus examination revealed bilateral, off-white, large, globular  vitreous opacities and bilateral retinal lesions. These retinal lesions had a  pale yellow appearance with a cuff of haemorrhage. The unpigmented appearance of   the vitreous opacities raised the suspicion of candida endophthalmitis. RESULTS:   Bilateral, sequential pars plana vitrectomy with pathomorphologic examination of   the vitreous specimen demonstrated metastatic melanoma. Ocular radiotherapy  followed by cataract surgery resulted in the regression of retinal lesions in  both eyes and no recurrence of the vitreous metastases. CONCLUSION: The  development of vitreous and retinal metastases despite a systemic response to  ipilimumab identifies the challenge of immunotherapy in an immune privileged  site. Treatment is challenging, and outcomes are variable. A local approach of  bilateral pars plana vitrectomy, external beam radiotherapy, and subsequent  bilateral cataract surgery provided an excellent visual result with no recurrence  at 12 months.
CANIT0000814	27838762	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	3	N/A	Case	Feasible treatment option in carefully selected	Rechallenge with combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity with initial combination therapy is feasible, and responses are seen. We highlight the fact that grade 3 toxicity is likely to recur, but if so, can be manageable.	N/A	N/A	N/A	N/A	N/A	 2017 Jan	 Efficacy and toxicity of rechallenge with combination immune checkpoint blockade   in metastatic melanoma: a case series.	 Cancer Immunol Immunother	 BACKGROUND: The efficacy and potential toxicity of rechallenge with combination  ipilimumab and nivolumab has not been described. Retreatment of patients with  immune checkpoint inhibitors in the setting of prior significant toxicity lacks  evidence-based guidance. METHODS: We present the first three, consecutive  patients who received re-treatment with combination ipilimumab and nivolumab for   metastatic melanoma managed at our institution. RESULTS: Rechallenge with  combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity  with initial combination therapy is feasible, and responses are seen. We  highlight the fact that grade 3 toxicity is likely to recur, but if so, can be  manageable. CONCLUSIONS: Retreatment with ipi + nivo may be considered an option   in carefully selected, well-informed patients. More research is required to  delineate the benefits and risks with this approach.
CANIT0000815	27841872	Clinical research	Multiple myeloma	Multiple myeloma	EFO:0001378	Skin	C-IAP2 (Q13489); C-IAP1 (Q13490); 	C-IAP2; C-IAP1	LCL161	N/A	Immune checkpoint therapy	LCL161 (DB12085); 	25	N/A	N/A	Robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2016 Dec	 IAP antagonists induce anti-tumor immunity in multiple myeloma.	 Nat Med	 The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of   cancers and have been identified in multiple malignancies as being potential  therapeutic targets as a result of their role in the evasion of apoptosis.  Consequently, small-molecule IAP antagonists, such as LCL161, have entered  clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated   apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously   deleted in multiple myeloma (MM), resulting in constitutive activation of the  noncanonical nuclear factor (NF)-kappaB pathway. To our surprise, we observed  robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse  model and in patients with relapsed-refractory MM, where the addition of  cyclophosphamide resulted in a median progression-free-survival of 10 months.  This effect was not a result of direct induction of tumor cell death, but rather   of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a   strong inflammatory response that resulted in the activation of macrophages and  dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse   model with LCL161 established long-term anti-tumor protection and induced  regression in a fraction of the mice. Notably, combination of LCL161 with the  immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.
CANIT0000816	27856600	Basic research	Aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model.	Acute myeloid leukemia	EFO:0000222	Blood and lymph nodes	CD47 (Q08722); 	CD47; 	TTI-621	N/A	Immune checkpoint therapy	TTI-621 (NCIT:C125718); 	Cell lines/ animal models	N/A	Basic research	TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications.	Minimal Erythrocyte Binding	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2017 Feb 15	 TTI-621 (SIRPalphaFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with  Broad Antitumor Activity and Minimal Erythrocyte Binding.	 Clin Cancer Res	 Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an  anti-phagocytic (do not eat) signal by binding signal-regulatory protein alpha  (SIRPalpha) on macrophages. CD47 is overexpressed in cancer cells and its  expression is associated with poor clinical outcomes. TTI-621 (SIRPalphaFc) is a   fully human recombinant fusion protein that blocks the CD47-SIRPalpha axis by  binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of   this inhibitory axis using TTI-621 has emerged as a promising therapeutic  strategy to promote tumor cell eradication.Experimental Design: The ability of  TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was  assessed using both confocal microscopy and flow cytometry. In vivo antitumor  efficacy was evaluated in xenograft and syngeneic models and the role of the Fc  region in antitumor activity was evaluated using SIRPalphaFc constructs with  different Fc tails.Results: TTI-621 enhanced macrophage-mediated phagocytosis of   both hematologic and solid tumor cells, while sparing normal cells. In vivo,  TTI-621 effectively controlled the growth of aggressive AML and B lymphoma  xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail   of TTI-621 plays a critical role in its antitumor activity, presumably by  engaging activating Fcgamma receptors on macrophages. Finally, TTI-621 exhibits  minimal binding to human erythrocytes, thereby differentiating it from CD47  blocking antibodies.Conclusions: These data indicate that TTI-621 is active  across a broad range of human tumors. These results further establish CD47 as a  critical regulator of innate immune surveillance and form the basis for clinical   development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4);   1068-79. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000817	27856600	Basic research	Aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model.	B-cell lymphoma	EFO:1001938	Blood and lymph nodes	CD47 (Q08722); 	CD47; 	TTI-621	N/A	Immune checkpoint therapy	TTI-621 (NCIT:C125718); 	Cell lines/ animal models	N/A	Basic research	TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications.	Minimal Erythrocyte Binding	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2017 Feb 15	 TTI-621 (SIRPalphaFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with  Broad Antitumor Activity and Minimal Erythrocyte Binding.	 Clin Cancer Res	 Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an  anti-phagocytic (do not eat) signal by binding signal-regulatory protein alpha  (SIRPalpha) on macrophages. CD47 is overexpressed in cancer cells and its  expression is associated with poor clinical outcomes. TTI-621 (SIRPalphaFc) is a   fully human recombinant fusion protein that blocks the CD47-SIRPalpha axis by  binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of   this inhibitory axis using TTI-621 has emerged as a promising therapeutic  strategy to promote tumor cell eradication.Experimental Design: The ability of  TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was  assessed using both confocal microscopy and flow cytometry. In vivo antitumor  efficacy was evaluated in xenograft and syngeneic models and the role of the Fc  region in antitumor activity was evaluated using SIRPalphaFc constructs with  different Fc tails.Results: TTI-621 enhanced macrophage-mediated phagocytosis of   both hematologic and solid tumor cells, while sparing normal cells. In vivo,  TTI-621 effectively controlled the growth of aggressive AML and B lymphoma  xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail   of TTI-621 plays a critical role in its antitumor activity, presumably by  engaging activating Fcgamma receptors on macrophages. Finally, TTI-621 exhibits  minimal binding to human erythrocytes, thereby differentiating it from CD47  blocking antibodies.Conclusions: These data indicate that TTI-621 is active  across a broad range of human tumors. These results further establish CD47 as a  critical regulator of innate immune surveillance and form the basis for clinical   development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4);   1068-79. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000818	27858578	Case report	Pediatric glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Poor prognosis	Severe cerebral edema	N/A	N/A	N/A	N/A	N/A	 2017 Feb	 Severe cerebral edema following nivolumab treatment for pediatric glioblastoma:  case report.	 J Neurosurg Pediatr	 Nivolumab is an immune checkpoint inhibitor (ICI) currently undergoing Phase III   clinical trials for the treatment of glioblastoma. The authors present the case  of a 10-year-old girl with glioblastoma treated with nivolumab under  compassionate-use guidelines. After the first dose of nivolumab the patient  developed hemiparesis, cerebral edema, and significant midline shift due to  severe tumor necrosis. She was managed using intravenous dexamethasone and  discharged on a dexamethasone taper. The patient's condition rapidly deteriorated  after the second dose of nivolumab, demonstrating hemiplegia, seizures, and  eventually unresponsiveness with a fixed and dilated left pupil. Computed  tomography of her brain revealed malignant cerebral edema requiring emergency  decompressive hemicraniectomy. Repeat imaging demonstrated increased size of the   lesion, reflecting immune-mediated inflammation and tumor necrosis. The patient  remained densely hemiplegic, but became progressively more interactive and was  ultimately extubated. She resumed nivolumab several weeks later, but again her  condition deteriorated with headache, vomiting, swelling at the craniectomy site,  and limited right-sided facial movement following the sixth dose. MRI  demonstrated severe midline shift and uncal herniation despite her craniectomy.  Her condition gradually declined, and she died several days later under do not  resuscitate/do not intubate orders. To the authors' knowledge, this represents  the first case of malignant cerebral edema requiring operative intervention  following nivolumab treatment for glioblastoma in a pediatric patient.
CANIT0000819	27861725	Case report	Lymphoma 	Lymphoma	EFO:0000574	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	Case	In conclusion, our initial series of PD-1 inhibitor-related pneumonitis in lymphoma patients demonstrated a relatively early onset, the frequent occurrence of symptoms, a radiographic COP pattern and steroid responsiveness. 	PD-1 inhibitor-related pneumonitis	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 PD-1 inhibitor-related pneumonitis in lymphoma patients treated with single-agent  pembrolizumab therapy.	 Br J Haematol	Unable to provide
CANIT0000820	27870733	Case report	Cutaneous metastatic melanoma resembling a halo nevus	Cutaneous melanoma	EFO:0000389	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Cutaneous Metastatic Melanoma Resembling a Halo Nevus, in the Setting of PD-1  Inhibition.	 Am J Dermatopathol	 Malignant melanoma is a common source of cutaneous metastases and can  occasionally adopt a histological appearance which mimics a primary melanocytic  lesion, either benign or malignant. The authors describe a case of new cutaneous   deposits of metastatic melanoma in a 70-year-old woman with a prominent admixed  lymphocytic infiltrate, imparting a striking resemblance to a halo nevus. The  authors believe this appearance was a direct reflection of treatment with  pembrolizumab, a humanized antibody against the immune checkpoint inhibitor  programmed death-1. With increasing use of immune-modulating drugs, this  potential histological mimic may be seen more frequently in the future.
CANIT0000821	27878363	Clinical research	Stage IV melanoma patients	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Dabrafenib or vemurafenib	Immune checkpoint therapy	Ipilimumab (DB06186); vemurafenib (DB08881); dabrafenib (DB08912); 	52	68	N/A	The analysis of real-world data of treatment of metastatic melanoma showed an improvement of OS with both immunotherapy and targeted therapy. In case of cerebral metastasis, patients treated with targeted therapy showed a longer  median OS than patients treated with ipilimumab.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2017 Mar	 Improvement of overall survival in stage IV melanoma patients during 2011-2014:  analysis of real-world data in 441 patients of the German Central Malignant  Melanoma Registry (CMMR).	 J Cancer Res Clin Oncol	 BACKGROUND: During 2011 and 2014, new treatment modalities like tyrosine kinase  inhibitors and checkpoint inhibitors were introduced into the therapy of  metastatic melanoma. This study addresses the question whether overall survival  (OS) of metastatic melanoma patients has already been improved in 441 patients  diagnosed with metastatic melanoma between 2011 and 2014 in the real-world  setting at the University Hospital Tuebingen. METHODS: All patients were  documented with their different therapies by the CMMR and followed up until March  2016. Survival probabilities were calculated by Kaplan-Meier estimators, and  log-rank tests were used to evaluate significances. Hazard ratios were estimated   by Cox regression analysis for survival probabilities and prognostic factors in  stage IV melanoma. RESULTS: Best OS was observed in patients (n = 93) treated by   metastasectomy as primary treatment with the intention to completely excise all  metastases (3-year OS 61%). OS for patients with first-line systemic treatment (n  = 258) was unfavorable in general (3-year OS 23%). Of those, the most favorable  outcome was observed in patients without brain metastasis and treated with  immunotherapy (mostly ipilimumab), as first-line treatment (median OS 35 months,   3-year OS 43%). In case of brain metastases, patients with targeted therapy had a  better OS (median 14 months) than patients with ipilimumab treatment (median 7  months). Among all patients with first-line systemic treatment, outcome of  patients diagnosed in the years 2013/2014, compared to 2011 and 2012, showed an  improved survival. Three-year OS for patients that entered stage IV in 2013/2014   was 37% compared to those that entered stage IV in 2011 (18%) and 2012 (20%).  CONCLUSION: The analysis of real-world data of treatment of metastatic melanoma  showed an improvement of OS with both immunotherapy and targeted therapy. In case  of cerebral metastasis, patients treated with targeted therapy showed a longer  median OS than patients treated with ipilimumab.
CANIT0000822	27879972	Case report	Basal cell carcinoma	Basal cell carcinoma	EFO:0004193	Skin	PD-1 (Q15116); 	PD-1; 	Cemiplimab	N/A	Immune checkpoint therapy	Cemiplimab (DB14707); 	1	N/A	Case	These case reports suggest that UV-associated skin cancers, beyond melanoma, are sensitive to PD-1 blockade.	N/A	N/A	N/A	N/A	N/A	N/A	2016	 Responses of metastatic basal cell and cutaneous squamous cell carcinomas to  anti-PD1 monoclonal antibody REGN2810.	 J Immunother Cancer	 BACKGROUND: Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma  (CSCC) share exposure to UV light as the dominant risk factor, and these tumors  therefore harbor high mutation burdens. In other malignancies, high mutation  burden has been associated with clinical benefit from therapy with antibodies  directed against the Programmed Death 1 (PD-1) immune checkpoint receptor. Highly  mutated tumors are more likely to express immunogenic tumor neoantigens that  attract effector T cells, which can be unleashed by blockade of the PD-1 immune  checkpoint. CASE PRESENTATIONS: This report describes a patient with metastatic  BCC and a patient with metastatic CSCC who were treated with REGN2810, a fully  human anti-PD-1 monoclonal antibody, in an ongoing phase 1 trial (NCT02383212).  The CSCC patient has experienced an ongoing complete response (16+ months), and  the BCC patient has experienced an ongoing partial response (12+ months).  CONCLUSIONS: These case reports suggest that UV-associated skin cancers, beyond  melanoma, are sensitive to PD-1 blockade. TRIAL REGISTRATION: Clinicaltrials.gov   NCT02383212. Registered 2 February 2015.
CANIT0000823	27879972	Case report	Cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Cemiplimab	N/A	Immune checkpoint therapy	Cemiplimab (DB14707); 	1	N/A	Case	These case reports suggest that UV-associated skin cancers, beyond melanoma, are sensitive to PD-1 blockade.	N/A	N/A	N/A	N/A	N/A	N/A	2016	 Responses of metastatic basal cell and cutaneous squamous cell carcinomas to  anti-PD1 monoclonal antibody REGN2810.	 J Immunother Cancer	 BACKGROUND: Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma  (CSCC) share exposure to UV light as the dominant risk factor, and these tumors  therefore harbor high mutation burdens. In other malignancies, high mutation  burden has been associated with clinical benefit from therapy with antibodies  directed against the Programmed Death 1 (PD-1) immune checkpoint receptor. Highly  mutated tumors are more likely to express immunogenic tumor neoantigens that  attract effector T cells, which can be unleashed by blockade of the PD-1 immune  checkpoint. CASE PRESENTATIONS: This report describes a patient with metastatic  BCC and a patient with metastatic CSCC who were treated with REGN2810, a fully  human anti-PD-1 monoclonal antibody, in an ongoing phase 1 trial (NCT02383212).  The CSCC patient has experienced an ongoing complete response (16+ months), and  the BCC patient has experienced an ongoing partial response (12+ months).  CONCLUSIONS: These case reports suggest that UV-associated skin cancers, beyond  melanoma, are sensitive to PD-1 blockade. TRIAL REGISTRATION: Clinicaltrials.gov   NCT02383212. Registered 2 February 2015.
CANIT0000824	27881588	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Diabetic ketoacidosis	N/A	N/A	N/A	N/A	N/A	 2016 Nov 23	 Glucocorticoids did not reverse type 1 diabetes mellitus secondary to  pembrolizumab in a patient with metastatic melanoma.	 BMJ Case Rep	 Immune checkpoint inhibitors offer patients with advanced melanoma substantial  improvements in survival. Unlike chemotherapy, immune checkpoint inhibitors such   as ipilimumab and pembrolizumab cause unique immune-related adverse events  (irAEs), including the development of endocrinopathies. We report a case of a man  aged 60 years who developed diabetic ketoacidosis (DKA) following the use of  pembrolizumab for the treatment of metastatic melanoma. He received four cycles  of ipilimumab, before proceeding to pembrolizumab. Five weeks after initiating  pembrolizumab, he presented in DKA with a pH of 7.0, bicarbonate of 7 mmol/L,  blood glucose of 27 mmol/L and serum ketones of 5.9 mmol/L. Antibodies to  glutamic acid decarboxylase (anti-GAD) and Islet antigen 2 (IA-2) were negative  and C-peptide was low at 57 pmol/L (300-2350 pmol/L). There was no personal or  family history of autoimmune conditions. Standard immunosuppression for irAEs was  started using prednisolone in an attempt to salvage beta cell function but was  unsuccessful. To the best of our knowledge, this is the first reported attempt at  reversing pembrolizumab-induced type 1 diabetes using glucocorticoids.CI  - 2016 BMJ Publishing Group Ltd.
CANIT0000825	27891225	Clinical research	Prostate cancer	Prostate cancer	MONDO:0008315	Prostate	HER2 (P04626); 	HER2; 	AE36 vaccine	N/A	Tumor vaccine	AE36 vaccine (NCIT:C2537); 	29	N/A	A phase II clinical trial	HLA-A2+ patients with high preexisting or vaccine-induced immunity to E75, showed a trend for shorter PFS.	N/A	N/A	N/A	Immunity to E75 (); 	Preexisting or vaccine-induced immunity to E75	Immune response	2016	 Unraveling the role of preexisting immunity in prostate cancer patients  vaccinated with a HER-2/neu hybrid peptide.	 J Immunother Cancer	 BACKGROUND: Cancer vaccines aim at eliciting not only an immune response against   specific tumor antigens, but also at enhancing a preexisting immunity against the  tumor. In this context, we recently reported on the levels of preexisting  immunity in prostate cancer patients vaccinated with the HER-2 hybrid peptide  (AE37), during a phase I clinical trial. The purpose of the current study was to   correlate between preexisting immunity to the native HER-2 peptide, AE36, and  expression of HLA-A2 and -A24 molecules with the clinical outcome. Additionally,   we investigated the ability of the AE37 vaccine to induce an antitumor immune  response against other tumor associated antigens, not integrated in the vaccine  formulation, with respect to the clinical response. METHODS: We analyzed prostate  cancer patients who were vaccinated with the AE37 vaccine  [Ii-Key-HER-2/neu(776-790) hybrid peptide vaccine (AE37), which is a MHC class II  long peptide vaccine encompassing MHC class I epitopes, during a phase I clinical  trial. Preexisting immunity to the native HER-2/neu(776-790) (AE36) peptide was  assessed by IFNG response or dermal reaction at the inoculation site. Antigen  specificity against other tumor antigens was defined using multimer analysis.  Progression free survival (PFS) was considered as the patients' clinical outcome.  Two-tailed Wilcoxon signed rank test at 95 % confidence interval was used for  statistical evaluation at different time points and Kaplan-Meier curves with  log-rank (Mantel-Cox) test were used for the evaluation of PFS. RESULTS:  Preexisting immunity to AE36, irrespectively of HLA expression, was correlated  with longer PFS. Specific CD8(+) T cell immunity against E75 and PSA146-151  (HLA-A2 restricted), as well as, PSA153-161 (HLA-A24 restricted) was detected at   relatively high frequencies which were further enhanced during vaccinations.  Specific immunity against PSA153-161 correlated with longer PFS in HLA-A24(+)  patients. However, HLA-A2(+) patients with high preexisting or vaccine-induced  immunity to E75, showed a trend for shorter PFS. CONCLUSIONS: Our data cast doubt  on whether preexisting immunity or epitope spreading specific for HLA-class  I-restricted peptides can actually predict a favorable clinical outcome. They  also impose that preexisting immunity to long vaccine peptides, encompassing both  HLA class II and I epitopes should be considered as an important prerequisite for  the improvement of future immunotherapeutic protocols. Protocol ID Code:  Generex-06-07 National Organization for Medicines (EOF) ID Code: IS-107-01-06 NEC  Study Code: EED107/1/06 EudraCT Number: 2006-003299-37 Date of registration:  07/06/2006 Date of enrolment of the first participant to the trial: Nov 1st,  2007.
CANIT0000826	27891225	Clinical research	Prostate cancer	Prostate cancer	MONDO:0008315	Prostate	HER2 (P04626); 	HER2; 	AE36 vaccine	N/A	Tumor vaccine	AE36 vaccine (NCIT:C2537); 	29	N/A	A phase II clinical trial	Preexisting immunity to AE36, irrespectively of HLA expression, was correlated with longer PFS.	N/A	N/A	N/A	HLA (P04439); Immunity to AE36 (); 	Preexisting immunity to AE36, irrespectively of HLA expression	Gene expression signature on/in tumor cell	2016	 Unraveling the role of preexisting immunity in prostate cancer patients  vaccinated with a HER-2/neu hybrid peptide.	 J Immunother Cancer	 BACKGROUND: Cancer vaccines aim at eliciting not only an immune response against   specific tumor antigens, but also at enhancing a preexisting immunity against the  tumor. In this context, we recently reported on the levels of preexisting  immunity in prostate cancer patients vaccinated with the HER-2 hybrid peptide  (AE37), during a phase I clinical trial. The purpose of the current study was to   correlate between preexisting immunity to the native HER-2 peptide, AE36, and  expression of HLA-A2 and -A24 molecules with the clinical outcome. Additionally,   we investigated the ability of the AE37 vaccine to induce an antitumor immune  response against other tumor associated antigens, not integrated in the vaccine  formulation, with respect to the clinical response. METHODS: We analyzed prostate  cancer patients who were vaccinated with the AE37 vaccine  [Ii-Key-HER-2/neu(776-790) hybrid peptide vaccine (AE37), which is a MHC class II  long peptide vaccine encompassing MHC class I epitopes, during a phase I clinical  trial. Preexisting immunity to the native HER-2/neu(776-790) (AE36) peptide was  assessed by IFNG response or dermal reaction at the inoculation site. Antigen  specificity against other tumor antigens was defined using multimer analysis.  Progression free survival (PFS) was considered as the patients' clinical outcome.  Two-tailed Wilcoxon signed rank test at 95 % confidence interval was used for  statistical evaluation at different time points and Kaplan-Meier curves with  log-rank (Mantel-Cox) test were used for the evaluation of PFS. RESULTS:  Preexisting immunity to AE36, irrespectively of HLA expression, was correlated  with longer PFS. Specific CD8(+) T cell immunity against E75 and PSA146-151  (HLA-A2 restricted), as well as, PSA153-161 (HLA-A24 restricted) was detected at   relatively high frequencies which were further enhanced during vaccinations.  Specific immunity against PSA153-161 correlated with longer PFS in HLA-A24(+)  patients. However, HLA-A2(+) patients with high preexisting or vaccine-induced  immunity to E75, showed a trend for shorter PFS. CONCLUSIONS: Our data cast doubt  on whether preexisting immunity or epitope spreading specific for HLA-class  I-restricted peptides can actually predict a favorable clinical outcome. They  also impose that preexisting immunity to long vaccine peptides, encompassing both  HLA class II and I epitopes should be considered as an important prerequisite for  the improvement of future immunotherapeutic protocols. Protocol ID Code:  Generex-06-07 National Organization for Medicines (EOF) ID Code: IS-107-01-06 NEC  Study Code: EED107/1/06 EudraCT Number: 2006-003299-37 Date of registration:  07/06/2006 Date of enrolment of the first participant to the trial: Nov 1st,  2007.
CANIT0000827	27891225	Clinical research	Prostate cancer	Prostate cancer	MONDO:0008315	Prostate	HER2 (P04626); 	HER2; 	AE36 vaccine	N/A	Tumor vaccine	AE36 vaccine (NCIT:C2537); 	29	N/A	A phase II clinical trial	Specific immunity against PSA153-161 correlated with longer PFS in HLA-A24+ patients. 	N/A	N/A	N/A	Specific immunity against prostate-specific antigen 153-161 (NCIT:C17525); 	Specific immunity against PSA153-161	Immune response	2016	 Unraveling the role of preexisting immunity in prostate cancer patients  vaccinated with a HER-2/neu hybrid peptide.	 J Immunother Cancer	 BACKGROUND: Cancer vaccines aim at eliciting not only an immune response against   specific tumor antigens, but also at enhancing a preexisting immunity against the  tumor. In this context, we recently reported on the levels of preexisting  immunity in prostate cancer patients vaccinated with the HER-2 hybrid peptide  (AE37), during a phase I clinical trial. The purpose of the current study was to   correlate between preexisting immunity to the native HER-2 peptide, AE36, and  expression of HLA-A2 and -A24 molecules with the clinical outcome. Additionally,   we investigated the ability of the AE37 vaccine to induce an antitumor immune  response against other tumor associated antigens, not integrated in the vaccine  formulation, with respect to the clinical response. METHODS: We analyzed prostate  cancer patients who were vaccinated with the AE37 vaccine  [Ii-Key-HER-2/neu(776-790) hybrid peptide vaccine (AE37), which is a MHC class II  long peptide vaccine encompassing MHC class I epitopes, during a phase I clinical  trial. Preexisting immunity to the native HER-2/neu(776-790) (AE36) peptide was  assessed by IFNG response or dermal reaction at the inoculation site. Antigen  specificity against other tumor antigens was defined using multimer analysis.  Progression free survival (PFS) was considered as the patients' clinical outcome.  Two-tailed Wilcoxon signed rank test at 95 % confidence interval was used for  statistical evaluation at different time points and Kaplan-Meier curves with  log-rank (Mantel-Cox) test were used for the evaluation of PFS. RESULTS:  Preexisting immunity to AE36, irrespectively of HLA expression, was correlated  with longer PFS. Specific CD8(+) T cell immunity against E75 and PSA146-151  (HLA-A2 restricted), as well as, PSA153-161 (HLA-A24 restricted) was detected at   relatively high frequencies which were further enhanced during vaccinations.  Specific immunity against PSA153-161 correlated with longer PFS in HLA-A24(+)  patients. However, HLA-A2(+) patients with high preexisting or vaccine-induced  immunity to E75, showed a trend for shorter PFS. CONCLUSIONS: Our data cast doubt  on whether preexisting immunity or epitope spreading specific for HLA-class  I-restricted peptides can actually predict a favorable clinical outcome. They  also impose that preexisting immunity to long vaccine peptides, encompassing both  HLA class II and I epitopes should be considered as an important prerequisite for  the improvement of future immunotherapeutic protocols. Protocol ID Code:  Generex-06-07 National Organization for Medicines (EOF) ID Code: IS-107-01-06 NEC  Study Code: EED107/1/06 EudraCT Number: 2006-003299-37 Date of registration:  07/06/2006 Date of enrolment of the first participant to the trial: Nov 1st,  2007.
CANIT0000828	27892773	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	58	N/A	A phase I clinical trial	Bilateral, sequential pars plana vitrectomy with pathomorphologic examination of the vitreous specimen demonstrated metastatic melanoma. Ocular radiotherapy followed by cataract surgery resulted in the regression of retinal lesions in both eyes and no recurrence of the vitreous metastases.	Four patients (7%) were off treatment due to toxicity, none were grade 4 or 5.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	 2017 Mar	 Real-world data on nivolumab treatment of non-small cell lung cancer.	 Acta Oncol	 BACKGROUND: Checkpoint inhibitors have proven effectiveness in clinical trials  for non-small cell lung cancer (NSCLC) patients, but if this is congruent with  routine patient care is discussed. We present real-world experience with the  PD1-inhibitor nivolumab in NSCLC. PATIENTS AND METHODS: Patients with NSCLC were   considered eligible for nivolumab treatment after one or more lines of  chemotherapy, and when in reasonable performance status (PS) [Eastern Cooperative  Oncology Group (ECOG) < 3]. Treatment was given according to guidelines in the  two phase III studies, CA209017 and CA209057. Response evaluation was done  according to Recist 1.1, and treatment given until unequivocal progression or  intolerable toxicity. RESULTS: Fifty-eight patients (30 females) commenced  therapy in the period June-August 2015. Median age was 64.6 years (range  32.3-88.2). Twenty-four patients had squamous cell carcinoma and 32  adenocarcinoma, 38 had received two or more prior lines of therapy. Fourteen  cases (24%) were in ECOG PS 2. After a medium observation time of 14.3 months, 13  (22%) are still in treatment. Median time to treatment failure (TTF) was 4.0  months, 34% were off treatment during the first two months. Median overall  survival (OS) is 11.7 months. There was no difference in TTF or OS among patients  with squamous versus non-squamous histology or between 1 versus >1 prior line of   therapy. Four patients (7%) were off treatment due to toxicity, none were grade 4  or 5. CONCLUSION: Nivolumab treatment outside clinical trials seems to perform as  expected.
CANIT0000829	27893699	Case report	Recurrence of lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Severe akathisia	N/A	N/A	N/A	N/A	N/A	 2016 Nov 23	 Nivolumab-Induced Severe Akathisia in an Advanced Lung Cancer Patient.	 Am J Case Rep	 BACKGROUND Nivolumab is an anti-PD-1 immune checkpoint inhibitor that was  recently developed for cancer immunotherapy. In the clinical trials of nivolumab,  its adverse effects were reported to be less likely than those of conventional  anti-cancer agents; however, after practical clinical distribution, it has come  to be known that nivolumab induces various immune-related adverse events. CASE  REPORT A 58-year-old male with a recurrence of lung adenocarcinoma was treated  with nivolumab. Only four days after the initial administration of nivolumab, the  patient presented with unbearable restlessness and distress that was resistant to  all therapeutic agents used, and it gradually became worse. He finally came to  need deep sedation despite his cancer status being stable during the course.  Clinical tests including magnetic resonance imaging, cerebrospinal fluid  cytology, and antibodies of paraneoplastic syndrome exhibited no signs of  encephalitis or another possible cause of the neuropathy. The diagnosis of  akathisia could be made only by his somatoform presentation. It was uncertain  whether or not this complication was correlated with the activation of his immune  system. CONCLUSIONS Anti-immune check point inhibitors may induce many unknown  adverse events. Severe akathisia induced by nivolumab, as in our case, has not  been reported yet. Collecting every adverse event of nivolumab may be important  to make a better algorithm to manage its huge variety of complications.
CANIT0000830	27895919	Case report	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Recurrent pleural effusions and cardiac tamponade as possible manifestations of pseudoprogression associated with nivolumab therapy.	N/A	N/A	N/A	N/A	N/A	2016	 Recurrent pleural effusions and cardiac tamponade as possible manifestations of  pseudoprogression associated with nivolumab therapy- a report of two cases.	 J Immunother Cancer	 BACKGROUND: Checkpoint inhibitors are a class of agents that employ host's  adaptive immune defenses in fighting cancer. With many new indications and  several ongoing clinical trials in a variety of malignancies, the usage of these   agents is set to increase significantly. One of the key challenges patients and  physicians face while using these drugs is with the appropriate assessment of  response to therapy. CASE PRESENTATION: We are reporting two patients with lung  cancer who were treated with nivolumab and experienced rapidly accumulating  recurrent pleural effusions requiring multiple thoracenteses (6 and 4 times each   for patient 1 and 2 respectively) with in the first few weeks of initiation of  therapy and also developed pericardial effusion with cardiac tamponade requiring   pericardiocentesis. Both patients had prior history of malignant spread to  pleural and pericardial space in their disease course. Therapy was continued in  the first patient with spontaneous resolution of effusions after 8 weeks and the   disease showed near complete response to treatment on imaging at 16 weeks. Second  patient declined to continue further treatment with nivolumab after 3 cycles due   to recurrent effusions and cardiac tamponade, although there was some evidence of  clinical response at discontinuation. CONCLUSIONS: Patients with history of  malignant involvement of visceral spaces should be monitored closely for rapidly   accumulating effusions and particularly for cardiac tamponade, after initiation  of therapy with nivolumab. This presentation could represent pseudoprogression,  and continuation of therapy with close monitoring is prudent as long as effusions  are manageable and there is no definitive evidence of progression elsewhere.
CANIT0000831	27899158	Clinical research	Relapsed or refractory Hodgkin lymphoma previously exposed to epigenetic therapy	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	N/A	We documented an unprecedented CR rate after ICI in patients with R/R cHL. We hypothesize that hypomethylating agents might have an immune priming effect and enhance the efficacy of ICI.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov 30	 High rate of complete responses to immune checkpoint inhibitors in patients with   relapsed or refractory Hodgkin lymphoma previously exposed to epigenetic therapy.	 J Hematol Oncol	 Options for patients with relapsed or refractory (R/R) classical Hodgkin lymphoma  (cHL) after brentuximab vedotin (Bv) and autologous stem cell transplantation  (ASCT) are limited. Immune checkpoint inhibitors (ICI) are active in this  population but rarely induce complete response (CR). Ten patients with R/R cHL  after ASCT and Bv received pembrolizumab (n = 8) or nivolumab (n = 2). Five had  been previously exposed to 5-azacitidine on a phase 1 study. Among nine evaluable  patients, seven (78%) achieved CR, one partial response, and one reduction of  tumor burden. All five patients who had received 5-azacitidine prior to ICI  achieved CR, while only two of four who did not receive prior 5-azacitidine  achieved CR. At a median follow-up of 9.9 months [0.5-14.3], eight patients are  alive and five are still receiving treatment. We documented an unprecedented CR  rate after ICI in patients with R/R cHL. We hypothesize that hypomethylating  agents might have an immune priming effect and enhance the efficacy of ICI.
CANIT0000832	27899158	Clinical research	Relapsed or refractory Hodgkin lymphoma previously exposed to epigenetic therapy	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	N/A	We documented an unprecedented CR rate after ICI in patients with R/R cHL. We hypothesize that hypomethylating agents might have an immune priming effect and enhance the efficacy of ICI.	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Nov 30	 High rate of complete responses to immune checkpoint inhibitors in patients with   relapsed or refractory Hodgkin lymphoma previously exposed to epigenetic therapy.	 J Hematol Oncol	 Options for patients with relapsed or refractory (R/R) classical Hodgkin lymphoma  (cHL) after brentuximab vedotin (Bv) and autologous stem cell transplantation  (ASCT) are limited. Immune checkpoint inhibitors (ICI) are active in this  population but rarely induce complete response (CR). Ten patients with R/R cHL  after ASCT and Bv received pembrolizumab (n = 8) or nivolumab (n = 2). Five had  been previously exposed to 5-azacitidine on a phase 1 study. Among nine evaluable  patients, seven (78%) achieved CR, one partial response, and one reduction of  tumor burden. All five patients who had received 5-azacitidine prior to ICI  achieved CR, while only two of four who did not receive prior 5-azacitidine  achieved CR. At a median follow-up of 9.9 months [0.5-14.3], eight patients are  alive and five are still receiving treatment. We documented an unprecedented CR  rate after ICI in patients with R/R cHL. We hypothesize that hypomethylating  agents might have an immune priming effect and enhance the efficacy of ICI.
CANIT0000833	27903791	Case report	Lung squamous carcinoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Rapid and partial remission of primary lesion but complicated by secondary fibrosis	Fibrosis	N/A	N/A	N/A	N/A	N/A	 2017 Feb	 Rapid and partial remission of primary lesion but complicated by secondary  fibrosis after treatment with nivolumab in a lung squamous carcinoma.	 Ther Adv Respir Dis	Unable to provide
CANIT0000834	27911979	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	176	N/A	N/A	 The  prevalence of BRAF(V600) , NRAS, TP53, and BRAF(Non-V600) mutations was 43%, 21%,  19%, and 7%, respectively. The presence of a TP53 mutation was associated with  older age (P = .019), a head and neck primary tumor site (P = .0001), and longer   overall survival (OS) from the diagnosis of stage IV disease in univariate (P =  .039) and multivariate analyses (P = .015). BRAF(Non-V600) mutations were  associated with older age (P = .005) but not with primary tumor features or OS  from stage IV. Neither TP53 nor BRAF(Non-V600) mutations correlated significantly  with OS with frontline ipilimumab treatment, and the TP53 status was not  significantly associated with outcomes with frontline BRAF inhibitor therapy.  Eleven patients with BRAF(Non-V600) mutations were treated with a BRAF inhibitor.  Three patients were not evaluable for a response because of treatment cessation  for toxicities; the remaining patients had disease progression as the best  response to therapy. CONCLUSIONS: These results add to the understanding of the  clinical features associated with TP53 and BRAF(Non-V600) mutations in advanced  cutaneous melanoma patients, and they support the rationale for evaluating the  prognostic significance of TP53 in other cohorts of melanoma patients.	N/A	N/A	N/A	TP53 (P04637); 	TP53 mutational status	Mutational status	 2017 Apr 15	 Clinicopathological features and clinical outcomes associated with TP53 and  BRAF(N)(on-)(V)(600) mutations in cutaneous melanoma patients.	 Cancer	 BACKGROUND: BRAF(V600) , NRAS, TP53, and BRAF(Non-V600) are among the most common  mutations detected in non-acral cutaneous melanoma patients. Although several  studies have identified clinical and pathological features associated with  BRAF(V600) and NRAS mutations, limited data are available regarding the  correlates and significance of TP53 and BRAF(Non-V600) mutations. METHODS: This  study analyzed the patient demographics, primary tumor features, and clinical  outcomes of a large cohort of non-acral cutaneous melanoma patients who had  undergone clinically indicated molecular testing (n = 926). RESULTS: The  prevalence of BRAF(V600) , NRAS, TP53, and BRAF(Non-V600) mutations was 43%, 21%,  19%, and 7%, respectively. The presence of a TP53 mutation was associated with  older age (P = .019), a head and neck primary tumor site (P = .0001), and longer   overall survival (OS) from the diagnosis of stage IV disease in univariate (P =  .039) and multivariate analyses (P = .015). BRAF(Non-V600) mutations were  associated with older age (P = .005) but not with primary tumor features or OS  from stage IV. Neither TP53 nor BRAF(Non-V600) mutations correlated significantly  with OS with frontline ipilimumab treatment, and the TP53 status was not  significantly associated with outcomes with frontline BRAF inhibitor therapy.  Eleven patients with BRAF(Non-V600) mutations were treated with a BRAF inhibitor.  Three patients were not evaluable for a response because of treatment cessation  for toxicities; the remaining patients had disease progression as the best  response to therapy. CONCLUSIONS: These results add to the understanding of the  clinical features associated with TP53 and BRAF(Non-V600) mutations in advanced  cutaneous melanoma patients, and they support the rationale for evaluating the  prognostic significance of TP53 in other cohorts of melanoma patients. Cancer  2017;123:1372-1381. (c) 2016 American Cancer Society.CI  - (c) 2016 American Cancer Society.
CANIT0000835	27911979	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	463	N/A	N/A	 The  prevalence of BRAF(V600) , NRAS, TP53, and BRAF(Non-V600) mutations was 43%, 21%,  19%, and 7%, respectively. The presence of a TP53 mutation was associated with  older age (P = .019), a head and neck primary tumor site (P = .0001), and longer   overall survival (OS) from the diagnosis of stage IV disease in univariate (P =  .039) and multivariate analyses (P = .015). BRAF(Non-V600) mutations were  associated with older age (P = .005) but not with primary tumor features or OS  from stage IV. Neither TP53 nor BRAF(Non-V600) mutations correlated significantly  with OS with frontline ipilimumab treatment, and the TP53 status was not  significantly associated with outcomes with frontline BRAF inhibitor therapy.  Eleven patients with BRAF(Non-V600) mutations were treated with a BRAF inhibitor.  Three patients were not evaluable for a response because of treatment cessation  for toxicities; the remaining patients had disease progression as the best  response to therapy. CONCLUSIONS: These results add to the understanding of the  clinical features associated with TP53 and BRAF(Non-V600) mutations in advanced  cutaneous melanoma patients, and they support the rationale for evaluating the  prognostic significance of TP53 in other cohorts of melanoma patients.	N/A	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2017 Apr 15	 Clinicopathological features and clinical outcomes associated with TP53 and  BRAF(N)(on-)(V)(600) mutations in cutaneous melanoma patients.	 Cancer	 BACKGROUND: BRAF(V600) , NRAS, TP53, and BRAF(Non-V600) are among the most common  mutations detected in non-acral cutaneous melanoma patients. Although several  studies have identified clinical and pathological features associated with  BRAF(V600) and NRAS mutations, limited data are available regarding the  correlates and significance of TP53 and BRAF(Non-V600) mutations. METHODS: This  study analyzed the patient demographics, primary tumor features, and clinical  outcomes of a large cohort of non-acral cutaneous melanoma patients who had  undergone clinically indicated molecular testing (n = 926). RESULTS: The  prevalence of BRAF(V600) , NRAS, TP53, and BRAF(Non-V600) mutations was 43%, 21%,  19%, and 7%, respectively. The presence of a TP53 mutation was associated with  older age (P = .019), a head and neck primary tumor site (P = .0001), and longer   overall survival (OS) from the diagnosis of stage IV disease in univariate (P =  .039) and multivariate analyses (P = .015). BRAF(Non-V600) mutations were  associated with older age (P = .005) but not with primary tumor features or OS  from stage IV. Neither TP53 nor BRAF(Non-V600) mutations correlated significantly  with OS with frontline ipilimumab treatment, and the TP53 status was not  significantly associated with outcomes with frontline BRAF inhibitor therapy.  Eleven patients with BRAF(Non-V600) mutations were treated with a BRAF inhibitor.  Three patients were not evaluable for a response because of treatment cessation  for toxicities; the remaining patients had disease progression as the best  response to therapy. CONCLUSIONS: These results add to the understanding of the  clinical features associated with TP53 and BRAF(Non-V600) mutations in advanced  cutaneous melanoma patients, and they support the rationale for evaluating the  prognostic significance of TP53 in other cohorts of melanoma patients. Cancer  2017;123:1372-1381. (c) 2016 American Cancer Society.CI  - (c) 2016 American Cancer Society.
CANIT0000836	27914096	Case report	Multiple in-transit melanomas on the leg	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	CyberKnife plus ipilimumab	N/A	Immune checkpoint therapy plus Radiotherapy	CyberKnife (NCIT:C95484); ipilimumab (DB06186); 	2	N/A	Case	Feasible treatment option	N/A	N/A	N/A	N/A	N/A	N/A	 2017 May	 Successful treatment of multiple in-transit melanomas on the leg with  intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two   cases.	 J Dermatol	 Because the efficacy rates of monotherapy with immune checkpoint inhibitors such   as nivolumab or ipilimumab are not sufficient, to enhance the antitumor effects  of these reagents is of great interest among dermato-oncologists. In this report,  we describe two cases of multiple in-transit metastatic melanomas on the leg  successfully treated with intensity-modulated radiotherapy (IMRT) using a  CyberKnife in combination with ipilimumab or nivolumab. Our cases suggested that   IMRT could enhance the antitumor effects of immune checkpoint inhibitors in  patients with multiple in-transit melanomas.CI  - (c) 2016 Japanese Dermatological Association.
CANIT0000837	27914096	Case report	Multiple in-transit melanomas on the leg	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	CyberKnife plus nivolumab	N/A	Immune checkpoint therapy plus Radiotherapy	CyberKnife (NCIT:C95484); nivolumab (DB09035); 	2	N/A	Case	Feasible treatment option	N/A	N/A	N/A	N/A	N/A	N/A	 2017 May	 Successful treatment of multiple in-transit melanomas on the leg with  intensity-modulated radiotherapy and immune checkpoint inhibitors: Report of two   cases.	 J Dermatol	 Because the efficacy rates of monotherapy with immune checkpoint inhibitors such   as nivolumab or ipilimumab are not sufficient, to enhance the antitumor effects  of these reagents is of great interest among dermato-oncologists. In this report,  we describe two cases of multiple in-transit metastatic melanomas on the leg  successfully treated with intensity-modulated radiotherapy (IMRT) using a  CyberKnife in combination with ipilimumab or nivolumab. Our cases suggested that   IMRT could enhance the antitumor effects of immune checkpoint inhibitors in  patients with multiple in-transit melanomas.CI  - (c) 2016 Japanese Dermatological Association.
CANIT0000838	27926587	Clinical research	Previously treated with ipilimumab for unresectable stage III or IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Ipilimumab followed by nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	39	N/A	N/A	The number of patients was too small to enable a meaningful statistical comparison. We did not observe any difference in anti-PD1 toxicity onset incidence according to the occurrence of previous IPI AEs. These reassuring real-life data should be confirmed in a wider analysis.	The incidence of severe anti-PD1-related AEs (grades 3-4) was 12, 23, and 10% in groups A, B, and C, respectively.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Anti-programmed cell death protein 1 tolerance and efficacy after ipilimumab  immunotherapy: observational study of 39 patients.	 Melanoma Res	 In patients with ipilimumab (IPI)-refractory melanoma, the anti-programmed cell  death proteins 1 (PD1s) nivolumab (NIV) and pembrolizumab (PEM) are considered to  be a new standard of treatment. Few data are available on anti-PD1 safety in  patients who develop IPI-related severe adverse events (AEs) (grade>/=3). The aim  of this study was to compare the anti-PD1 safety and efficacy in patients with  previous severe toxicity to IPI versus in those showing moderate and no previous   IPI-related AEs. This single institution-based observational study included all  patients treated with anti-PD1 (PEM or NIV) and previously treated with IPI for  unresectable stage III or IV melanoma. The patients enrolled were classified  according to the occurrence of IPI-related AEs: group A: no previous IPI-related   AEs; group B: mild to moderate IPI-related AEs; and group C: severe to  life-threatening IPI-related AEs. The main outcome measure was safety of the  anti-PD1 among the three groups. The secondary endpoints included response  parameters. Groups A, B, and C included, respectively, 16, 13, and 10 patients.  The incidence of severe anti-PD1-related AEs (grades 3-4) was 12, 23, and 10% in   groups A, B, and C, respectively. One-year estimates of survival were 52.2, 73.4,  and 66.7% among the patients in groups A, B, and C, respectively. The number of  patients was too small to enable a meaningful statistical comparison. We did not   observe any difference in anti-PD1 toxicity onset incidence according to the  occurrence of previous IPI AEs. These reassuring real-life data should be  confirmed in a wider analysis.
CANIT0000839	27926587	Clinical research	Previously treated with ipilimumab for unresectable stage III or IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Ipilimumab followed by pembrolizumab 	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); ipilimumab (DB06186); 	39	N/A	N/A	The number of patients was too small to enable a meaningful statistical comparison. We did not observe any difference in anti-PD1 toxicity onset incidence according to the occurrence of previous IPI AEs. These reassuring real-life data should be confirmed in a wider analysis.	The incidence of severe anti-PD1-related AEs (grades 3-4) was 12, 23, and 10% in groups A, B, and C, respectively.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Anti-programmed cell death protein 1 tolerance and efficacy after ipilimumab  immunotherapy: observational study of 39 patients.	 Melanoma Res	 In patients with ipilimumab (IPI)-refractory melanoma, the anti-programmed cell  death proteins 1 (PD1s) nivolumab (NIV) and pembrolizumab (PEM) are considered to  be a new standard of treatment. Few data are available on anti-PD1 safety in  patients who develop IPI-related severe adverse events (AEs) (grade>/=3). The aim  of this study was to compare the anti-PD1 safety and efficacy in patients with  previous severe toxicity to IPI versus in those showing moderate and no previous   IPI-related AEs. This single institution-based observational study included all  patients treated with anti-PD1 (PEM or NIV) and previously treated with IPI for  unresectable stage III or IV melanoma. The patients enrolled were classified  according to the occurrence of IPI-related AEs: group A: no previous IPI-related   AEs; group B: mild to moderate IPI-related AEs; and group C: severe to  life-threatening IPI-related AEs. The main outcome measure was safety of the  anti-PD1 among the three groups. The secondary endpoints included response  parameters. Groups A, B, and C included, respectively, 16, 13, and 10 patients.  The incidence of severe anti-PD1-related AEs (grades 3-4) was 12, 23, and 10% in   groups A, B, and C, respectively. One-year estimates of survival were 52.2, 73.4,  and 66.7% among the patients in groups A, B, and C, respectively. The number of  patients was too small to enable a meaningful statistical comparison. We did not   observe any difference in anti-PD1 toxicity onset incidence according to the  occurrence of previous IPI AEs. These reassuring real-life data should be  confirmed in a wider analysis.
CANIT0000840	27928714	Clinical research	Patients with malignant solid tumors(5 Lung adenocarcinoma, 2 Rectal cancer, 2 Thymic carcinoma, 1 Esophageal carcinoma, 4 Melanoma, 1 colorectal cancer, 1 Thyroid cancer).	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	17	N/A	An open-label, dose-escalation study	One durable complete response and two partial responses. Nivolumab at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors.	The commonest adverse drug reaction was lymphopenia, which occurred in 10 (58.8%) patients, including two (11.8%) with Grade 3 events. No dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant  solid tumors.	 Invest New Drugs	 Background This study evaluated the safety, tolerability, pharmacokinetics,  immunogenicity and antitumor activity of single and multiple doses of nivolumab  in Japanese patients with malignant solid tumors. Subjects and Methods This was  an open-label, dose-escalation study in 17 patients with advanced solid tumors  with a life expectancy of >/=3 months. Patients were observed for 3 weeks after a  single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of   nivolumab every 2 weeks until unacceptable toxicity or disease progression  occurred. This study included a maximum dose of 20 mg/kg, which is the highest  dose of nivolumab evaluated to date. The maximum dose was 10 mg/kg in previous  studies. Results The commonest adverse drug reaction was lymphopenia, which  occurred in 10 (58.8%) patients, including two (11.8%) with Grade >/=3 events. No  dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.  The area under the concentration-time curve from time 0 to the last measurable  concentration was linear up to 20 mg/kg. The maximum concentration showed  dose-dependency up to 10 mg/kg, but not between 10 and 20 mg/kg. One durable  complete response and two partial responses were observed. Conclusions Nivolumab   at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well  tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid  tumors.
CANIT0000841	27928714	Clinical research	Patients with malignant solid tumors(5 Lung adenocarcinoma, 2 Rectal cancer, 2 Thymic carcinoma, 1 Esophageal carcinoma, 4 Melanoma, 1 colorectal cancer, 1 Thyroid cancer).	Esophageal carcinoma	EFO:0002916	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	17	N/A	An open-label, dose-escalation study	One durable complete response and two partial responses. Nivolumab at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors.	The commonest adverse drug reaction was lymphopenia, which occurred in 10 (58.8%) patients, including two (11.8%) with Grade 3 events. No dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant  solid tumors.	 Invest New Drugs	 Background This study evaluated the safety, tolerability, pharmacokinetics,  immunogenicity and antitumor activity of single and multiple doses of nivolumab  in Japanese patients with malignant solid tumors. Subjects and Methods This was  an open-label, dose-escalation study in 17 patients with advanced solid tumors  with a life expectancy of >/=3 months. Patients were observed for 3 weeks after a  single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of   nivolumab every 2 weeks until unacceptable toxicity or disease progression  occurred. This study included a maximum dose of 20 mg/kg, which is the highest  dose of nivolumab evaluated to date. The maximum dose was 10 mg/kg in previous  studies. Results The commonest adverse drug reaction was lymphopenia, which  occurred in 10 (58.8%) patients, including two (11.8%) with Grade >/=3 events. No  dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.  The area under the concentration-time curve from time 0 to the last measurable  concentration was linear up to 20 mg/kg. The maximum concentration showed  dose-dependency up to 10 mg/kg, but not between 10 and 20 mg/kg. One durable  complete response and two partial responses were observed. Conclusions Nivolumab   at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well  tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid  tumors.
CANIT0000842	27928714	Clinical research	Patients with malignant solid tumors(5 Lung adenocarcinoma, 2 Rectal cancer, 2 Thymic carcinoma, 1 Esophageal carcinoma, 4 Melanoma, 1 colorectal cancer, 1 Thyroid cancer).	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	17	N/A	An open-label, dose-escalation study	One durable complete response and two partial responses. Nivolumab at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors.	The commonest adverse drug reaction was lymphopenia, which occurred in 10 (58.8%) patients, including two (11.8%) with Grade 3 events. No dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant  solid tumors.	 Invest New Drugs	 Background This study evaluated the safety, tolerability, pharmacokinetics,  immunogenicity and antitumor activity of single and multiple doses of nivolumab  in Japanese patients with malignant solid tumors. Subjects and Methods This was  an open-label, dose-escalation study in 17 patients with advanced solid tumors  with a life expectancy of >/=3 months. Patients were observed for 3 weeks after a  single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of   nivolumab every 2 weeks until unacceptable toxicity or disease progression  occurred. This study included a maximum dose of 20 mg/kg, which is the highest  dose of nivolumab evaluated to date. The maximum dose was 10 mg/kg in previous  studies. Results The commonest adverse drug reaction was lymphopenia, which  occurred in 10 (58.8%) patients, including two (11.8%) with Grade >/=3 events. No  dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.  The area under the concentration-time curve from time 0 to the last measurable  concentration was linear up to 20 mg/kg. The maximum concentration showed  dose-dependency up to 10 mg/kg, but not between 10 and 20 mg/kg. One durable  complete response and two partial responses were observed. Conclusions Nivolumab   at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well  tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid  tumors.
CANIT0000843	27928714	Clinical research	Patients with malignant solid tumors(5 Lung adenocarcinoma, 2 Rectal cancer, 2 Thymic carcinoma, 1 Esophageal carcinoma, 4 Melanoma, 1 colorectal cancer, 1 Thyroid cancer).	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	17	N/A	An open-label, dose-escalation study	One durable complete response and two partial responses. Nivolumab at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors.	The commonest adverse drug reaction was lymphopenia, which occurred in 10 (58.8%) patients, including two (11.8%) with Grade 3 events. No dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant  solid tumors.	 Invest New Drugs	 Background This study evaluated the safety, tolerability, pharmacokinetics,  immunogenicity and antitumor activity of single and multiple doses of nivolumab  in Japanese patients with malignant solid tumors. Subjects and Methods This was  an open-label, dose-escalation study in 17 patients with advanced solid tumors  with a life expectancy of >/=3 months. Patients were observed for 3 weeks after a  single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of   nivolumab every 2 weeks until unacceptable toxicity or disease progression  occurred. This study included a maximum dose of 20 mg/kg, which is the highest  dose of nivolumab evaluated to date. The maximum dose was 10 mg/kg in previous  studies. Results The commonest adverse drug reaction was lymphopenia, which  occurred in 10 (58.8%) patients, including two (11.8%) with Grade >/=3 events. No  dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.  The area under the concentration-time curve from time 0 to the last measurable  concentration was linear up to 20 mg/kg. The maximum concentration showed  dose-dependency up to 10 mg/kg, but not between 10 and 20 mg/kg. One durable  complete response and two partial responses were observed. Conclusions Nivolumab   at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well  tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid  tumors.
CANIT0000844	27928714	Clinical research	Patients with malignant solid tumors(5 Lung adenocarcinoma, 2 Rectal cancer, 2 Thymic carcinoma, 1 Esophageal carcinoma, 4 Melanoma, 1 colorectal cancer, 1 Thyroid cancer).	Rectum cancer	EFO:1000657	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	17	N/A	An open-label, dose-escalation study	One durable complete response and two partial responses. Nivolumab at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors.	The commonest adverse drug reaction was lymphopenia, which occurred in 10 (58.8%) patients, including two (11.8%) with Grade 3 events. No dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant  solid tumors.	 Invest New Drugs	 Background This study evaluated the safety, tolerability, pharmacokinetics,  immunogenicity and antitumor activity of single and multiple doses of nivolumab  in Japanese patients with malignant solid tumors. Subjects and Methods This was  an open-label, dose-escalation study in 17 patients with advanced solid tumors  with a life expectancy of >/=3 months. Patients were observed for 3 weeks after a  single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of   nivolumab every 2 weeks until unacceptable toxicity or disease progression  occurred. This study included a maximum dose of 20 mg/kg, which is the highest  dose of nivolumab evaluated to date. The maximum dose was 10 mg/kg in previous  studies. Results The commonest adverse drug reaction was lymphopenia, which  occurred in 10 (58.8%) patients, including two (11.8%) with Grade >/=3 events. No  dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.  The area under the concentration-time curve from time 0 to the last measurable  concentration was linear up to 20 mg/kg. The maximum concentration showed  dose-dependency up to 10 mg/kg, but not between 10 and 20 mg/kg. One durable  complete response and two partial responses were observed. Conclusions Nivolumab   at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well  tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid  tumors.
CANIT0000845	27928714	Clinical research	Patients with malignant solid tumors(5 Lung adenocarcinoma, 2 Rectal cancer, 2 Thymic carcinoma, 1 Esophageal carcinoma, 4 Melanoma, 1 colorectal cancer, 1 Thyroid cancer).	Thymic cancer	MONDO:0002586	Thymus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	17	N/A	An open-label, dose-escalation study	One durable complete response and two partial responses. Nivolumab at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors.	The commonest adverse drug reaction was lymphopenia, which occurred in 10 (58.8%) patients, including two (11.8%) with Grade 3 events. No dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant  solid tumors.	 Invest New Drugs	 Background This study evaluated the safety, tolerability, pharmacokinetics,  immunogenicity and antitumor activity of single and multiple doses of nivolumab  in Japanese patients with malignant solid tumors. Subjects and Methods This was  an open-label, dose-escalation study in 17 patients with advanced solid tumors  with a life expectancy of >/=3 months. Patients were observed for 3 weeks after a  single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of   nivolumab every 2 weeks until unacceptable toxicity or disease progression  occurred. This study included a maximum dose of 20 mg/kg, which is the highest  dose of nivolumab evaluated to date. The maximum dose was 10 mg/kg in previous  studies. Results The commonest adverse drug reaction was lymphopenia, which  occurred in 10 (58.8%) patients, including two (11.8%) with Grade >/=3 events. No  dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.  The area under the concentration-time curve from time 0 to the last measurable  concentration was linear up to 20 mg/kg. The maximum concentration showed  dose-dependency up to 10 mg/kg, but not between 10 and 20 mg/kg. One durable  complete response and two partial responses were observed. Conclusions Nivolumab   at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well  tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid  tumors.
CANIT0000846	27928714	Clinical research	Patients with malignant solid tumors(5 Lung adenocarcinoma, 2 Rectal cancer, 2 Thymic carcinoma, 1 Esophageal carcinoma, 4 Melanoma, 1 colorectal cancer, 1 Thyroid cancer).	Thyroid cancer	MONDO:0002108	Thyroid	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	17	N/A	An open-label, dose-escalation study	One durable complete response and two partial responses. Nivolumab at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors.	The commonest adverse drug reaction was lymphopenia, which occurred in 10 (58.8%) patients, including two (11.8%) with Grade 3 events. No dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant  solid tumors.	 Invest New Drugs	 Background This study evaluated the safety, tolerability, pharmacokinetics,  immunogenicity and antitumor activity of single and multiple doses of nivolumab  in Japanese patients with malignant solid tumors. Subjects and Methods This was  an open-label, dose-escalation study in 17 patients with advanced solid tumors  with a life expectancy of >/=3 months. Patients were observed for 3 weeks after a  single dose of nivolumab at 1, 3, 10 or 20 mg/kg, then received the same dose of   nivolumab every 2 weeks until unacceptable toxicity or disease progression  occurred. This study included a maximum dose of 20 mg/kg, which is the highest  dose of nivolumab evaluated to date. The maximum dose was 10 mg/kg in previous  studies. Results The commonest adverse drug reaction was lymphopenia, which  occurred in 10 (58.8%) patients, including two (11.8%) with Grade >/=3 events. No  dose-limiting toxicities (DLTs) were observed up to the maximum dose of 20 mg/kg.  The area under the concentration-time curve from time 0 to the last measurable  concentration was linear up to 20 mg/kg. The maximum concentration showed  dose-dependency up to 10 mg/kg, but not between 10 and 20 mg/kg. One durable  complete response and two partial responses were observed. Conclusions Nivolumab   at doses of 1-20 mg/kg was not associated with DLTs, and it was generally well  tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid  tumors.
CANIT0000847	27932067	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	78	N/A	An open-label, phase I, multicohort study	In NSCLC,  first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study.	Grade 3-4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three [8%] and no patients), pneumonitis (two [5%] and one [3%] patients), adrenal insufficiency (one [3%] and two [5%] patients), and colitis (one [3%] and two [5%] patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2017 Jan	 Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell  lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort  study.	 Lancet Oncol	 BACKGROUND: Nivolumab has shown improved survival in the treatment of advanced  non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We  assessed the safety and activity of combination nivolumab plus ipilimumab as  first-line therapy for NSCLC. METHODS: The open-label, phase 1, multicohort study  (CheckMate 012) cohorts reported here were enrolled at eight US academic centres.  Eligible patients were aged 18 years or older with histologically or  cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive  NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response  system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6  weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or  nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until  disease progression, unacceptable toxicities, or withdrawal of consent. Data from  the latter two cohorts, which were considered potentially suitable for further  clinical development, are presented in this report; data from the other cohort  (as well as several earlier cohorts) are described in the appendix. The primary  outcome was safety and tolerability, assessed in all treated patients. This  ongoing study is registered with ClinicalTrials.gov, number NCT01454102.  FINDINGS: Between May 15, 2014, and March 25, 2015, 78 patients were randomly  assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38)  or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in  the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77  patients actually received treatment (38 in the ipilimumab every-12-weeks cohort;  39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29  (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the  ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3-4  treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab   every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most  commonly reported grade 3 or 4 treatment-related adverse events were increased  lipase (three [8%] and no patients), pneumonitis (two [5%] and one [3%]  patients), adrenal insufficiency (one [3%] and two [5%] patients), and colitis  (one [3%] and two [5%] patients). Treatment-related serious adverse events were  reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11  (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any  grade) prompted treatment discontinuation in four (11%) patients in the  every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No  treatment-related deaths occurred. Confirmed objective responses were achieved in  18 (47% [95% CI 31-64]) patients in the ipilimumab every-12-weeks cohort and 15  (38% [95% CI 23-55]) patients in the ipilimumab every-6-weeks cohort; median  duration of response was not reached in either cohort, with median follow-up  times of 12.8 months (IQR 9.3-15.5) in the ipilimumab every-12-weeks cohort and  11.8 months (6.7-15.9) in the ipilimumab every-6-weeks cohort. In patients with  PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%)  of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23  patients in the ipilimumab every-6-weeks cohort. INTERPRETATION: In NSCLC,  first-line nivolumab plus ipilimumab had a tolerable safety profile and showed  encouraging clinical activity characterised by a high response rate and durable  response. To our knowledge, the results of this study are the first suggestion of  improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC,  supporting further assessment of this combination in a phase 3 study. FUNDING:  Bristol-Myers Squibb.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000848	27934619	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Fulminant type 1 diabetes mellitus, with a precipitous decrease in pancreatic volume	N/A	N/A	N/A	N/A	N/A	 2017 Apr 1	 A case of fulminant type 1 diabetes mellitus, with a precipitous decrease in  pancreatic volume, induced by nivolumab for malignant melanoma: analysis of HLA  and CTLA-4 polymorphisms.	 Eur J Dermatol	Unable to provide
CANIT0000849	27935080	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	New-onset antibody-positive myasthenia gravis	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 A case of new-onset antibody-positive myasthenia gravis in a patient treated with  pembrolizumab for melanoma.	 Muscle Nerve	Unable to provide
CANIT0000850	27939400	Clinical research	Cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	119	N/A	A single-arm, multicentre, phase II trial	Feasible treatment option and increasted respone in patients with high mutation load	Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2017 Jan 7	 Atezolizumab as first-line treatment in cisplatin-ineligible patients with  locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre,   phase 2 trial.	 Lancet	 BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible  locally advanced or metastatic urothelial carcinoma is associated with short  response duration, poor survival, and high toxicity. This study assessed  atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic  urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm,  multicentre, phase 2 study, in 47 academic medical centres and community oncology  practices in seven countries in North America and Europe, we recruited previously  untreated patients with locally advanced or metastatic urothelial cancer who were  cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every   21 days until progression. The primary endpoint was independently confirmed  objective response rate per Response Evaluation Criteria in Solid Tumors version   1.1 (central review), assessed in prespecified subgroups based on PD-L1  expression and in all patients. All participants who received one or more doses  of atezolizumab were included in the primary and safety analyses. This study was   registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9,  2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or  more doses of atezolizumab. At 17.2 months' median follow-up, the objective  response rate was 23% (95% CI 16 to 31), the complete response rate was 9%  (n=11), and 19 of 27 responses were ongoing. Median response duration was not  reached. Responses occurred across all PD-L1 and poor prognostic factor  subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median  overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load  was associated with response. Treatment-related adverse events that occurred in  10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%]  patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis)  occurred. Nine (8%) patients had an adverse event leading to treatment  discontinuation. Immune-mediated events occurred in 14 (12%) patients.  INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival,  and tolerability, supporting its therapeutic use in untreated metastatic  urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000851	27939400	Clinical research	Cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	119	N/A	A single-arm, multicentre, phase III trial	Feasible treatment option and increasted respone in patients with lower  PD-L1 status on immune cells	Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on immune cells	Gene expression signature on/in immune cell	 2017 Jan 7	 Atezolizumab as first-line treatment in cisplatin-ineligible patients with  locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre,   phase 2 trial.	 Lancet	 BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible  locally advanced or metastatic urothelial carcinoma is associated with short  response duration, poor survival, and high toxicity. This study assessed  atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic  urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm,  multicentre, phase 2 study, in 47 academic medical centres and community oncology  practices in seven countries in North America and Europe, we recruited previously  untreated patients with locally advanced or metastatic urothelial cancer who were  cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every   21 days until progression. The primary endpoint was independently confirmed  objective response rate per Response Evaluation Criteria in Solid Tumors version   1.1 (central review), assessed in prespecified subgroups based on PD-L1  expression and in all patients. All participants who received one or more doses  of atezolizumab were included in the primary and safety analyses. This study was   registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9,  2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or  more doses of atezolizumab. At 17.2 months' median follow-up, the objective  response rate was 23% (95% CI 16 to 31), the complete response rate was 9%  (n=11), and 19 of 27 responses were ongoing. Median response duration was not  reached. Responses occurred across all PD-L1 and poor prognostic factor  subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median  overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load  was associated with response. Treatment-related adverse events that occurred in  10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%]  patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis)  occurred. Nine (8%) patients had an adverse event leading to treatment  discontinuation. Immune-mediated events occurred in 14 (12%) patients.  INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival,  and tolerability, supporting its therapeutic use in untreated metastatic  urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000852	27943234	Case report	2 metastatic melanoma, 1 clear cell renal cell carcinoma metastatic to the lungs, liver, and pancreas, renal cell carcinoma metastatic to the lungs	Clear cell renal carcinoma	EFO:0000349	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	4	N/A	Case	Immune-related alopecia (areata and universalis)	Three patients (75%) had alopecia areata and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Immune-related alopecia (areata and universalis) in cancer patients receiving  immune checkpoint inhibitors.	 Br J Dermatol	 Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and  programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint  inhibitors), are used to treat various malignancies. Their mechanism of action  involves the inhibition of negative regulators of immune activation, resulting in  immune-related adverse events (irAEs) including endocrinopathies, pneumonitis,  colitis, hepatitis and dermatological events. Dermatological irAEs include  maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous  lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia  secondary to immune checkpoint inhibitors has been reported in 1.0-2.0% of  treated patients. Our objective is to characterize for the first time the  clinicopathology of patients with alopecia areata (AA) secondary to immune  checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced  AA, and review of the literature. Four cases of patients who developed partial or  complete alopecia during treatment with immune checkpoint inhibitors for  underlying cancer were identified from our clinics. Methods include the review of  the history and clinicopathologic features. Three patients (75%) had AA and one  had universalis. Two patients had a resolution after topical, oral or  intralesional therapies and one had a resolution after immunotherapy was  discontinued; all regrown hair exhibited poliosis. One of the four patients had  coincident onychodystrophy. This report describes a series of four patients who  developed partial or complete alopecia (i.e. areata and universalis) during  treatment with immune checkpoint inhibitor therapies for cancer. The recognition   and management of hair-related irAEs are important for pretherapy counselling and  interventions that contribute to maintaining optimal health-related quality of  life in patients.CI  - (c) 2016 British Association of Dermatologists.
CANIT0000853	27943234	Case report	2 metastatic melanoma, 1 clear cell renal cell carcinoma metastatic to the lungs, liver, and pancreas, renal cell carcinoma metastatic to the lungs	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	4	N/A	Case	Immune-related alopecia (areata and universalis)	Three patients (75%) had alopecia areata and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Immune-related alopecia (areata and universalis) in cancer patients receiving  immune checkpoint inhibitors.	 Br J Dermatol	 Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and  programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint  inhibitors), are used to treat various malignancies. Their mechanism of action  involves the inhibition of negative regulators of immune activation, resulting in  immune-related adverse events (irAEs) including endocrinopathies, pneumonitis,  colitis, hepatitis and dermatological events. Dermatological irAEs include  maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous  lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia  secondary to immune checkpoint inhibitors has been reported in 1.0-2.0% of  treated patients. Our objective is to characterize for the first time the  clinicopathology of patients with alopecia areata (AA) secondary to immune  checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced  AA, and review of the literature. Four cases of patients who developed partial or  complete alopecia during treatment with immune checkpoint inhibitors for  underlying cancer were identified from our clinics. Methods include the review of  the history and clinicopathologic features. Three patients (75%) had AA and one  had universalis. Two patients had a resolution after topical, oral or  intralesional therapies and one had a resolution after immunotherapy was  discontinued; all regrown hair exhibited poliosis. One of the four patients had  coincident onychodystrophy. This report describes a series of four patients who  developed partial or complete alopecia (i.e. areata and universalis) during  treatment with immune checkpoint inhibitor therapies for cancer. The recognition   and management of hair-related irAEs are important for pretherapy counselling and  interventions that contribute to maintaining optimal health-related quality of  life in patients.CI  - (c) 2016 British Association of Dermatologists.
CANIT0000854	27943234	Case report	2 metastatic melanoma, 1 clear cell renal cell carcinoma metastatic to the lungs, liver, and pancreas, renal cell carcinoma metastatic to the lungs	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	4	N/A	Case	Immune-related alopecia (areata and universalis)	Three patients (75%) had alopecia areata and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Immune-related alopecia (areata and universalis) in cancer patients receiving  immune checkpoint inhibitors.	 Br J Dermatol	 Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and  programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint  inhibitors), are used to treat various malignancies. Their mechanism of action  involves the inhibition of negative regulators of immune activation, resulting in  immune-related adverse events (irAEs) including endocrinopathies, pneumonitis,  colitis, hepatitis and dermatological events. Dermatological irAEs include  maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous  lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia  secondary to immune checkpoint inhibitors has been reported in 1.0-2.0% of  treated patients. Our objective is to characterize for the first time the  clinicopathology of patients with alopecia areata (AA) secondary to immune  checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced  AA, and review of the literature. Four cases of patients who developed partial or  complete alopecia during treatment with immune checkpoint inhibitors for  underlying cancer were identified from our clinics. Methods include the review of  the history and clinicopathologic features. Three patients (75%) had AA and one  had universalis. Two patients had a resolution after topical, oral or  intralesional therapies and one had a resolution after immunotherapy was  discontinued; all regrown hair exhibited poliosis. One of the four patients had  coincident onychodystrophy. This report describes a series of four patients who  developed partial or complete alopecia (i.e. areata and universalis) during  treatment with immune checkpoint inhibitor therapies for cancer. The recognition   and management of hair-related irAEs are important for pretherapy counselling and  interventions that contribute to maintaining optimal health-related quality of  life in patients.CI  - (c) 2016 British Association of Dermatologists.
CANIT0000855	27943234	Case report	2 metastatic melanoma, 1 clear cell renal cell carcinoma metastatic to the lungs, liver, and pancreas, renal cell carcinoma metastatic to the lungs	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	4	N/A	Case	Immune-related alopecia (areata and universalis)	Three patients (75%) had alopecia areata and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Immune-related alopecia (areata and universalis) in cancer patients receiving  immune checkpoint inhibitors.	 Br J Dermatol	 Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and  programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint  inhibitors), are used to treat various malignancies. Their mechanism of action  involves the inhibition of negative regulators of immune activation, resulting in  immune-related adverse events (irAEs) including endocrinopathies, pneumonitis,  colitis, hepatitis and dermatological events. Dermatological irAEs include  maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous  lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia  secondary to immune checkpoint inhibitors has been reported in 1.0-2.0% of  treated patients. Our objective is to characterize for the first time the  clinicopathology of patients with alopecia areata (AA) secondary to immune  checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced  AA, and review of the literature. Four cases of patients who developed partial or  complete alopecia during treatment with immune checkpoint inhibitors for  underlying cancer were identified from our clinics. Methods include the review of  the history and clinicopathologic features. Three patients (75%) had AA and one  had universalis. Two patients had a resolution after topical, oral or  intralesional therapies and one had a resolution after immunotherapy was  discontinued; all regrown hair exhibited poliosis. One of the four patients had  coincident onychodystrophy. This report describes a series of four patients who  developed partial or complete alopecia (i.e. areata and universalis) during  treatment with immune checkpoint inhibitor therapies for cancer. The recognition   and management of hair-related irAEs are important for pretherapy counselling and  interventions that contribute to maintaining optimal health-related quality of  life in patients.CI  - (c) 2016 British Association of Dermatologists.
CANIT0000856	27943234	Case report	2 metastatic melanoma, 1 clear cell renal cell carcinoma metastatic to the lungs, liver, and pancreas, renal cell carcinoma metastatic to the lungs	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	4	N/A	Case	Immune-related alopecia (areata and universalis)	Three patients (75%) had alopecia areata and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Immune-related alopecia (areata and universalis) in cancer patients receiving  immune checkpoint inhibitors.	 Br J Dermatol	 Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and  programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint  inhibitors), are used to treat various malignancies. Their mechanism of action  involves the inhibition of negative regulators of immune activation, resulting in  immune-related adverse events (irAEs) including endocrinopathies, pneumonitis,  colitis, hepatitis and dermatological events. Dermatological irAEs include  maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous  lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia  secondary to immune checkpoint inhibitors has been reported in 1.0-2.0% of  treated patients. Our objective is to characterize for the first time the  clinicopathology of patients with alopecia areata (AA) secondary to immune  checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced  AA, and review of the literature. Four cases of patients who developed partial or  complete alopecia during treatment with immune checkpoint inhibitors for  underlying cancer were identified from our clinics. Methods include the review of  the history and clinicopathologic features. Three patients (75%) had AA and one  had universalis. Two patients had a resolution after topical, oral or  intralesional therapies and one had a resolution after immunotherapy was  discontinued; all regrown hair exhibited poliosis. One of the four patients had  coincident onychodystrophy. This report describes a series of four patients who  developed partial or complete alopecia (i.e. areata and universalis) during  treatment with immune checkpoint inhibitor therapies for cancer. The recognition   and management of hair-related irAEs are important for pretherapy counselling and  interventions that contribute to maintaining optimal health-related quality of  life in patients.CI  - (c) 2016 British Association of Dermatologists.
CANIT0000857	27943234	Case report	2 metastatic melanoma, 1 clear cell renal cell carcinoma metastatic to the lungs, liver, and pancreas, renal cell carcinoma metastatic to the lungs	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	4	N/A	Case	Immune-related alopecia (areata and universalis)	Three patients (75%) had alopecia areata and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Immune-related alopecia (areata and universalis) in cancer patients receiving  immune checkpoint inhibitors.	 Br J Dermatol	 Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and  programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint  inhibitors), are used to treat various malignancies. Their mechanism of action  involves the inhibition of negative regulators of immune activation, resulting in  immune-related adverse events (irAEs) including endocrinopathies, pneumonitis,  colitis, hepatitis and dermatological events. Dermatological irAEs include  maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous  lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia  secondary to immune checkpoint inhibitors has been reported in 1.0-2.0% of  treated patients. Our objective is to characterize for the first time the  clinicopathology of patients with alopecia areata (AA) secondary to immune  checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced  AA, and review of the literature. Four cases of patients who developed partial or  complete alopecia during treatment with immune checkpoint inhibitors for  underlying cancer were identified from our clinics. Methods include the review of  the history and clinicopathologic features. Three patients (75%) had AA and one  had universalis. Two patients had a resolution after topical, oral or  intralesional therapies and one had a resolution after immunotherapy was  discontinued; all regrown hair exhibited poliosis. One of the four patients had  coincident onychodystrophy. This report describes a series of four patients who  developed partial or complete alopecia (i.e. areata and universalis) during  treatment with immune checkpoint inhibitor therapies for cancer. The recognition   and management of hair-related irAEs are important for pretherapy counselling and  interventions that contribute to maintaining optimal health-related quality of  life in patients.CI  - (c) 2016 British Association of Dermatologists.
CANIT0000858	27965309	Clinical research	 head and neck cancer	Head and neck carcinoma	MONDO:0002038	Head and neck	TRAILR2 (O14763); 	TRAILR2; 	DS-8273a	N/A	Immune checkpoint therapy	DS-8273a (NCIT:C121158); 	16	12	A phase I clinical trial	Targeting TRAIL-R2 resulted in  elimination of different populations of MDSCs without affecting mature myeloid or  lymphoid cells. These data support the use of this antibody in combination  immmunotherapy of cancer.	Only mild to moderate adverse events	N/A	N/A	N/A	N/A	N/A	 2017 Jun 15	 Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using   DS-8273a, an Agonistic TRAIL-R2 Antibody.	 Clin Cancer Res	 Purpose: Myeloid-derived suppressor cells (MDSC) are one of the major  contributors to immune suppression in cancer. We recently have demonstrated in  preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2)  agonist. The goal of this study was to clinically test the hypothesis that  targeting TRAIL-R2 can selectively eliminate MDSCs.Experimental Design: The  TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with  advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was  administered intravenously once every 3 weeks till disease progression,  unacceptable toxicities, or withdrawal of consent. The safety and the presence of  various populations of myeloid and lymphoid cells in peripheral blood and tumor  tissues were evaluated.Results: The treatment was well tolerated with only mild  to moderate adverse events attributable to the study drug. Treatment with  DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral  blood of most patients to the levels observed in healthy volunteers. However, in   several patients, MDSCs rebounded back to the pretreatment level by day 42. In  contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other  populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated  with the length of progression-free survival. In tumors, DS-8273a treatment  resulted in a decrease of MDSCs in 50% of the patients who were able to provide  pre- and on-treatment biopsies.Conclusions: Targeting TRAIL-R2 resulted in  elimination of different populations of MDSCs without affecting mature myeloid or  lymphoid cells. These data support the use of this antibody in combination  immmunotherapy of cancer. Clin Cancer Res; 23(12); 2942-50. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000859	27977496	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Third-degree atrioventricular block	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 New-onset third-degree atrioventricular block because of autoimmune-induced  myositis under treatment with anti-programmed cell death-1 (nivolumab) for  metastatic melanoma.	 Melanoma Res	 There has been considerable progress in treating malignant melanoma over the last  few years. The immune-checkpoint-inhibitors nivolumab and pembrolizumab have been  approved by the Food and Drug Administration in 2014 for the therapy of  metastatic melanoma. Anti-programmed cell death-1-blocking antibodies are known  to cause immune-related adverse events. Physicians should be aware of common and   rare side effects and pay attention to new ones. We therefore report a severe and  life-threatening side effect of anti-programmed cell death-1 immunotherapy with  nivolumab that has not been previously reported: the development of a  third-degree atrioventricular block. After a second infusion with nivolumab, our   patient developed a troponin I-positive and autoantibody-positive myositis and a   few days later a new-onset third-degree atrioventricular block. This is most  likely because of an autoimmune-induced myositis with a cardiac impairment in  terms of a myocarditis, which led to an impairment of the conduction of cardiac  electrical stimuli.
CANIT0000860	27979383	Clinical research	Previously treated non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Docetaxel	Immune checkpoint therapy	Docetaxel (DB01248); atezolizumab (DB11595); 	425	425	A phase III, open-label, multicentre randomised controlled trial	OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting  in a clinically relevant improvement of overall survival versus docetaxel in  previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile.	Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients).	N/A	N/A	N/A	N/A	N/A	 2017 Jan 21	 Atezolizumab versus docetaxel in patients with previously treated non-small-cell   lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled  trial.	 Lancet	 BACKGROUND: Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1)  monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1  and B7-1 interactions, reinvigorating anticancer immunity. We assessed its  efficacy and safety versus docetaxel in previously treated patients with  non-small-cell lung cancer. METHODS: We did a randomised, open-label, phase 3  trial (OAK) in 194 academic or community oncology centres in 31 countries. We  enrolled patients who had squamous or non-squamous non-small-cell lung cancer,  were 18 years or older, had measurable disease per Response Evaluation Criteria  in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status  of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy  regimens (one or more platinum based combination therapies) for stage IIIB or IV   non-small-cell lung cancer. Patients with a history of autoimmune disease and  those who had received previous treatments with docetaxel, CD137 agonists,  anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded.  Patients were randomly assigned (1:1) to intravenously receive either  atezolizumab 1200 mg or docetaxel 75 mg/m(2) every 3 weeks by permuted block  randomisation (block size of eight) via an interactive voice or web response  system. Coprimary endpoints were overall survival in the intention-to-treat (ITT)  and PD-L1-expression population TC1/2/3 or IC1/2/3 (>/=1% PD-L1 on tumour cells  or tumour-infiltrating immune cells). The primary efficacy analysis was done in  the first 850 of 1225 enrolled patients. This study is registered with  ClinicalTrials.gov, number NCT02008227. FINDINGS: Between March 11, 2014, and  April 29, 2015, 1225 patients were recruited. In the primary population, 425  patients were randomly assigned to receive atezolizumab and 425 patients were  assigned to receive docetaxel. Overall survival was significantly longer with  atezolizumab in the ITT and PD-L1-expression populations. In the ITT population,   overall survival was improved with atezolizumab compared with docetaxel (median  overall survival was 13.8 months [95% CI 11.8-15.7] vs 9.6 months [8.6-11.2];  hazard ratio [HR] 0.73 [95% CI 0.62-0.87], p=0.0003). Overall survival in the  TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared  with docetaxel (n=222; median overall survival was 15.7 months [95% CI 12.6-18.0]  with atezolizumab vs 10.3 months [8.8-12.0] with docetaxel; HR 0.74 [95% CI  0.58-0.93]; p=0.0102). Patients in the PD-L1 low or undetectable subgroup (TC0  and IC0) also had improved survival with atezolizumab (median overall survival  12.6 months vs 8.9 months; HR 0.75 [95% CI 0.59-0.96]). Overall survival  improvement was similar in patients with squamous (HR 0.73 [95% CI 0.54-0.98];  n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous  (0.73 [0.60-0.89]; n=313 and n=315) histology. Fewer patients had  treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609   patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related  death from a respiratory tract infection was reported in the docetaxel group.  INTERPRETATION: To our knowledge, OAK is the first randomised phase 3 study to  report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting  in a clinically relevant improvement of overall survival versus docetaxel in  previously treated non-small-cell lung cancer, regardless of PD-L1 expression or   histology, with a favourable safety profile. FUNDING: F. Hoffmann-La Roche Ltd,  Genentech, Inc.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000861	27981760	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	13	N/A	A retrospective cohort study	Despite treatment with infliximab a high proportion of patients do not achieve resolution of colitis. Review of these cases has highlighted the  absence of evidence-based guidelines to treat severe, steroid refractory colitis   secondary to ipilimumab.	Colitis	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Infliximab for ipilimumab-induced colitis: A series of 13 patients.	 Asia Pac J Clin Oncol	 OBJECTIVE: To review the outcomes of metastatic melanoma patients treated with  infliximab for severe steroid-refractory colitis secondary to ipilimumab therapy.  BACKGROUND: Immune-related colitis is a known potential adverse effect of  ipilimumab, that causes significant morbidity and extended hospital stays. There   are limited outcome data for patients treated with infliximab for  ipilimumab-induced colitis refractory to corticosteroids. Management guidelines  have been developed based on case study evidence only. DESIGN AND SETTING: A  retrospective review of all patients administered infliximab for  ipilimumab-induced colitis at South Australian public hospitals between October  2011 and April 2015. MAIN OUTCOME MEASURES: Resolution of colitis/diarrhea,  duration of hospital stay, dosage regimen of infliximab used (single dose vs  multiple dose) and surgical intervention if required. RESULTS: Between October  2011 and April 2015, 106 patients were dispensed ipilimumab from South Australian  public hospitals for the treatment of metastatic melanoma. Thirteen were  administered infliximab for severe, steroid-refractory colitis secondary to  ipilimumab. Sixty-two percent received a single dose of infliximab only. Four  patients achieved resolution of colitis symptoms at 1 month postinfliximab.  Thirty-three percent required surgical intervention despite treatment with  infliximab. One patient declined surgery and subsequently died due to bowel  perforation. The average number of overnight bed days due to colitis was 27.  CONCLUSION: This series of patients with severe ipilimumab-induced colitis  suggests that despite treatment with infliximab a high proportion of patients do   not achieve resolution of symptoms. Review of these cases has highlighted the  absence of evidence-based guidelines to treat severe, steroid refractory colitis   secondary to ipilimumab. Further prospective studies may clarify the role of  infliximab for the treatment of ipilimumab-induced colitis.CI  - (c) 2016 John Wiley & Sons Australia, Ltd.
CANIT0000862	27987584	Case report	Unresectable squamous non-small cell lung cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Corneal graft rejection	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Corneal graft rejection in a patient treated with nivolumab for primary lung  cancer.	 Lung Cancer	 We report the case of a 58-year-old woman treated with nivolumab for an  unresectable squamous non-small cell lung cancer, after first-line cisplatin and   gemcitabine combination chemotherapy. This woman had a history of left corneal  graft. After 9 cycles of nivolumab, the patient described decreased visual acuity  in the left eye with watering and conjunctival erythema. Ophthalmological  examination revealed chronic corneal graft rejection. The patient was then  treated with an intravenous bolus of corticosteroids (500mg of  methylprednisolone) for 3 days, followed by oral prednisone for 4 weeks and  subconjunctival corticosteroid injections every 48h, while treatment with  nivolumab was discontinued. No clinical benefit was observed 4 weeks later and  the corneal graft became totally unfunctional despite of the therapy. We  hypothesise that the treatment was started too late. To our knowledge, this is  the first reported case of corneal graft rejection related to nivolumab.CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
CANIT0000863	27987588	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	Pseudoprogression	N/A	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Report of two cases of pseudoprogression in patients with non-small cell lung  cancer treated with nivolumab-including histological analysis of one case after  tumor regression.	 Lung Cancer	 The recent approval of nivolumab and other immune-checkpoint inhibitors for the  treatment of certain solid tumors including non-small cell lung cancer (NSCLC)  has transformed cancer therapy. However, it will be important to characterize  effects of such agents not seen with classical cytotoxic drugs or other targeted   therapeutics. We here report two cases of NSCLC showing so-called  pseudoprogression during nivolumab treatment. In both cases, imaging assessment  revealed that liver metastatic lesions initially progressed but subsequently  shrank during continuous nivolumab administration, with treatment also resulting   in a decline in serum levels of carcinoembryonic antigen. Histological evaluation  of the liver metastatic lesion of one case after regression revealed fibrotic  tissue containing infiltrated lymphocytes positive for CD3, CD4, or CD8 but no  viable tumor cells, suggestive of a durable immune reaction even after a  pathological complete response. Given the increasing use of immune-checkpoint  inhibitors in patients with NSCLC or other solid tumors, further clinical  evaluation and pathological assessment are warranted to provide a better  understanding of such pseudoprogression.CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
CANIT0000864	27992901	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	This is the first reported case of a patient with cancer who had a nivolumab-induced clinical recurrence of a previously diagnosed autoimmune disorder that was successfully treated with corticosteroids without discontinuation of the culprit drug.	Recurrence of rheumatoid arthritis	N/A	N/A	N/A	N/A	N/A	 2016 Dec 20	 Nivolumab-Induced Recurrence of Rheumatoid Arthritis in a Patient With Advanced  Non-Small Cell Lung Cancer: A Case Report.	 Ann Intern Med	Unable to provide
CANIT0000865	27998967	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	51	N/A	N/A	Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.	Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic.	N/A	N/A	Autoimmune thyroid dysfunction (NCIT:C91510); 	Thyroid dysfunction	Disease status	 2017 Mar 1	 Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in  patients with non-small-cell lung cancer.	 Ann Oncol	 Background: Programmed cell death protein-1 (PD-1) blockade therapies have  demonstrated durable responses and prolonged survival in a variety of  malignancies. Treatment is generally well tolerated although immune-related  adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the  most common irAE, but an assessment of the clinical, mechanistic, and immunologic  features has not been previously described. Patient and methods: Patients with  advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at  Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001  (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies  were assessed prospectively at each study visit, beginning before the first  treatment. Frequency of development of thyroid dysfunction, association with  anti-thyroid antibodies, clinical course, and relationship with progression-free   survival and overall survival to treatment with pembrolizumab was evaluated.  Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline.   Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed  thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were  present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of  38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early  (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients)   experienced brief, transient hyperthyroidism preceding the onset of  hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and   hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was  significantly longer in subjects who developed thyroid dysfunction (hazard ratio,  0.29; 95% CI 0.09-0.94; P = 0.04). Conclusions: Thyroid dysfunction during  pembrolizumab treatment of NSCLC is common and is characterized by early-onset,  frequently preceded by transient hyperthyroidism, closely associated with  anti-thyroid antibodies, and may be associated with improved outcomes. The  presence of antibody-mediated toxicity in T-cell-directed therapy suggests an  under-recognized impact of PD-1 biology in modulating humoral immunity.CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For Permissions,  please email: journals.permissions@oup.com.
CANIT0000866	28000240	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Epidermal programmed cell death-ligand 1 expression in fatal toxic epidermal necrolysis (TEN) eruption	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Epidermal programmed cell death-ligand 1 expression in TEN associated with  nivolumab therapy.	 J Cutan Pathol	 Nivolumab is a programmed cell death receptor-1 (PD-1) antibody used in the  treatment of metastatic or unresectable melanoma. Cutaneous reactions are the  most common adverse events reported with these agents and are rarely severe or  life-threatening. Here we present a case report describing the  clinicopathological findings of a patient with a fatal toxic epidermal necrolysis  (TEN) eruption associated with use of nivolumab for treatment of metastatic  melanoma. The patient developed a pruritic, morbiliform eruption, which slowly  progressed over 3 months to a tender, exfoliative dermatosis. Histology initially  showed interface dermatitis and subsequently revealed full thickness epidermal  necrosis. The diagnosis of TEN was made. From initial biopsy to TEN presentation,  there was an increase in the number of CD8+ lymphocytes within the  dermal-epidermal junction and an increase of programmed death ligand 1 (PD-L1)  expression in both lymphocytes and keratinocytes. Despite treatment with  infliximab, high-dose steroids and intravenous immunoglobulin, the patient  expired. Herein we describe what we believe is the second case of TEN associated   with anti-PD1 therapy reported in the literature. Increased expression of PD-L1  by immunohistochemistry was observed as the eruption progressed to TEN. Early  diagnosis and treatment is necessary in these fatal TEN reactions secondary to  the anti-PD-1 antibody therapies.CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0000867	28000537	Case report	Glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Severe liver-injury	Severe liver-injury	N/A	N/A	N/A	N/A	N/A	 2016 Dec	 Pathological characterization of nivolumab-related liver injury in a patient with  glioblastoma.	 Immunotherapy	 Immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal  antibodies have dramatically changed the paradigm of cancer therapy over the past  few years. The use of these agents is associated with a unique pattern of  autoimmune-like/inflammatory side effects termed immune-related adverse events  (irAEs), that may cause collateral damage to normal tissues. Although severe  irAEs remain rare, they can become life-threatening if not anticipated and  managed appropriately. Improving our knowledge of the mechanisms underlying the  development of these toxicities is crucial to optimize clinical efficacy and  safety of these new immunotherapeutics. Herein we describe for the first time the  pathological features of a severe liver-injury associated with the administration  of the anti-PD-1 agent nivolumab in a patient with glioblastoma.
CANIT0000868	28003187	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	134	N/A	N/A	Serum ANGPT2 may be considered as a  predictive and prognostic biomarker for immune checkpoint therapy and may  contribute to treatment resistance via increasing proangiogenic and  immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2  provides a rational combinatorial approach to improve the efficacy of immune  therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	ANGPT2 (O15123); 	Serum ANGPT2 levels	Gene expression signature in serum	 2017 Jan	 Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.	 Cancer Immunol Res	 Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in  cancer treatment. However, the identification of biomarkers for predicting  clinical outcomes and mechanisms to overcome resistance remain as critical needs.  Angiogenesis is increasingly appreciated as an immune modulator with potential  for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an  immune target in patients and is involved in resistance to anti-VEGF treatment  with the monoclonal antibody bevacizumab. We investigated the predictive and  prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving   immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with  reduced overall survival in CTLA-4 and PD-1 blockade-treated patients. These  treatments also increased serum ANGPT2 in many patients early after treatment  initiation, whereas ipilimumab plus bevacizumab treatment decreased serum  concentrations. ANGPT2 increases were associated with reduced response and/or  overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab  decreased, tumor vascular ANGPT2 expression in a subset of patients, which was  associated with increased and decreased tumor infiltration by CD68(+) and  CD163(+) macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced  ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased  PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting  and functional antibody responses to ANGPT2 in a subset of patients receiving  clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a  predictive and prognostic biomarker for immune checkpoint therapy and may  contribute to treatment resistance via increasing proangiogenic and  immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2  provides a rational combinatorial approach to improve the efficacy of immune  therapy. Cancer Immunol Res; 5(1); 17-28. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000869	28003187	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); VEGF (P15692); 	CTLA-4; VEGF	Ipilimumab plus bevacizumab	N/A	Immune checkpoint therapy plus Target therapy	Bevacizumab (DB00112); ipilimumab (DB06186); 	134	N/A	N/A	Serum ANGPT2 may be considered as a  predictive and prognostic biomarker for immune checkpoint therapy and may  contribute to treatment resistance via increasing proangiogenic and  immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2  provides a rational combinatorial approach to improve the efficacy of immune  therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	ANGPT2 (O15123); 	Serum ANGPT2 levels	Gene expression signature in serum	 2017 Jan	 Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.	 Cancer Immunol Res	 Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in  cancer treatment. However, the identification of biomarkers for predicting  clinical outcomes and mechanisms to overcome resistance remain as critical needs.  Angiogenesis is increasingly appreciated as an immune modulator with potential  for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an  immune target in patients and is involved in resistance to anti-VEGF treatment  with the monoclonal antibody bevacizumab. We investigated the predictive and  prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving   immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with  reduced overall survival in CTLA-4 and PD-1 blockade-treated patients. These  treatments also increased serum ANGPT2 in many patients early after treatment  initiation, whereas ipilimumab plus bevacizumab treatment decreased serum  concentrations. ANGPT2 increases were associated with reduced response and/or  overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab  decreased, tumor vascular ANGPT2 expression in a subset of patients, which was  associated with increased and decreased tumor infiltration by CD68(+) and  CD163(+) macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced  ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased  PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting  and functional antibody responses to ANGPT2 in a subset of patients receiving  clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a  predictive and prognostic biomarker for immune checkpoint therapy and may  contribute to treatment resistance via increasing proangiogenic and  immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2  provides a rational combinatorial approach to improve the efficacy of immune  therapy. Cancer Immunol Res; 5(1); 17-28. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000870	28003187	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	134	N/A	N/A	Serum ANGPT2 may be considered as a  predictive and prognostic biomarker for immune checkpoint therapy and may  contribute to treatment resistance via increasing proangiogenic and  immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2  provides a rational combinatorial approach to improve the efficacy of immune  therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	ANGPT2 (O15123); 	Serum ANGPT2 levels	Gene expression signature in serum	 2017 Jan	 Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.	 Cancer Immunol Res	 Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in  cancer treatment. However, the identification of biomarkers for predicting  clinical outcomes and mechanisms to overcome resistance remain as critical needs.  Angiogenesis is increasingly appreciated as an immune modulator with potential  for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an  immune target in patients and is involved in resistance to anti-VEGF treatment  with the monoclonal antibody bevacizumab. We investigated the predictive and  prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving   immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with  reduced overall survival in CTLA-4 and PD-1 blockade-treated patients. These  treatments also increased serum ANGPT2 in many patients early after treatment  initiation, whereas ipilimumab plus bevacizumab treatment decreased serum  concentrations. ANGPT2 increases were associated with reduced response and/or  overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab  decreased, tumor vascular ANGPT2 expression in a subset of patients, which was  associated with increased and decreased tumor infiltration by CD68(+) and  CD163(+) macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced  ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased  PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting  and functional antibody responses to ANGPT2 in a subset of patients receiving  clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a  predictive and prognostic biomarker for immune checkpoint therapy and may  contribute to treatment resistance via increasing proangiogenic and  immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2  provides a rational combinatorial approach to improve the efficacy of immune  therapy. Cancer Immunol Res; 5(1); 17-28. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000871	28007774	Clinical research	Gastrointestinal stromal tumor (GIST) and other sarcomas	Gastrointestinal stromal tumor	Orphanet:44890	Stomach	CTLA-4 (P16410); C-KIT (P10721); 	CTLA-4; C-KIT	Dasatinib plus Ipilimumab	N/A	Immune checkpoint therapy plus Target therapy	Ipilimumab (DB06186); dasatinib (DB01254); 	28	N/A	A phase Ib study	Dasatinib and ipilimumab can be safely administered to GIST and sarcoma patients. However, dasatinib was not synergistic with  ipilimumab, as there was limited clinical efficacy with the combination. This  limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST. Given the small cohort, it is only hypothesis generating and additional data would be required.	Dose-limiting toxicities included grade 3 gastric hemorrhage and anemia.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 15	 Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other  Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab.	 Clin Cancer Res	 Purpose: A phase Ib study of dasatinib plus ipilimumab in patients with  gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the  basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is   synergistic.Experimental Design: A standard 3 + 3 design was used to evaluate the  safety, efficacy, and immune correlates of treatment. Dose escalation cohorts  received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12  weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg  twice daily). Response was assessed by RECIST 1.1, Choi, and immune-related  RECIST criteria (irRC).Results: A total of 28 patients (17 male) were enrolled.  Histologic subtypes included GISTs (n = 20) and other sarcomas (n = 8.) Dasatinib  70 mg/day with ipilimumab 10 mg/kg or dasatinib 140 mg/day with ipilimumab 3  mg/kg can be safely administered. Dose-limiting toxicities included grade 3  gastric hemorrhage and anemia. No partial or complete responses were noted by  RECIST or irRC. There were 7 of 13 partial responses in the GIST patients by Choi  criteria, and 3 of 13 patients each had stable and progressive disease,  respectively.Conclusions: Dasatinib and ipilimumab can be safely administered to   GIST and sarcoma patients. However, dasatinib was not synergistic with  ipilimumab, as there was limited clinical efficacy with the combination. This  limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO)  suppression may potentially correlate with antitumor efficacy in GIST. Given the   small cohort, it is only hypothesis generating and additional data would be  required. In the era of more modern and effective checkpoint inhibitors, next  steps could be consideration of tyrosine kinase inhibitors or IDO inhibitors in  combination with anti-PD-1 therapy. Clin Cancer Res; 23(12); 2972-80. (c)2016  AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000872	28008452	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); IL2R (A2N4P8); 	CTLA-4; IL2R	Ipilimumab plus intratumoral IL2	N/A	Immune checkpoint therapy plus Immune cytokine	IL2 (NCIT:C24498); ipilimumab (DB06186); 	15	N/A	A phase II clinical trial	Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.	Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated  patients with stage IV melanoma-safety and efficacy in a phase II study.	 Cancer Immunol Immunother	 Treatment of advanced melanoma patients with ipilimumab results in improved  survival. However, only about 20% of treated patients experience long-term  benefit. Combining treatment of ipilimumab with other drugs may improve immune  activation and potentially enhance clinical efficacy. The aims of the phase II  clinical trial reported here were to investigate tolerability and efficacy of a  combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3   mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU  daily twice weekly for four weeks in pretreated melanoma patients with distant  metastasis. The primary endpoint was the disease control rate according to  immune-related response criteria at week 12; tolerability according to Common  Terminology Criteria for Adverse Events criteria was secondary endpoint. No  objective responses were observed in the 15 enrolled patients. Three patients had  stable disease 12 weeks after starting treatment, yielding a disease control rate  of 20%. Tolerability of this combination treatment was acceptable. Observed  adverse events were those expected from the respective monotherapies. Autoimmune   colitis was observed in two patients. Grade III/IV adverse events were observed  in 40% of patients, and no treatment-related deaths occurred. Thus, this combined  immunotherapy is associated with adverse events similar to those associated with   the respective monotherapies. However, this study does not provide any evidence  of improved efficacy of the combination over ipilimumab alone.
CANIT0000873	28017788	Case report	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	Association of Serum Anti-GAD Antibody and HLA Haplotypes with Type 1 Diabetes Mellitus Triggered by Nivolumab in Patients with Non-Small Cell Lung Cancer	Type 1 Diabetes Mellitus	N/A	N/A	N/A	N/A	N/A	 2017 May	 Association of Serum Anti-GAD Antibody and HLA Haplotypes with Type 1 Diabetes  Mellitus Triggered by Nivolumab in Patients with Non-Small Cell Lung Cancer.	 J Thorac Oncol	Unable to provide
CANIT0000874	28028828	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	143	N/A	N/A	Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.	Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 130% treated with a programmed death receptor-1 (PD-1) inhibitor and 222% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 130% treated with a PD-1 inhibitor, 159% following a PD-1 inhibitor, and 222% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 230% following ipilimumab, 391% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and  programmed death receptor protein-1 inhibitors in the treatment of melanoma.	 Clin Endocrinol (Oxf)	 CONTEXT: Checkpoint inhibitors are emerging as important cancer therapies but are  associated with a high rate of immune side effects, including endocrinopathy.  OBJECTIVE: To determine the burden of thyroid dysfunction in patients with  melanoma treated with immune checkpoint inhibitors and describe the clinical  course. DESIGN AND PATIENTS: Consecutive patients with melanoma treated with  either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and   nivolumab were identified. Baseline thyroid function tests were used to exclude  those with pre-existing thyroid abnormalities, and thyroid function tests during   treatment used to identify those with thyroid dysfunction. RESULTS: Rates of  overt thyroid dysfunction were in keeping with the published phase 3 trials.  Hypothyroidism occurred in 13.0% treated with a programmed death receptor-1  (PD-1) inhibitor and 22.2% with a combination of PD-1 inhibitor and ipilimumab.  Transient subclinical hyperthyroidism was observed in 13.0% treated with a PD-1  inhibitor, 15.9% following a PD-1 inhibitor, and 22.2% following combination  treatment with investigations suggesting a thyroiditic mechanism rather than  Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid  abnormality occurred in 23.0% following ipilimumab, 39.1% following a PD-1  inhibitor and 50% following combination treatment. Abnormal thyroid function was   more common in female patients. CONCLUSION: Thyroid dysfunction occurs commonly  in patients with melanoma treated with immune checkpoint inhibitors, with rates,   including subclinical dysfunction, occurring in up to 50%.CI  - (c) 2016 John Wiley & Sons Ltd.
CANIT0000875	28028828	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	143	N/A	N/A	Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.	Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 130% treated with a programmed death receptor-1 (PD-1) inhibitor and 222% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 130% treated with a PD-1 inhibitor, 159% following a PD-1 inhibitor, and 222% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 230% following ipilimumab, 391% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and  programmed death receptor protein-1 inhibitors in the treatment of melanoma.	 Clin Endocrinol (Oxf)	 CONTEXT: Checkpoint inhibitors are emerging as important cancer therapies but are  associated with a high rate of immune side effects, including endocrinopathy.  OBJECTIVE: To determine the burden of thyroid dysfunction in patients with  melanoma treated with immune checkpoint inhibitors and describe the clinical  course. DESIGN AND PATIENTS: Consecutive patients with melanoma treated with  either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and   nivolumab were identified. Baseline thyroid function tests were used to exclude  those with pre-existing thyroid abnormalities, and thyroid function tests during   treatment used to identify those with thyroid dysfunction. RESULTS: Rates of  overt thyroid dysfunction were in keeping with the published phase 3 trials.  Hypothyroidism occurred in 13.0% treated with a programmed death receptor-1  (PD-1) inhibitor and 22.2% with a combination of PD-1 inhibitor and ipilimumab.  Transient subclinical hyperthyroidism was observed in 13.0% treated with a PD-1  inhibitor, 15.9% following a PD-1 inhibitor, and 22.2% following combination  treatment with investigations suggesting a thyroiditic mechanism rather than  Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid  abnormality occurred in 23.0% following ipilimumab, 39.1% following a PD-1  inhibitor and 50% following combination treatment. Abnormal thyroid function was   more common in female patients. CONCLUSION: Thyroid dysfunction occurs commonly  in patients with melanoma treated with immune checkpoint inhibitors, with rates,   including subclinical dysfunction, occurring in up to 50%.CI  - (c) 2016 John Wiley & Sons Ltd.
CANIT0000876	28028828	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	143	N/A	N/A	Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.	Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 130% treated with a programmed death receptor-1 (PD-1) inhibitor and 222% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 130% treated with a PD-1 inhibitor, 159% following a PD-1 inhibitor, and 222% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 230% following ipilimumab, 391% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and  programmed death receptor protein-1 inhibitors in the treatment of melanoma.	 Clin Endocrinol (Oxf)	 CONTEXT: Checkpoint inhibitors are emerging as important cancer therapies but are  associated with a high rate of immune side effects, including endocrinopathy.  OBJECTIVE: To determine the burden of thyroid dysfunction in patients with  melanoma treated with immune checkpoint inhibitors and describe the clinical  course. DESIGN AND PATIENTS: Consecutive patients with melanoma treated with  either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and   nivolumab were identified. Baseline thyroid function tests were used to exclude  those with pre-existing thyroid abnormalities, and thyroid function tests during   treatment used to identify those with thyroid dysfunction. RESULTS: Rates of  overt thyroid dysfunction were in keeping with the published phase 3 trials.  Hypothyroidism occurred in 13.0% treated with a programmed death receptor-1  (PD-1) inhibitor and 22.2% with a combination of PD-1 inhibitor and ipilimumab.  Transient subclinical hyperthyroidism was observed in 13.0% treated with a PD-1  inhibitor, 15.9% following a PD-1 inhibitor, and 22.2% following combination  treatment with investigations suggesting a thyroiditic mechanism rather than  Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid  abnormality occurred in 23.0% following ipilimumab, 39.1% following a PD-1  inhibitor and 50% following combination treatment. Abnormal thyroid function was   more common in female patients. CONCLUSION: Thyroid dysfunction occurs commonly  in patients with melanoma treated with immune checkpoint inhibitors, with rates,   including subclinical dysfunction, occurring in up to 50%.CI  - (c) 2016 John Wiley & Sons Ltd.
CANIT0000877	28028828	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	143	N/A	N/A	Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.	Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 130% treated with a programmed death receptor-1 (PD-1) inhibitor and 222% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 130% treated with a PD-1 inhibitor, 159% following a PD-1 inhibitor, and 222% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 230% following ipilimumab, 391% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and  programmed death receptor protein-1 inhibitors in the treatment of melanoma.	 Clin Endocrinol (Oxf)	 CONTEXT: Checkpoint inhibitors are emerging as important cancer therapies but are  associated with a high rate of immune side effects, including endocrinopathy.  OBJECTIVE: To determine the burden of thyroid dysfunction in patients with  melanoma treated with immune checkpoint inhibitors and describe the clinical  course. DESIGN AND PATIENTS: Consecutive patients with melanoma treated with  either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and   nivolumab were identified. Baseline thyroid function tests were used to exclude  those with pre-existing thyroid abnormalities, and thyroid function tests during   treatment used to identify those with thyroid dysfunction. RESULTS: Rates of  overt thyroid dysfunction were in keeping with the published phase 3 trials.  Hypothyroidism occurred in 13.0% treated with a programmed death receptor-1  (PD-1) inhibitor and 22.2% with a combination of PD-1 inhibitor and ipilimumab.  Transient subclinical hyperthyroidism was observed in 13.0% treated with a PD-1  inhibitor, 15.9% following a PD-1 inhibitor, and 22.2% following combination  treatment with investigations suggesting a thyroiditic mechanism rather than  Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid  abnormality occurred in 23.0% following ipilimumab, 39.1% following a PD-1  inhibitor and 50% following combination treatment. Abnormal thyroid function was   more common in female patients. CONCLUSION: Thyroid dysfunction occurs commonly  in patients with melanoma treated with immune checkpoint inhibitors, with rates,   including subclinical dysfunction, occurring in up to 50%.CI  - (c) 2016 John Wiley & Sons Ltd.
CANIT0000878	28031229	Basic research	Patients with metastatic castrate-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Basic research	Immune toxicities elicted by CTLA-4 blockade in cancer patients are associated with early diversification of the T cell repertoire	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-cell repertoire (NCIT:C129657); T-Lymphocyte (NCIT:C12476); 	Early diversification of the T-cell repertoire	Cell percentage/counts in blood	 2017 Mar 15	 Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated  with Early Diversification of the T-cell Repertoire.	 Cancer Res	 While immune checkpoint blockade elicits efficacious responses in many patients  with cancer, it also produces a diverse and unpredictable number of  immune-related adverse events (IRAE). Mechanisms driving IRAEs are generally  unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells,  we examined in this study whether ipilimumab treatment leads to clonal expansion   of tissue-reactive T cells. Rather than narrowing the T-cell repertoire to a  limited number of clones, ipilimumab induced greater diversification in the  T-cell repertoire in IRAE patients compared with patients without IRAEs.  Specifically, ipilimumab triggered increases in the numbers of clonotypes,  including newly detected clones and a decline in overall T-cell clonality.  Initial broadening in the repertoire occurred within 2 weeks of treatment,  preceding IRAE onset. IRAE patients exhibited greater diversity of CD4(+) and  CD8(+) T cells, but showed no differences in regulatory T-cell numbers relative  to patients without IRAEs. Prostate-specific antigen responses to ipilimumab were  also associated with increased T-cell diversity. Our results show how rapid  diversification in the immune repertoire immediately after checkpoint blockade  can be both detrimental and beneficial for patients with cancer. Cancer Res;  77(6); 1322-30. (c)2016 AACR.CI  - (c)2016 American Association for Cancer Research.
CANIT0000879	28034081	Clinical research	Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Placebo	Immune checkpoint therapy	Ipilimumab (DB06186); 	399	199	A multicenter, double-blind, phase III trial	Ipilimumab did not improve OS in patients with  metastatic castration-resistant prostate cancer. The observed increases in  progression-free survival and prostate-specific antigen response rates suggest  antitumor activity in a patient subset.	Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in  10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively.	N/A	N/A	Metastasis (NCIT:C19151); 	Metastatic castration-resistant	Disease status	 2017 Jan	 Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in  Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive  Castration-Resistant Prostate Cancer.	 J Clin Oncol	 Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic  T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or  minimally symptomatic patients with chemotherapy-naive metastatic  castration-resistant prostate cancer without visceral metastases. Patients and  Methods In this multicenter, double-blind, phase III trial, patients were  randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to  four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered  to nonprogressing patients every 3 months. The primary end point was overall  survival (OS). Results Four hundred patients were randomly assigned to ipilimumab  and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median  OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus  29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11;  95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6  months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67;  95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific   antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea  (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in   >/= 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the  ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo  arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients,  respectively. Conclusion Ipilimumab did not improve OS in patients with  metastatic castration-resistant prostate cancer. The observed increases in  progression-free survival and prostate-specific antigen response rates suggest  antitumor activity in a patient subset.
CANIT0000880	28040701	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	119	N/A	A retrospective cohort study	The application of the CTCAE, especially in grading independent lab values, should be considered carefully in clinical trials of novel immunotherapeutic agents.	Of the 119 patients, there were only two cases of pancreatitis, representing 20% of patients with grade 3 or higher amylase, 6.3% of patients with grade 3 or higher lipase, and 20% of patients with grade 3 or higher elevations of both enzymes.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Thinking Critically About Classifying Adverse Events: Incidence of Pancreatitis  in Patients Treated With Nivolumab + Ipilimumab.	 J Natl Cancer Inst	 The Common Terminology Criteria for Adverse Events (CTCAE) were developed to  document the adverse effects of chemotherapy but are now also used to document  immune-related adverse events (irAE). Characterization of irAE by the CTCAE has  implications for determining dose-limiting toxicity (DLT) and, consequently, the   recommended phase II dose (RP2D) of investigational agents. In the phase I trial   of nivolumab + ipilimumab, an asymptomatic increase in lipase was the primary DLT  that informed the RP2D. We performed a retrospective study of 119 patients with  melanoma who were treated at Memorial Sloan Kettering Cancer Center with the  combination of nivolumab + ipilimumab to investigate the relationship between  asymptomatic grade 3 or higher increases in amylase and/or lipase and  pancreatitis, a known irAE. Of the 119 patients, there were only two cases of  pancreatitis, representing 20% of patients with grade 3 or higher amylase, 6.3%  of patients with grade 3 or higher lipase, and 20% of patients with grade 3 or  higher elevations of both enzymes. The application of the CTCAE, especially in  grading independent lab values, should be considered carefully in clinical trials  of novel immunotherapeutic agents.CI  - (c) The Author 2016. Published by Oxford University Press. All rights reserved.  For Permissions, please email: journals.permissions@oup.com.
CANIT0000881	28050790	Clinical research	10 Colorectal cancer, 5 Sarcoma, 3 Breast cancer, 3 Pancreatic cancer, 2 Ovarian cancer, 2 Melanoma, 2 Liver cancer, 2 Head and Neck cancer	Breast cancer	MONDO:0007254	Breast	DR5 (O14763); 	DR5; 	DS-8273a	N/A	Immune checkpoint therapy	DS-8273a (NCIT:C121158); 	32	N/A	A phase I clinical trial 	DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure.	No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 First-in-human study of the antibody DR5 agonist DS-8273a in patients with  advanced solid tumors.	 Invest New Drugs	 Background DR5 is a transmembrane receptor that transduces extracellular  ligand-binding to activate apoptosis signaling cascades. This phase 1 study  evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics  of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with  advanced solid tumors. Methods The study comprised dose escalation and dose  expansion cohorts. The dose escalation cohorts intended to determine the safety  and to identify the maximum tolerated dose (MTD) or maximum administered dose  (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a  conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and  24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects  were treated at the MAD for further evaluation of PK and safety. Results Thirty  two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16   in the dose expansion cohort. No subjects experienced a dose limiting toxicity  (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14  (44%) of which were attributed to study-drug; all drug-related events were grade   1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.  Measures of plasma exposure increased dose-proportionally and the mean terminal  elimination half-life was 11 days. Blood samples available from a subset of  patients treated at 24 mg/kg revealed declines in myeloid derived suppressor  cells (MDSC) at 2 weeks. No objective responses were observed in any subjects.  Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics.  Decreases in MDSC were temporally associated with DS-8273a exposure. This agent  could be studied further in combination with other agents, pending further  proof-of-target-engagement.
CANIT0000882	28050790	Clinical research	10 Colorectal cancer, 5 Sarcoma, 3 Breast cancer, 3 Pancreatic cancer, 2 Ovarian cancer, 2 Melanoma, 2 Liver cancer, 2 Head and Neck cancer	Colorectal cancer	EFO:0005842	Intestines	DR5 (O14763); 	DR5; 	DS-8273a	N/A	Immune checkpoint therapy	DS-8273a (NCIT:C121158); 	32	N/A	A phase I clinical trial 	DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure.	No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 First-in-human study of the antibody DR5 agonist DS-8273a in patients with  advanced solid tumors.	 Invest New Drugs	 Background DR5 is a transmembrane receptor that transduces extracellular  ligand-binding to activate apoptosis signaling cascades. This phase 1 study  evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics  of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with  advanced solid tumors. Methods The study comprised dose escalation and dose  expansion cohorts. The dose escalation cohorts intended to determine the safety  and to identify the maximum tolerated dose (MTD) or maximum administered dose  (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a  conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and  24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects  were treated at the MAD for further evaluation of PK and safety. Results Thirty  two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16   in the dose expansion cohort. No subjects experienced a dose limiting toxicity  (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14  (44%) of which were attributed to study-drug; all drug-related events were grade   1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.  Measures of plasma exposure increased dose-proportionally and the mean terminal  elimination half-life was 11 days. Blood samples available from a subset of  patients treated at 24 mg/kg revealed declines in myeloid derived suppressor  cells (MDSC) at 2 weeks. No objective responses were observed in any subjects.  Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics.  Decreases in MDSC were temporally associated with DS-8273a exposure. This agent  could be studied further in combination with other agents, pending further  proof-of-target-engagement.
CANIT0000883	28050790	Clinical research	10 Colorectal cancer, 5 Sarcoma, 3 Breast cancer, 3 Pancreatic cancer, 2 Ovarian cancer, 2 Melanoma, 2 Liver cancer, 2 Head and Neck cancer	Head and neck carcinoma	MONDO:0002038	Head and neck	DR5 (O14763); 	DR5; 	DS-8273a	N/A	Immune checkpoint therapy	DS-8273a (NCIT:C121158); 	32	N/A	A phase I clinical trial 	DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure.	No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 First-in-human study of the antibody DR5 agonist DS-8273a in patients with  advanced solid tumors.	 Invest New Drugs	 Background DR5 is a transmembrane receptor that transduces extracellular  ligand-binding to activate apoptosis signaling cascades. This phase 1 study  evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics  of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with  advanced solid tumors. Methods The study comprised dose escalation and dose  expansion cohorts. The dose escalation cohorts intended to determine the safety  and to identify the maximum tolerated dose (MTD) or maximum administered dose  (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a  conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and  24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects  were treated at the MAD for further evaluation of PK and safety. Results Thirty  two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16   in the dose expansion cohort. No subjects experienced a dose limiting toxicity  (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14  (44%) of which were attributed to study-drug; all drug-related events were grade   1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.  Measures of plasma exposure increased dose-proportionally and the mean terminal  elimination half-life was 11 days. Blood samples available from a subset of  patients treated at 24 mg/kg revealed declines in myeloid derived suppressor  cells (MDSC) at 2 weeks. No objective responses were observed in any subjects.  Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics.  Decreases in MDSC were temporally associated with DS-8273a exposure. This agent  could be studied further in combination with other agents, pending further  proof-of-target-engagement.
CANIT0000884	28050790	Clinical research	10 Colorectal cancer, 5 Sarcoma, 3 Breast cancer, 3 Pancreatic cancer, 2 Ovarian cancer, 2 Melanoma, 2 Liver cancer, 2 Head and Neck cancer	Hepatocellular carcinoma	EFO:0000182	Liver	DR5 (O14763); 	DR5; 	DS-8273a	N/A	Immune checkpoint therapy	DS-8273a (NCIT:C121158); 	32	N/A	A phase I clinical trial 	DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure.	No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 First-in-human study of the antibody DR5 agonist DS-8273a in patients with  advanced solid tumors.	 Invest New Drugs	 Background DR5 is a transmembrane receptor that transduces extracellular  ligand-binding to activate apoptosis signaling cascades. This phase 1 study  evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics  of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with  advanced solid tumors. Methods The study comprised dose escalation and dose  expansion cohorts. The dose escalation cohorts intended to determine the safety  and to identify the maximum tolerated dose (MTD) or maximum administered dose  (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a  conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and  24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects  were treated at the MAD for further evaluation of PK and safety. Results Thirty  two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16   in the dose expansion cohort. No subjects experienced a dose limiting toxicity  (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14  (44%) of which were attributed to study-drug; all drug-related events were grade   1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.  Measures of plasma exposure increased dose-proportionally and the mean terminal  elimination half-life was 11 days. Blood samples available from a subset of  patients treated at 24 mg/kg revealed declines in myeloid derived suppressor  cells (MDSC) at 2 weeks. No objective responses were observed in any subjects.  Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics.  Decreases in MDSC were temporally associated with DS-8273a exposure. This agent  could be studied further in combination with other agents, pending further  proof-of-target-engagement.
CANIT0000885	28050790	Clinical research	10 Colorectal cancer, 5 Sarcoma, 3 Breast cancer, 3 Pancreatic cancer, 2 Ovarian cancer, 2 Melanoma, 2 Liver cancer, 2 Head and Neck cancer	Melanoma	EFO:0000756	Skin	DR5 (O14763); 	DR5; 	DS-8273a	N/A	Immune checkpoint therapy	DS-8273a (NCIT:C121158); 	32	N/A	A phase I clinical trial 	DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure.	No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 First-in-human study of the antibody DR5 agonist DS-8273a in patients with  advanced solid tumors.	 Invest New Drugs	 Background DR5 is a transmembrane receptor that transduces extracellular  ligand-binding to activate apoptosis signaling cascades. This phase 1 study  evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics  of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with  advanced solid tumors. Methods The study comprised dose escalation and dose  expansion cohorts. The dose escalation cohorts intended to determine the safety  and to identify the maximum tolerated dose (MTD) or maximum administered dose  (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a  conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and  24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects  were treated at the MAD for further evaluation of PK and safety. Results Thirty  two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16   in the dose expansion cohort. No subjects experienced a dose limiting toxicity  (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14  (44%) of which were attributed to study-drug; all drug-related events were grade   1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.  Measures of plasma exposure increased dose-proportionally and the mean terminal  elimination half-life was 11 days. Blood samples available from a subset of  patients treated at 24 mg/kg revealed declines in myeloid derived suppressor  cells (MDSC) at 2 weeks. No objective responses were observed in any subjects.  Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics.  Decreases in MDSC were temporally associated with DS-8273a exposure. This agent  could be studied further in combination with other agents, pending further  proof-of-target-engagement.
CANIT0000886	28050790	Clinical research	10 Colorectal cancer, 5 Sarcoma, 3 Breast cancer, 3 Pancreatic cancer, 2 Ovarian cancer, 2 Melanoma, 2 Liver cancer, 2 Head and Neck cancer	Ovarian carcinoma	EFO:0001075	Ovary	DR5 (O14763); 	DR5; 	DS-8273a	N/A	Immune checkpoint therapy	DS-8273a (NCIT:C121158); 	32	N/A	A phase I clinical trial 	DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure.	No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 First-in-human study of the antibody DR5 agonist DS-8273a in patients with  advanced solid tumors.	 Invest New Drugs	 Background DR5 is a transmembrane receptor that transduces extracellular  ligand-binding to activate apoptosis signaling cascades. This phase 1 study  evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics  of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with  advanced solid tumors. Methods The study comprised dose escalation and dose  expansion cohorts. The dose escalation cohorts intended to determine the safety  and to identify the maximum tolerated dose (MTD) or maximum administered dose  (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a  conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and  24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects  were treated at the MAD for further evaluation of PK and safety. Results Thirty  two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16   in the dose expansion cohort. No subjects experienced a dose limiting toxicity  (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14  (44%) of which were attributed to study-drug; all drug-related events were grade   1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.  Measures of plasma exposure increased dose-proportionally and the mean terminal  elimination half-life was 11 days. Blood samples available from a subset of  patients treated at 24 mg/kg revealed declines in myeloid derived suppressor  cells (MDSC) at 2 weeks. No objective responses were observed in any subjects.  Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics.  Decreases in MDSC were temporally associated with DS-8273a exposure. This agent  could be studied further in combination with other agents, pending further  proof-of-target-engagement.
CANIT0000887	28050790	Clinical research	10 Colorectal cancer, 5 Sarcoma, 3 Breast cancer, 3 Pancreatic cancer, 2 Ovarian cancer, 2 Melanoma, 2 Liver cancer, 2 Head and Neck cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	DR5 (O14763); 	DR5; 	DS-8273a	N/A	Immune checkpoint therapy	DS-8273a (NCIT:C121158); 	32	N/A	A phase I clinical trial 	DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure.	No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 First-in-human study of the antibody DR5 agonist DS-8273a in patients with  advanced solid tumors.	 Invest New Drugs	 Background DR5 is a transmembrane receptor that transduces extracellular  ligand-binding to activate apoptosis signaling cascades. This phase 1 study  evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics  of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with  advanced solid tumors. Methods The study comprised dose escalation and dose  expansion cohorts. The dose escalation cohorts intended to determine the safety  and to identify the maximum tolerated dose (MTD) or maximum administered dose  (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a  conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and  24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects  were treated at the MAD for further evaluation of PK and safety. Results Thirty  two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16   in the dose expansion cohort. No subjects experienced a dose limiting toxicity  (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14  (44%) of which were attributed to study-drug; all drug-related events were grade   1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.  Measures of plasma exposure increased dose-proportionally and the mean terminal  elimination half-life was 11 days. Blood samples available from a subset of  patients treated at 24 mg/kg revealed declines in myeloid derived suppressor  cells (MDSC) at 2 weeks. No objective responses were observed in any subjects.  Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics.  Decreases in MDSC were temporally associated with DS-8273a exposure. This agent  could be studied further in combination with other agents, pending further  proof-of-target-engagement.
CANIT0000888	28050790	Clinical research	10 Colorectal cancer, 5 Sarcoma, 3 Breast cancer, 3 Pancreatic cancer, 2 Ovarian cancer, 2 Melanoma, 2 Liver cancer, 2 Head and Neck cancer	Sarcoma	EFO:0000691	Soft tissue	DR5 (O14763); 	DR5; 	DS-8273a	N/A	Immune checkpoint therapy	DS-8273a (NCIT:C121158); 	32	N/A	A phase I clinical trial 	DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure.	No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 First-in-human study of the antibody DR5 agonist DS-8273a in patients with  advanced solid tumors.	 Invest New Drugs	 Background DR5 is a transmembrane receptor that transduces extracellular  ligand-binding to activate apoptosis signaling cascades. This phase 1 study  evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics  of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with  advanced solid tumors. Methods The study comprised dose escalation and dose  expansion cohorts. The dose escalation cohorts intended to determine the safety  and to identify the maximum tolerated dose (MTD) or maximum administered dose  (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a  conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and  24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects  were treated at the MAD for further evaluation of PK and safety. Results Thirty  two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16   in the dose expansion cohort. No subjects experienced a dose limiting toxicity  (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14  (44%) of which were attributed to study-drug; all drug-related events were grade   1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea.  Measures of plasma exposure increased dose-proportionally and the mean terminal  elimination half-life was 11 days. Blood samples available from a subset of  patients treated at 24 mg/kg revealed declines in myeloid derived suppressor  cells (MDSC) at 2 weeks. No objective responses were observed in any subjects.  Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics.  Decreases in MDSC were temporally associated with DS-8273a exposure. This agent  could be studied further in combination with other agents, pending further  proof-of-target-engagement.
CANIT0000889	28062513	Case report	Metastatic melanoma with extensive brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Durable complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Feb	 Metastatic Melanoma Patient Had a Complete Response with Clonal Expansion after  Whole Brain Radiation and PD-1 Blockade.	 Cancer Immunol Res	 We report here on a patient with metastatic melanoma who had extensive brain  metastases. After being treated with the sequential combination of whole brain  radiation therapy followed by the PD-1-inhibitory antibody, pembrolizumab, the  patient had a durable complete response. Retrospective laboratory studies of T  cells revealed that, after treatment with anti-PD-1 commenced, effector CD8(+) T   cells in the blood expanded and the ratio of CD8(+):Treg T cells increased. A  CD8(+) T-cell clone present in the initial brain metastases was expanded in the  blood after anti-PD-1 treatment, which suggested an antitumor role for this  clone. Immunohistochemical analysis confirmed the presence of CD8(+) T cells and   low PD-L1 expression in the brain metastases before immunotherapy initiation.  This sequence of therapy may provide an option for melanoma patients with  unresponsive brain metastases. Cancer Immunol Res; 5(2); 100-5. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0000890	28069323	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	7	N/A	Case	Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor- is a biomarker of nivolumab recativity	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform  dermatitis and tumor necrosis factor-alpha is a biomarker of nivolumab  recativity.	 J Dermatol Sci	Unable to provide
CANIT0000891	28072561	Case report	Multiple congenital melanocytic nevi	Papillary renal cell carcinoma	EFO:0000640	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Primary leptomeningeal melanoma	N/A	N/A	N/A	N/A	N/A	 2017 Mar	 Primary Leptomeningeal Melanoma in a Patient With Multiple Congenital Melanocytic  Nevi Treated With Ipilimumab.	 J Oncol Pract	Unable to provide
CANIT0000892	28072766	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	84	N/A	N/A	Patients with sarcopenia and low muscle attenuation (MA) are more likely to experience severe treatment-related toxicity to Ipi. Loss of muscle during treatment was predictive of worse survival.	At baseline, 24% were sarcopenic and 33% had low muscle attenuation (MA). On multivariate analysis, sarcopenia and low MA were significantly associated with high-grade AEs (OR=5.34, 95% CI: 1.15-24.88, P=0.033; OR=5.23, 95% CI: 1.41-19.30, P=0.013, respectively), and low MA was associated with high-grade irAEs (OR=3.57, 95% CI: 1.09-11.77, P=0.036).	N/A	N/A	Muscle attenuation (EFO:0004515); 	Muscle attenuation	Disease status	 2017 Jan	 The impact of body composition parameters on ipilimumab toxicity and survival in   patients with metastatic melanoma.	 Br J Cancer	 BACKGROUND: Body composition is an important predictor of drug toxicity and  outcome. Ipilimumab (Ipi), a monoclonal antibody used to treat metastatic  melanoma, has specific toxicities. No validated biomarkers that predict Ipi  toxicity and efficacy exist. Also, the impact of Ipi on body composition has not   been established. METHODS: Patients with metastatic melanoma treated with Ipi  between 2009 and 2015 were included. Body composition was assessed by computed  tomography at baseline and after four cycles of Ipi. Sarcopenia and low muscle  attenuation (MA) were defined using published cut-points. All adverse events  (AEs) and immune-related AEs (irAEs) were recorded (Common Terminology Criteria  For Adverse Event V.4.0). RESULTS: Eighty-four patients were included in this  study (62% male, median age 54 years). At baseline, 24% were sarcopenic and 33%  had low MA. On multivariate analysis, sarcopenia and low MA were significantly  associated with high-grade AEs (OR=5.34, 95% CI: 1.15-24.88, P=0.033; OR=5.23,  95% CI: 1.41-19.30, P=0.013, respectively), and low MA was associated with  high-grade irAEs (OR=3.57, 95% CI: 1.09-11.77, P=0.036). Longitudinal analysis  (n=59) revealed significant reductions in skeletal muscle area (SMA), total body   fat-free mass, fat mass (all P<0.001) and MA (P=0.030). Mean reduction in SMA was  3.3%/100 days (95% CI: -4.48 to -1.79%, P<0.001). A loss of SMA 7.5%/100 days  (highest quartile) was a significant predictor of overall survival in  multivariable Cox regression analysis (HR: 2.1, 95% CI: 1.02-4.56, P=0.046).  CONCLUSIONS: Patients with sarcopenia and low MA are more likely to experience  severe treatment-related toxicity to Ipi. Loss of muscle during treatment was  predictive of worse survival. Treatments to increase muscle mass and influence  outcome warrant further investigation.
CANIT0000893	28081914	Clinical research	Locally advanced or metastatic urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	33	N/A	A non-randomised, open-label, phase Ib	Pembrolizumab showed anti-tumour activity and acceptable safety in patients with advanced urothelial cancer, supporting ongoing phase 2 and 3 studies of pembrolizumab in this population.	The most common treatment-related adverse events were fatigue (six [18%] of 33 patients) and peripheral oedema (4 [12%]). Five (15%) patients had 11 grade 3 treatment-related adverse events; no single event occurred in more than one patient. Three (9%) patients experienced five serious treatment-related adverse events. Of the four deaths that occurred during the study (cardiac arrest, pneumonia, sepsis, and subarachnoid haemorrhage), none were deemed treatment related.	N/A	N/A	N/A	N/A	N/A	 2017 Feb	 Safety and activity of pembrolizumab in patients with locally advanced or  metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase  1b study.	 Lancet Oncol	 BACKGROUND: PD-1 and its ligands are expressed in urothelial cancer, and findings  have shown that inhibition of the PD-1 pathway has clinical benefit. We aimed to   assess the safety and activity of an anti-PD-1 antibody pembrolizumab in patients  with locally advanced or metastatic urothelial cancer. METHODS: This study was  part of the non-randomised, multi-cohort, open-label, phase 1b KEYNOTE-012 basket  trial. We enrolled patients aged 18 years and older with a histologically or  cytologically confirmed diagnosis of locally advanced or metastatic urothelial  cancer, including cancers of the renal pelvis, ureter, bladder, or urethra, from   eight hospitals in the USA and Israel. Patients were required to have at least 1%  PD-L1 expression detected on the tumour cells or in tumour stroma, as determined   by immunohistochemistry. Patients were given 10 mg/kg intravenous pembrolizumab  every 2 weeks until disease progression, unacceptable toxic effects, or the end  of the study (ie, 24 months of treatment). Primary endpoints were safety and  overall response (defined by Response Evaluation Criteria In Solid Tumors  [RECIST] version 1.1), as assessed by a masked, independent central review.  Safety was assessed in patients who received one or more doses of pembrolizumab  (all-patients-as-treated population); activity was assessed in patients who  received pembrolizumab, had measurable disease at baseline, and had one or more  post-baseline scans, or discontinued because of progressive disease or  treatment-related adverse events (full analysis set). This study is registered  with ClinicalTrials.gov, number NCT01848834, and is no longer enrolling patients;  follow-up is ongoing. FINDINGS: Between May 14, 2013, and Dec 10, 2013, 115  patients were tissue pre-screened as part of a two-part consent process. 61 (53%)  patients were PD-L1 positive, of whom 33 were enrolled in this study. All  enrolled patients received at least one dose of pembrolizumab and were included  in the safety analyses. 27 patients comprised the full analysis set and were  deemed assessable for activity. Six patients were not assessable: three  discontinued study drug because of a non-treatment-related adverse event before  the first post-baseline scan, two withdrew before the first post-baseline scan,  and one had no measurable disease at baseline. The most common treatment-related   adverse events were fatigue (six [18%] of 33 patients) and peripheral oedema (4  [12%]). Five (15%) patients had 11 grade 3 treatment-related adverse events; no  single event occurred in more than one patient. Three (9%) patients experienced  five serious treatment-related adverse events. After median follow-up of 13  months (range 1-26, IQR 5-23), an overall response was achieved in seven (26%  [95% CI 11-46]) of 27 assessable patients, with three (11% [2-29]) complete and  four (15% [4-34]) partial responses. Of the four deaths that occurred during the   study (cardiac arrest, pneumonia, sepsis, and subarachnoid haemorrhage), none  were deemed treatment related. INTERPRETATION: Pembrolizumab showed anti-tumour  activity and acceptable safety in patients with advanced urothelial cancer,  supporting ongoing phase 2 and 3 studies of pembrolizumab in this population.  FUNDING: Merck & Co., Inc.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000894	28082048	Case report	RET Fusion Lung Carcinoma	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	14	N/A	Case	Not respond	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 RET Fusion Lung Carcinoma: Response to Therapy and Clinical Features in a Case  Series of 14 Patients.	 Clin Lung Cancer	 BACKGROUND: RET (rearranged during transfection) fusions have been reported in 1%  to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET  fusion genes have been identified in 70% to 90% and 10% to 25% of tumors,  respectively. The natural history and management of RET-rearranged LADC are still  being delineated. MATERIALS AND METHODS: We present a series of 14 patients with   RET-rearranged LADC. The response to therapy was assessed by the clinical  response and an avatar model in 2 cases. Patients underwent chemotherapy,  targeted therapy, and immunotherapy. RESULTS: A total of 14 patients (8 women; 10  never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and   CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients  had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor.  The features of this subset included bilateral miliary lung metastases, bone  metastases, and unusual early visceral abdominal involvement. One such patient  demonstrated an early and durable complete response to cabozantinib for 7 months.  Another 2 patients treated with cabozantinib experienced a partial response, with  rapid significant clinical improvement. Four patients with tumors harboring  CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to  platinum-based chemotherapy that lasted for 8 to 15 months. Two patients' tumors   showed programmed cell death ligand 1-positive staining but did not respond to  pembrolizumab. The median overall survival was 22.8 months. CONCLUSION:  RET-rearranged LADC in our series tended to occur as bilateral disease with early  visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib  achieved responses, including 1 complete response. However, further studies are  required in this group of patients.CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
CANIT0000895	28094061	Clinical research	7 metastatic melanoma, 1 metastatic lung carcinoma)	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	8	N/A	N/A	Clinical and biological patterns of vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.	All patients developed lesions localized on photoexposed areas with a specific depigmentation pattern consisting of multiple flecked lesions without Koebner phenomenon. In contrast to vitiligo, patients receiving anti-PD-1 therapies who developed vitiligo-like lesions did not report any personal or family histories of vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin samples revealed increased C-X-C motif ligand 10 levels in serum of patients developing vitiligo-like lesions, associated with skin infiltration of CD8 T-cells expressing C-X-C motif receptor 3 and producing elevated levels of interferon- and tumor necrosis factor-alfa.	N/A	N/A	N/A	N/A	N/A	 2017 May	 Vitiligo-like lesions occurring in patients receiving anti-programmed cell  death-1 therapies are clinically and biologically distinct from vitiligo.	 J Am Acad Dermatol	 BACKGROUND: The use of anti-programmed cell death (PD)-1 therapies in metastatic   tumors is associated with cutaneous side effects including vitiligo-like lesions.  OBJECTIVE: We sought to characterize clinically and biologically vitiligo-like  lesions occurring in patients receiving anti-PD-1 therapies by studying a case  series of 8 patients with metastatic tumors and 30 control subjects with  vitiligo. METHODS: Eight patients receiving anti-PD-1 therapies with features of   vitiligo-like lesions seen in our department were recruited. Clinical features  and photographs were analyzed. For some patients, skin and blood samples were  obtained. Results were compared with the vitiligo group. RESULTS: All patients  developed lesions localized on photoexposed areas with a specific depigmentation   pattern consisting of multiple flecked lesions without Koebner phenomenon. In  contrast to vitiligo, patients receiving anti-PD-1 therapies who developed  vitiligo-like lesions did not report any personal or family histories of  vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin   samples revealed increased C-X-C motif ligand 10 levels in serum of patients  developing vitiligo-like lesions, associated with skin infiltration of CD8  T-cells expressing C-X-C motif receptor 3 and producing elevated levels of  interferonG and tumor necrosis factor-alfa. LIMITATIONS: This  cross-sectional study concerned a single center. CONCLUSIONS: Clinical and  biological patterns of vitiligo-like lesions occurring in patients receiving  anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.CI  - Copyright (c) 2016 American Academy of Dermatology, Inc. Published by Elsevier  Inc. All rights reserved.
CANIT0000896	28094061	Clinical research	7 metastatic melanoma, 1 metastatic lung carcinoma)	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	8	N/A	N/A	Clinical and biological patterns of vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.	All patients developed lesions localized on photoexposed areas with a specific depigmentation pattern consisting of multiple flecked lesions without Koebner phenomenon. In contrast to vitiligo, patients receiving anti-PD-1 therapies who developed vitiligo-like lesions did not report any personal or family histories of vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin samples revealed increased C-X-C motif ligand 10 levels in serum of patients developing vitiligo-like lesions, associated with skin infiltration of CD8 T-cells expressing C-X-C motif receptor 3 and producing elevated levels of interferon- and tumor necrosis factor-alfa.	N/A	N/A	N/A	N/A	N/A	 2017 May	 Vitiligo-like lesions occurring in patients receiving anti-programmed cell  death-1 therapies are clinically and biologically distinct from vitiligo.	 J Am Acad Dermatol	 BACKGROUND: The use of anti-programmed cell death (PD)-1 therapies in metastatic   tumors is associated with cutaneous side effects including vitiligo-like lesions.  OBJECTIVE: We sought to characterize clinically and biologically vitiligo-like  lesions occurring in patients receiving anti-PD-1 therapies by studying a case  series of 8 patients with metastatic tumors and 30 control subjects with  vitiligo. METHODS: Eight patients receiving anti-PD-1 therapies with features of   vitiligo-like lesions seen in our department were recruited. Clinical features  and photographs were analyzed. For some patients, skin and blood samples were  obtained. Results were compared with the vitiligo group. RESULTS: All patients  developed lesions localized on photoexposed areas with a specific depigmentation   pattern consisting of multiple flecked lesions without Koebner phenomenon. In  contrast to vitiligo, patients receiving anti-PD-1 therapies who developed  vitiligo-like lesions did not report any personal or family histories of  vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin   samples revealed increased C-X-C motif ligand 10 levels in serum of patients  developing vitiligo-like lesions, associated with skin infiltration of CD8  T-cells expressing C-X-C motif receptor 3 and producing elevated levels of  interferonG and tumor necrosis factor-alfa. LIMITATIONS: This  cross-sectional study concerned a single center. CONCLUSIONS: Clinical and  biological patterns of vitiligo-like lesions occurring in patients receiving  anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.CI  - Copyright (c) 2016 American Academy of Dermatology, Inc. Published by Elsevier  Inc. All rights reserved.
CANIT0000897	28094061	Clinical research	7 metastatic melanoma, 1 metastatic lung carcinoma)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	8	N/A	N/A	Clinical and biological patterns of vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.	All patients developed lesions localized on photoexposed areas with a specific depigmentation pattern consisting of multiple flecked lesions without Koebner phenomenon. In contrast to vitiligo, patients receiving anti-PD-1 therapies who developed vitiligo-like lesions did not report any personal or family histories of vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin samples revealed increased C-X-C motif ligand 10 levels in serum of patients developing vitiligo-like lesions, associated with skin infiltration of CD8 T-cells expressing C-X-C motif receptor 3 and producing elevated levels of interferon- and tumor necrosis factor-alfa.	N/A	N/A	N/A	N/A	N/A	 2017 May	 Vitiligo-like lesions occurring in patients receiving anti-programmed cell  death-1 therapies are clinically and biologically distinct from vitiligo.	 J Am Acad Dermatol	 BACKGROUND: The use of anti-programmed cell death (PD)-1 therapies in metastatic   tumors is associated with cutaneous side effects including vitiligo-like lesions.  OBJECTIVE: We sought to characterize clinically and biologically vitiligo-like  lesions occurring in patients receiving anti-PD-1 therapies by studying a case  series of 8 patients with metastatic tumors and 30 control subjects with  vitiligo. METHODS: Eight patients receiving anti-PD-1 therapies with features of   vitiligo-like lesions seen in our department were recruited. Clinical features  and photographs were analyzed. For some patients, skin and blood samples were  obtained. Results were compared with the vitiligo group. RESULTS: All patients  developed lesions localized on photoexposed areas with a specific depigmentation   pattern consisting of multiple flecked lesions without Koebner phenomenon. In  contrast to vitiligo, patients receiving anti-PD-1 therapies who developed  vitiligo-like lesions did not report any personal or family histories of  vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin   samples revealed increased C-X-C motif ligand 10 levels in serum of patients  developing vitiligo-like lesions, associated with skin infiltration of CD8  T-cells expressing C-X-C motif receptor 3 and producing elevated levels of  interferonG and tumor necrosis factor-alfa. LIMITATIONS: This  cross-sectional study concerned a single center. CONCLUSIONS: Clinical and  biological patterns of vitiligo-like lesions occurring in patients receiving  anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.CI  - Copyright (c) 2016 American Academy of Dermatology, Inc. Published by Elsevier  Inc. All rights reserved.
CANIT0000898	28094061	Clinical research	7 metastatic melanoma, 1 metastatic lung carcinoma)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	8	N/A	N/A	Clinical and biological patterns of vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.	All patients developed lesions localized on photoexposed areas with a specific depigmentation pattern consisting of multiple flecked lesions without Koebner phenomenon. In contrast to vitiligo, patients receiving anti-PD-1 therapies who developed vitiligo-like lesions did not report any personal or family histories of vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin samples revealed increased C-X-C motif ligand 10 levels in serum of patients developing vitiligo-like lesions, associated with skin infiltration of CD8 T-cells expressing C-X-C motif receptor 3 and producing elevated levels of interferon- and tumor necrosis factor-alfa.	N/A	N/A	N/A	N/A	N/A	 2017 May	 Vitiligo-like lesions occurring in patients receiving anti-programmed cell  death-1 therapies are clinically and biologically distinct from vitiligo.	 J Am Acad Dermatol	 BACKGROUND: The use of anti-programmed cell death (PD)-1 therapies in metastatic   tumors is associated with cutaneous side effects including vitiligo-like lesions.  OBJECTIVE: We sought to characterize clinically and biologically vitiligo-like  lesions occurring in patients receiving anti-PD-1 therapies by studying a case  series of 8 patients with metastatic tumors and 30 control subjects with  vitiligo. METHODS: Eight patients receiving anti-PD-1 therapies with features of   vitiligo-like lesions seen in our department were recruited. Clinical features  and photographs were analyzed. For some patients, skin and blood samples were  obtained. Results were compared with the vitiligo group. RESULTS: All patients  developed lesions localized on photoexposed areas with a specific depigmentation   pattern consisting of multiple flecked lesions without Koebner phenomenon. In  contrast to vitiligo, patients receiving anti-PD-1 therapies who developed  vitiligo-like lesions did not report any personal or family histories of  vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin   samples revealed increased C-X-C motif ligand 10 levels in serum of patients  developing vitiligo-like lesions, associated with skin infiltration of CD8  T-cells expressing C-X-C motif receptor 3 and producing elevated levels of  interferonG and tumor necrosis factor-alfa. LIMITATIONS: This  cross-sectional study concerned a single center. CONCLUSIONS: Clinical and  biological patterns of vitiligo-like lesions occurring in patients receiving  anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.CI  - Copyright (c) 2016 American Academy of Dermatology, Inc. Published by Elsevier  Inc. All rights reserved.
CANIT0000899	28097534	Case report	Refractory Hodgkin lymphoma after allogeneic stem cell transplantation	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Successful treatment	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after  allogeneic stem cell transplantation.	 Int J Hematol	 Previous studies have reported that an antibody that blocks programmed cell death  1 (PD-1) has therapeutic activity in patients with refractory/relapsed Hodgkin  lymphoma (HL). However, the safety and efficacy of these agents in the  post-allogeneic stem cell transplantation (allo-SCT) setting are not well known.   Here, we describe a patient who was diagnosed as classical HL and treated with  five regimens of chemotherapies with autologous SCT. Complete remission (CR) was   not achieved following this initial treatment, so we performed allo-SCT from an  HLA-matched sibling donor. Since his disease progressed at day 403 after  allo-SCT, we decided to use nivolumab in the treatment of his refractory disease.  To prevent the worsening of his chronic graft-versus-host disease (GVHD), we  reduced the initial dose and frequency of nivolumab compared with the previous  report. After four courses of 0.5 mg/kg of nivolumab every three weeks, FDG-PET  imaging showed partial response (PR) to the treatment, a remarkable result.  However, since the escalated dose of 2 mg/kg resulted in worsening of dyspnea and  skin sclerosis, we initiated systemic administration of prednisolone and reduced   nivolumab to 1 mg/kg. At the time of this report, his HL is in stable PR with  three weekly administration of nivolumab and steroid controlled mild chronic  GVHD.
CANIT0000900	28099369	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	29	N/A	A retrospective cohort study	This is the first report of patients who have intentionally ceased PD-1-based therapy because of CR. With a follow-up of 8 months off treatment, the risk of relapse was low.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 The cessation of anti-PD-1 antibodies of complete responders in metastatic  melanoma.	 Melanoma Res	 The optimal duration of PD-1 antibodies for metastatic melanoma is unknown. In  previous trials, there has been the potential to cease therapy if the patient  achieves a complete response (CR). We aimed to assess the outcomes of patients  who had ceased anti-PD-1 antibodies in this setting. A retrospective review was  carried out of CR to PD-1-based therapy across two institutions. Patients were  from the Pembrolizumab Named Patient Program (PEM NPP), Nivolumab monotherapy  (NIVO), and reimbursed Pembrolizumab (r PEM). Patients had to have experienced a   CR to PD-1-based therapy and ceased therapy because of this. Disease recurrence  was the primary outcome measured. Twenty-nine patients (PEM NPP, N=20; Nivo, N=3;  r PEM, N=6) ceased anti-PD-1 therapy after CR for observation. The median age was  64 (27-83) years. All patients had treatment discontinued for observation. The  median time to CR was 10.5 months in the PEM NPP, 7.5 months on r PEM groups, and  17 months in the NIVO group. The median time off therapy in PEM NPP was 10  months, NIVO was 9 months, and r PEM was 4.5 months. To date, three patients have  shown a relapse at a median follow-up off treatment of 8 months. This is the  first report of patients who have intentionally ceased PD-1-based therapy because  of CR. With a follow-up of 8 months off treatment, the risk of relapse was low.  Data such as these are clinically relevant as we need to be able to discuss  cessation of therapy and relevant from a pharmacoeconomic perspective, given the   cost of PD-1 antibodies to society.
CANIT0000901	28099369	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	29	N/A	A retrospective cohort study	This is the first report of patients who have intentionally ceased PD-1-based therapy because of CR. With a follow-up of 8 months off treatment, the risk of relapse was low.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 The cessation of anti-PD-1 antibodies of complete responders in metastatic  melanoma.	 Melanoma Res	 The optimal duration of PD-1 antibodies for metastatic melanoma is unknown. In  previous trials, there has been the potential to cease therapy if the patient  achieves a complete response (CR). We aimed to assess the outcomes of patients  who had ceased anti-PD-1 antibodies in this setting. A retrospective review was  carried out of CR to PD-1-based therapy across two institutions. Patients were  from the Pembrolizumab Named Patient Program (PEM NPP), Nivolumab monotherapy  (NIVO), and reimbursed Pembrolizumab (r PEM). Patients had to have experienced a   CR to PD-1-based therapy and ceased therapy because of this. Disease recurrence  was the primary outcome measured. Twenty-nine patients (PEM NPP, N=20; Nivo, N=3;  r PEM, N=6) ceased anti-PD-1 therapy after CR for observation. The median age was  64 (27-83) years. All patients had treatment discontinued for observation. The  median time to CR was 10.5 months in the PEM NPP, 7.5 months on r PEM groups, and  17 months in the NIVO group. The median time off therapy in PEM NPP was 10  months, NIVO was 9 months, and r PEM was 4.5 months. To date, three patients have  shown a relapse at a median follow-up off treatment of 8 months. This is the  first report of patients who have intentionally ceased PD-1-based therapy because  of CR. With a follow-up of 8 months off treatment, the risk of relapse was low.  Data such as these are clinically relevant as we need to be able to discuss  cessation of therapy and relevant from a pharmacoeconomic perspective, given the   cost of PD-1 antibodies to society.
CANIT0000902	28100090	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1043	N/A	A retrospective cohort study	This study provides insights into the treatment patterns for metastatic melanoma, including newer agents, in real-world clinical practice.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Patterns of use of systemic therapies among patients with metastatic melanoma: a   retrospective claims database analysis in the United States.	 J Dermatolog Treat	 OBJECTIVES: This retrospective analysis of the IMS PharMetrics Plus claims  database aimed to describe the current real-world treatment patterns for  metastatic melanoma in the USA. METHODS: Included patients (aged >/=18 years) had  >/=1 prescription for ipilimumab, vemurafenib, temozolomide or dacarbazine  between 1 January 2011 and 31 August 2013; diagnosis of melanoma and metastasis  before first use (index date); no index drug use prior to the index date;  continuous health plan enrollment for >/=6 months before and >/=3 months after  index date. Proportion of days covered (PDC) was defined as days exposed to index  therapy divided by continuously enrolled days between index date and last  prescription date. RESULTS: Overall, 1043 patients were included (median age 57  years, 63% male), of whom 39% received the index drug ipilimumab, 35%  vemurafenib, 19% temozolomide and 7% dacarbazine. Mean treatment duration (days)   was 174 (vemurafenib), 100 (temozolomide) and 64 (dacarbazine). Mean PDC was 81%   (vemurafenib), 67% (temozolomide) and 51% (dacarbazine). For patients receiving  ipilimumab, 58% had the full 4 doses, 20% 3 doses, 14% 2 doses and 9% 1 dose only  for the first induction course; 4% received re-induction, and none had a second  re-induction. CONCLUSIONS: This study provides insights into the treatment  patterns for metastatic melanoma, including newer agents, in real-world clinical   practice.
CANIT0000903	28102540	Case report	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Radiation recall dermatitis	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Radiation recall dermatitis associated with nivolumab for metastatic malignant  melanoma.	 Int J Dermatol	Unable to provide
CANIT0000904	28105368	Case report	Metastatic renal medullary carcinoma	Renal medullary carcinoma	EFO:0002890	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A complete response lasting greater than nine months	N/A	N/A	N/A	N/A	N/A	N/A	2017	 Clinical and immunologic correlates of response to PD-1 blockade in a patient  with metastatic renal medullary carcinoma.	 J Immunother Cancer	 BACKGROUND: Renal medullary carcinoma (RMC) is a rare kidney tumor that occurs in  adolescent and young adults, typically in association with sickle cell trait. RMC  exhibits rapid disease progression, frequent metastases at diagnosis, and dismal   clinical outcomes. Currently available therapies, including cisplatin-based  combination chemotherapy, multi-tyrosine kinase, and mTOR inhibitor strategies  demonstrate either transient responses or minimal activity. Therefore, further  molecular characterization and additional treatment strategies are urgently  needed in this aggressive disease. The role of immune system surveillance and  responsiveness to anti-PD-1 therapies in RMC are completely unexplored. CASE  PRESENTATION: A 29 year old male with sickle cell trait presented with painless  hematuria that ultimately resulted in a diagnosis of RMC. He underwent total  nephrectomy and adjuvant cytotoxic chemotherapy with carboplatin, gemcitabine,  paclitaxel, and bevacizumab. As is common in this aggressive form of kidney  cancer he recurred with biopsy proven lymph node metastasis. He was started on  checkpoint inhibitor therapy with nivolumab that inhibits program cell death  protein 1 (PD-1), and on his first follow-up imaging he was found to have a  partial response that on subsequent scans ultimately resulted in a complete  response lasting greater than nine months. In this report, we present a patient  with metastatic RMC who exhibited a clinical response to nivolumab, as well as  the genetic and immunologic correlates of the pre-treatment tumor. Provocatively,  robust immune infiltrate and expression of immune checkpoints were observed,  despite the presence of a low mutation burden. CONCLUSIONS: Here, we report the  first case of immune microenvironment profiling and response to anti-PD-1 in a  patient with RMC to our knowledge. This case suggests that anti-PD-1 based  therapies may have clinical activity in RMC.
CANIT0000905	28105370	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Interstitial nephritis	N/A	N/A	N/A	N/A	N/A	2017	 Interstitial nephritis in melanoma patients secondary to PD-1 checkpoint  inhibitor.	 J Immunother Cancer	 BACKGROUND: Immune checkpoint inhibitors have become the first line therapy in  melanoma treatment and their use is extending to other malignancies. However, we   are still learning about immune side effects produced by these drugs and their  severity especially in patients with history of inflammatory diseases. CASE  PRESENTATION: We present two cases of metastatic melanoma treated with nivolumab   and pembrolizumab (anti PD-1). Both patients developed acute interstitial  nephritis during immune checkpoint therapy. We emphasize the causal association  between immune checkpoint inhibitors and the nephritis. The timing of drug  administration and appearance of nephritis is suggestive of a causal relation  between the checkpoint inhibitor therapy and this adverse event. CONCLUSIONS:  Although uncommon, some side effects from checkpoint inhibitors can be severe and  may need to be addressed with immunosuppression. Given the increasing frequency  of immunotherapy use, awareness should be raised in regards to immune side  effects and their appropriate management.
CANIT0000906	28105370	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Interstitial nephritis	N/A	N/A	N/A	N/A	N/A	2017	 Interstitial nephritis in melanoma patients secondary to PD-1 checkpoint  inhibitor.	 J Immunother Cancer	 BACKGROUND: Immune checkpoint inhibitors have become the first line therapy in  melanoma treatment and their use is extending to other malignancies. However, we   are still learning about immune side effects produced by these drugs and their  severity especially in patients with history of inflammatory diseases. CASE  PRESENTATION: We present two cases of metastatic melanoma treated with nivolumab   and pembrolizumab (anti PD-1). Both patients developed acute interstitial  nephritis during immune checkpoint therapy. We emphasize the causal association  between immune checkpoint inhibitors and the nephritis. The timing of drug  administration and appearance of nephritis is suggestive of a causal relation  between the checkpoint inhibitor therapy and this adverse event. CONCLUSIONS:  Although uncommon, some side effects from checkpoint inhibitors can be severe and  may need to be addressed with immunosuppression. Given the increasing frequency  of immunotherapy use, awareness should be raised in regards to immune side  effects and their appropriate management.
CANIT0000907	28110836	Case report	Unclassified Renal Cell Carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Significant Response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Unclassified Renal Cell Carcinoma With Significant Response to Nivolumab.	 Clin Genitourin Cancer	Unable to provide
CANIT0000908	28128709	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	86	N/A	A retrospective cohort study	Eosinophilia is a  prognostic marker in patients with metastatic melanoma. In patients with checkpoint inhibitor  therapy, survival was significantly prolonged in every patient with eosinophilia   (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy  experienced at least once an eosinophilia of 5% or greater compared with 46% in  the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%,   respectively. Interestingly, in patients with more than 20% eosinophils (n = 7)  survival was prolonged with a median of 35 months (range 19-60 months) as  compared with 16 months (range 1-117 months).	N/A	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Eosinophil counts	Cell percentage/counts in blood	 2017 Jan	 Eosinophilic count as a biomarker for prognosis of melanoma patients and its  importance in the response to immunotherapy.	 Immunotherapy	 AIM: The prognostic role of eosinophils in cancer has been controversial. Some  entities such as gastrointestinal cancers show a better survival, while others  such as Hodgkin's lymphoma a worse survival in patients with eosinophilia.  Patients who exhibited an increase in eosinophils upon therapy with ipilimumab or  pembrolizumab were shown to survive longer. We wanted to investigate whether  eosinophilia is a prognostic marker in metastatic melanoma. METHODS: In total,  173 patients with metastatic melanoma from our data base (median age 60 years; n   = 86 with immunotherapy, n = 87 without immunotherapy) were analyzed for  eosinophil counts and survival over the course of 12 years. Eosinophilic count  was detected by peripheral blood smear. The ethical committee had approved this  retrospective study. RESULTS: Melanoma patients with eosinophilia at any point in  their course of disease show a trend toward longer survival independently of  their therapy. There is a statistically significant difference for the patients  who survive at least 12 months (p < 0.005). In patients with checkpoint inhibitor  therapy, survival was significantly prolonged in every patient with eosinophilia   (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy  experienced at least once an eosinophilia of 5% or greater compared with 46% in  the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%,   respectively. Interestingly, in patients with more than 20% eosinophils (n = 7)  survival was prolonged with a median of 35 months (range 19-60 months) as  compared with 16 months (range 1-117 months). CONCLUSION: Eosinophilia is a  prognostic marker in patients with metastatic melanoma.
CANIT0000909	28128709	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	86	N/A	A retrospective cohort study	Eosinophilia is a  prognostic marker in patients with metastatic melanoma. In patients with checkpoint inhibitor  therapy, survival was significantly prolonged in every patient with eosinophilia   (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy  experienced at least once an eosinophilia of 5% or greater compared with 46% in  the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%,   respectively. Interestingly, in patients with more than 20% eosinophils (n = 7)  survival was prolonged with a median of 35 months (range 19-60 months) as  compared with 16 months (range 1-117 months).	N/A	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Eosinophil counts	Cell percentage/counts in blood	 2017 Jan	 Eosinophilic count as a biomarker for prognosis of melanoma patients and its  importance in the response to immunotherapy.	 Immunotherapy	 AIM: The prognostic role of eosinophils in cancer has been controversial. Some  entities such as gastrointestinal cancers show a better survival, while others  such as Hodgkin's lymphoma a worse survival in patients with eosinophilia.  Patients who exhibited an increase in eosinophils upon therapy with ipilimumab or  pembrolizumab were shown to survive longer. We wanted to investigate whether  eosinophilia is a prognostic marker in metastatic melanoma. METHODS: In total,  173 patients with metastatic melanoma from our data base (median age 60 years; n   = 86 with immunotherapy, n = 87 without immunotherapy) were analyzed for  eosinophil counts and survival over the course of 12 years. Eosinophilic count  was detected by peripheral blood smear. The ethical committee had approved this  retrospective study. RESULTS: Melanoma patients with eosinophilia at any point in  their course of disease show a trend toward longer survival independently of  their therapy. There is a statistically significant difference for the patients  who survive at least 12 months (p < 0.005). In patients with checkpoint inhibitor  therapy, survival was significantly prolonged in every patient with eosinophilia   (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy  experienced at least once an eosinophilia of 5% or greater compared with 46% in  the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%,   respectively. Interestingly, in patients with more than 20% eosinophils (n = 7)  survival was prolonged with a median of 35 months (range 19-60 months) as  compared with 16 months (range 1-117 months). CONCLUSION: Eosinophilia is a  prognostic marker in patients with metastatic melanoma.
CANIT0000910	28128709	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	86	N/A	A retrospective cohort study	Eosinophilia is a  prognostic marker in patients with metastatic melanoma. In patients with checkpoint inhibitor  therapy, survival was significantly prolonged in every patient with eosinophilia   (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy  experienced at least once an eosinophilia of 5% or greater compared with 46% in  the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%,   respectively. Interestingly, in patients with more than 20% eosinophils (n = 7)  survival was prolonged with a median of 35 months (range 19-60 months) as  compared with 16 months (range 1-117 months).	N/A	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Eosinophil counts	Cell percentage/counts in blood	 2017 Jan	 Eosinophilic count as a biomarker for prognosis of melanoma patients and its  importance in the response to immunotherapy.	 Immunotherapy	 AIM: The prognostic role of eosinophils in cancer has been controversial. Some  entities such as gastrointestinal cancers show a better survival, while others  such as Hodgkin's lymphoma a worse survival in patients with eosinophilia.  Patients who exhibited an increase in eosinophils upon therapy with ipilimumab or  pembrolizumab were shown to survive longer. We wanted to investigate whether  eosinophilia is a prognostic marker in metastatic melanoma. METHODS: In total,  173 patients with metastatic melanoma from our data base (median age 60 years; n   = 86 with immunotherapy, n = 87 without immunotherapy) were analyzed for  eosinophil counts and survival over the course of 12 years. Eosinophilic count  was detected by peripheral blood smear. The ethical committee had approved this  retrospective study. RESULTS: Melanoma patients with eosinophilia at any point in  their course of disease show a trend toward longer survival independently of  their therapy. There is a statistically significant difference for the patients  who survive at least 12 months (p < 0.005). In patients with checkpoint inhibitor  therapy, survival was significantly prolonged in every patient with eosinophilia   (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy  experienced at least once an eosinophilia of 5% or greater compared with 46% in  the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%,   respectively. Interestingly, in patients with more than 20% eosinophils (n = 7)  survival was prolonged with a median of 35 months (range 19-60 months) as  compared with 16 months (range 1-117 months). CONCLUSION: Eosinophilia is a  prognostic marker in patients with metastatic melanoma.
CANIT0000911	28131785	Clinical research	Metastatic urothelial carcinoma after platinum therapy	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	265	N/A	A multicentre, phase II, single-arm study	Nivolumab monotherapy  provided meaningful clinical benefit, irrespective of PD-L1 expression, and was  associated with an acceptable safety profile in previously treated patients with   metastatic or surgically unresectable urothelial carcinoma.	Grade 3-4 treatment-related adverse events occurred in 48 (18%) of 270 patients-most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2017 Mar	 Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate  275): a multicentre, single-arm, phase 2 trial.	 Lancet Oncol	 BACKGROUND: Patients with metastatic urothelial carcinoma have a dismal prognosis  and few treatment options after first-line chemotherapy. Responses to second-line  treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune  checkpoint inhibitor antibody, for safety and activity in patients with  metastatic or surgically unresectable urothelial carcinoma whose disease  progressed or recurred despite previous treatment with at least one  platinum-based chemotherapy regimen. METHODS: In this multicentre, phase 2,  single-arm study, patients aged 18 years or older with metastatic or surgically  unresectable locally advanced urothelial carcinoma, measurable disease (according  to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative  Oncology Group performance statuses of 0 or 1, and available tumour samples for  biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until  disease progression and clinical deterioration, unacceptable toxicity, or other  protocol-defined reasons. The primary endpoint was overall objective response  confirmed by blinded independent review committee in all treated patients and by   tumour PD-L1 expression (>/=5% and >/=1%). This trial is registered with  ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still  ongoing. FINDINGS: Between March 9, 2015, and Oct 16, 2015, 270 patients from 63   sites in 11 countries received nivolumab, and 265 were evaluated for activity.  Median follow-up for overall survival was 7.00 months (IQR 2.96-8.77). Confirmed   objective response was achieved in 52 (19.6%, 95% CI 15.0-24.9) of 265 patients.   Confirmed objective response was achieved in 23 (28.4%, 95% CI 18.9-39.5) of the   81 patients with PD-L1 expression of 5% or greater, 29 (23.8%, 95% CI 16.5-32.3)   of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16.1%, 95% CI  10.5-23.1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3-4  treatment-related adverse events occurred in 48 (18%) of 270 patients-most  commonly grade 3 fatigue and diarrhoea, which each occurred in five patients.  Three deaths were attributed to treatment (pneumonitis, acute respiratory  failure, and cardiovascular failure). INTERPRETATION: Nivolumab monotherapy  provided meaningful clinical benefit, irrespective of PD-L1 expression, and was  associated with an acceptable safety profile in previously treated patients with   metastatic or surgically unresectable urothelial carcinoma. FUNDING:  Bristol-Myers Squibb.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000912	28132411	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Disappearing pigmented skin lesions with pembrolizumab treatment 	Disappearing pigmented skin lesions associated 	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 A case report of disappearing pigmented skin lesions associated with  pembrolizumab treatment for metastatic melanoma.	 Br J Dermatol	 Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell   death (PD)-1 receptor. Common cutaneous adverse side-effects of PD-1 inhibitors  include maculopapular rash, pruritus, vitiligo and lichenoid skin and mucosal  reactions. Here we describe a man in his sixties with metastatic melanoma treated  with pembrolizumab who subsequently developed fading or disappearance of  pigmented skin lesions, lightening of the skin, and poliosis of the eyebrows,  eyelashes and scalp and body hair. Compared with baseline high-resolution  three-dimensional total-body photography, we observed fading or disappearance of   solar lentigines, seborrhoeic keratoses and melanocytic naevi, suggesting that  PD-1 inhibitors may affect the evolution of these benign skin lesions. With  dermatoscopic follow-up, altered lesions showed either blue-grey  peppering/granularity or fading in colour without other identifiable features. No  halo lesions or lesions with surrounding inflammation were identified. One  changed pigmented lesion that showed blue-grey peppering/granularity on  dermoscopy was biopsied and interpreted as a macular seborrhoeic keratosis with  melanophages. Further studies are required to elucidate the effects of PD-1  inhibition on benign skin lesions.CI  - (c) 2017 British Association of Dermatologists.
CANIT0000913	28138869	Case report	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Two patients having early irradiated field recurrence who experienced tumor flare that showed pseudoprogression and rapid progression	N/A	N/A	N/A	N/A	N/A	 2017 Mar	 Risk of tumor flare after nivolumab treatment in patients with irradiated field  recurrence.	 Med Oncol	 Nivolumab offers a statistically superior survival benefit over docetaxel in  patients with advanced, previously treated squamous and non-squamous  non-small-cell lung cancer (NSCLC). However, we unexpectedly encountered tumor  flare that was associated with initially increased tumor lesion size and  subsequently decreased tumor burden in patients with NSCLC treated with  nivolumab, which is known as pseudoprogression. Tumor flare with rapid  progression related to accelerated progression after nivolumab treatment has also  been observed. Here we report two patients having early irradiated field  recurrence who experienced tumor flare that showed pseudoprogression and rapid   progression. In addition, we present a brief literature review on tumor flare  after nivolumab treatment.
CANIT0000914	28146044	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Eosinophilia and systemic symptom syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic  symptom syndrome.	 Melanoma Res	 Drug reaction with eosinophilia and systemic symptom syndrome is a potentially  fatal drug reaction that must be recognized quickly. Ipilimumab and nivolumab are  both important agents in the treatment of melanoma and continue to be studied in   other malignancies. We believe the mainstay of therapy for immunotherapy-induced   drug reaction with eosinophilia and systemic symptom syndrome is early  recognition, discontinuation of the inciting agent, supportive care, and  treatment with high dose corticosteroids with appropriate tapers that may reduce   the length of internal organ injury in cases with liver or kidney involvement.
CANIT0000915	28147928	Case report	Stage IV malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	While rare, evidence for the development of MG associated with pembrolizumab is growing. Prompt recognition of symptoms and discontinuation of pembrolizumab is necessary to help improve prognosis.	Diffuse, nonnecrotizing granulomatous lymphadenitishenia gravis	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Pembrolizumab-induced myasthenia gravis: A fatal case report.	 J Oncol Pharm Pract	 Purpose Pembrolizumab, a monoclonal antibody which inhibits the programmed cell  death 1 receptor, has been shown to efficaciously enhance pre-existing immune  responses to malignancies. However, safety concerns must also be considered as  pembrolizumab use has been associated with several life-threatening  immune-related adverse events (irAEs). We report a fatal case of  pembrolizumab-induced myasthenia gravis in a patient with no prior myasthenia  gravis history. Case report A 63-year-old male presented with right eyelid  drooping, puffiness, blurred vision, and shortness of breath two weeks after an  initial infusion of pembrolizumab. He was subsequently diagnosed with new onset  acetylcholine-receptor positive myasthenia gravis. Despite aggressive treatment  with corticosteroids, pyridostigmine, intravenous immunoglobulin, and  plasmapheresis, the patient clinically deteriorated and ultimately expired from  acute respiratory failure after a 12-day hospitalization. Discussion Current  package labeling for pembrolizumab warns against various irAEs associated with  its use including pneumonitis, colitis, and endocrinopathies. To date, only one  case of new onset myasthenia gravis and two case reports of myasthenia gravis  exacerbation have been identified. This case further highlights the mortality  risk associated with development of irAEs. Conclusion While rare, evidence for  the development of MG associated with pembrolizumab is growing. Prompt  recognition of symptoms and discontinuation of pembrolizumab is necessary to help  improve prognosis.
CANIT0000916	28158487	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); CTLA-4 (P16410); 	PD-1; CTLA-4	Short-term ipilimumab directly followed by nivolumab	Ipilimumab plus nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	29	11	A single-center retrospective cohort study	Treatment with short-term CTLA-4 blockade directly followed by PD-1 blockade may have similar efficacy but potentially lower toxicity when compared with concurrent therapy with anti-CTLA-4 and anti-PD-1.	Treatment-related AEs of grade 3 and 4 occurred in 38% of the patients.	N/A	N/A	N/A	N/A	N/A	 2017 Apr 1	 Short-term CTLA-4 blockade directly followed by PD-1 blockade in advanced  melanoma patients: a single-center experience.	 Ann Oncol	 Background: Combination of T cell checkpoint blockade by CTLA-4- and  PD-1-blockade is one of the most promising therapies in patients with advanced  melanoma. It induces superior response rates when compared with single-agent  therapy, but at the cost of a high percentage of grade 3 and 4 adverse events  (AEs). This combination therapy was until July 2016 not available in the  Netherlands, which prompted several physicians to treat patients with less than  standard numbers of courses of ipilimumab followed directly by nivolumab or  pembrolizumab. Patients and methods: In this retrospective analysis, patients  were included who were treated with two courses (day 0 and 21) anti-CTLA-4  (ipilimumab 3 mg/kg q3wk), directly followed by anti-PD-1 (starting at day 22  with nivolumab 3mg/kg q2wk or pembrolizumab 2 mg/kg q3wk). Data on  treatment-related AEs were collected from electronic patient records and scored  according to CTCAE 4.03 criteria. Overall response was evaluated using RECIST 1.1  for CT-scans and EORTC criteria for PET-scans. Results: Forty advanced melanoma  patients could be included (29/40 pembrolizumab, 11/40 nivolumab). Median  follow-up (FU) was 51 weeks (range: 4-63 weeks) with a minimum FU of 26 weeks.  Treatment-related AEs of grade 3 and 4 occurred in 38% of the patients. The best   overall response rate (BORR) was 55% (95% CI 39-70) and disease control rate was   75% (95% CI 59-87). Ongoing responses were observed in 82% of responding  patients. Conclusion: Treatment with short-term CTLA-4 blockade directly followed  by PD-1 blockade may have similar efficacy but potentially lower toxicity when  compared with concurrent therapy with anti-CTLA-4 and anti-PD-1. These results  warrant further investigation in a prospective randomized controlled clinical  trial.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000917	28162999	Clinical research	Stage III melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Placebo	Immune checkpoint therapy	Ipilimumab (DB06186); 	475	476	A multinational, double-blind, randomised, phase III	Despite increased toxicity, which led to treatment discontinuation for most  patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically  relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Mar	 Health-related quality of life with adjuvant ipilimumab versus placebo after  complete resection of high-risk stage III melanoma (EORTC 18071): secondary  outcomes of a multinational, randomised, double-blind, phase 3 trial.	 Lancet Oncol	 BACKGROUND: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with  placebo in patients with stage III melanoma. The primary endpoint,  recurrence-free survival, was significantly longer in the ipilimumab group than  in the placebo group. Investigator-reported toxic effects of ipilimumab consisted  mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse  events. Adjuvant treatment with ipilimumab in this setting was approved in  October, 2014, by the US Food and Drug Administration based on the results of the  primary outcome of this trial. Here, we report the results of the secondary  endpoint, health-related quality of life (HRQoL), of this trial. METHODS: EORTC  18071 was a multinational, double-blind, randomised, phase 3 trial in patients  with stage III cutaneous melanoma (excluding lymph node metastasis </=1 mm or  in-transit metastasis) in 19 countries worldwide. Participants were randomly  assigned (1:1) centrally by an interactive voice response system, to receive  either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3   months for up to 3 years. Using a minimisation technique, randomisation was  stratified by disease stage and geographical region. HRQoL was assessed with the   EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and  every 12 weeks thereafter up to 2 years, irrespective of disease progression.  Results were summarised by timepoint and in a longitudinal manner in the  intention-to-treat population. Two summary scores were calculated for each HRQoL   scale: the average score reported during induction (ipilimumab or placebo at a  dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43,  and 64-ie, four doses in 3 weeks), and the average score reported after  induction. A predefined threshold of a 10 point difference between arms was  considered clinically relevant. The primary HRQoL endpoint was the global health   scale, with the predefined hypothesis of no clinically relevant differences after  induction between groups. This trial is registered with EudraCT, number  2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between  July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment:  475 in the ipilimumab group and 476 in the placebo group. Compliance with  completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693  (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global  health scores during (77.32 [SD 17.36] vs 72.96 [17.82]; p=0.00011) and after  induction (76.48 [17.52] vs 72.32 [18.60]; p=0.00067) were statistically  significantly different between groups but were not clinically relevant. Mean  global health scores differed most between the groups at week 7 (77 [SD 19] in  the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70   [23]). Mean HRQoL scores differed by more than 10 points at week 10 between  treatment groups for diarrhoea (7.67 [SD 17.05] for placebo vs 18.17 [28.35] for   ipilimumab) and insomnia (15.17 [22.53] vs 25.60 [29.19]). INTERPRETATION:  Despite increased toxicity, which led to treatment discontinuation for most  patients during the induction phase of ipilimumab administration, overall HRQoL,   as measured by the EORTC QLQ-C30, was similar between groups, as no clinically  relevant differences (10 points or more) in global health status scores were  observed during or after induction. Clinically relevant deterioration for some  symptoms was observed at week 10, but after induction, no clinically relevant  differences remained. Together with the primary analysis, results from this trial  show that treatment with ipilimumab results in longer recurrence-free survival  compared with that for treatment with placebo, with little impairment in HRQoL  despite grade 3-4 investigator-reported adverse events. FUNDING: Bristol-Myers  Squibb.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000918	28167454	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	137	N/A	N/A	Following treatment, a decrease of CD8 cells from baseline to the time of the second drug dose and at later time points was strongly and consistently correlated with a high clinical response rate.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	A decrease of CD8 cells from baseline to the time of the second drug dose and at later time points	Gene expression signature on/in immune cell	 2017 Mar	 Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in  ipilimumab-treated stage IV melanoma patients.	 Eur J Cancer	 The role of the assessment of peripheral T-cell phenotypes in predicting overall   survival (OS) after ipilimumab treatment is unclear. Here, we analysed  mononuclear cells in the blood before and at different time points during  treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of  baseline naive and memory T-cells were measured by flow cytometry and correlated   with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8  effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p =  0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1   cells and the M category had independent impacts on OS (hazard ratio = 1.5, p =  0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies  of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively  associated with OS (p = 0.034) but did not correlate with clinical response.  Following treatment, a decrease of CD8 cells from baseline to the time of the  second drug dose and at later time points was strongly and consistently  correlated with a high clinical response rate. Our observations thus suggest an  important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for   clinical response of ipilimumab. Further validation of these biomarker candidates  is warranted.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000919	28167454	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	137	N/A	N/A	High baseline frequencies of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively associated with OS (p=0.034) but did not correlate with clinical response.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Baseline frequencies of late stage-differentiated effector memory CD8 cells (>23.8%)	Gene expression signature on/in immune cell	 2017 Mar	 Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in  ipilimumab-treated stage IV melanoma patients.	 Eur J Cancer	 The role of the assessment of peripheral T-cell phenotypes in predicting overall   survival (OS) after ipilimumab treatment is unclear. Here, we analysed  mononuclear cells in the blood before and at different time points during  treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of  baseline naive and memory T-cells were measured by flow cytometry and correlated   with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8  effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p =  0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1   cells and the M category had independent impacts on OS (hazard ratio = 1.5, p =  0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies  of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively  associated with OS (p = 0.034) but did not correlate with clinical response.  Following treatment, a decrease of CD8 cells from baseline to the time of the  second drug dose and at later time points was strongly and consistently  correlated with a high clinical response rate. Our observations thus suggest an  important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for   clinical response of ipilimumab. Further validation of these biomarker candidates  is warranted.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000920	28167454	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	137	N/A	N/A	High frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p = 0.029) and higher clinical response rates (p = 0.01).	N/A	N/A	N/A	Effector-memory type 1 T-cells (NCIT:C126419); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cell at baseline. 	Gene expression signature on/in immune cell	 2017 Mar	 Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in  ipilimumab-treated stage IV melanoma patients.	 Eur J Cancer	 The role of the assessment of peripheral T-cell phenotypes in predicting overall   survival (OS) after ipilimumab treatment is unclear. Here, we analysed  mononuclear cells in the blood before and at different time points during  treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of  baseline naive and memory T-cells were measured by flow cytometry and correlated   with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8  effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p =  0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1   cells and the M category had independent impacts on OS (hazard ratio = 1.5, p =  0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies  of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively  associated with OS (p = 0.034) but did not correlate with clinical response.  Following treatment, a decrease of CD8 cells from baseline to the time of the  second drug dose and at later time points was strongly and consistently  correlated with a high clinical response rate. Our observations thus suggest an  important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for   clinical response of ipilimumab. Further validation of these biomarker candidates  is warranted.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000921	28167454	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	137	N/A	N/A	The frequency of the M category had independent impacts on OS (hazard ratio = 1.9, p = 0.007).	N/A	N/A	N/A	M category (NCIT:C25727); 	M category	Disease status	 2017 Mar	 Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in  ipilimumab-treated stage IV melanoma patients.	 Eur J Cancer	 The role of the assessment of peripheral T-cell phenotypes in predicting overall   survival (OS) after ipilimumab treatment is unclear. Here, we analysed  mononuclear cells in the blood before and at different time points during  treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of  baseline naive and memory T-cells were measured by flow cytometry and correlated   with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8  effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p =  0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1   cells and the M category had independent impacts on OS (hazard ratio = 1.5, p =  0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies  of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively  associated with OS (p = 0.034) but did not correlate with clinical response.  Following treatment, a decrease of CD8 cells from baseline to the time of the  second drug dose and at later time points was strongly and consistently  correlated with a high clinical response rate. Our observations thus suggest an  important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for   clinical response of ipilimumab. Further validation of these biomarker candidates  is warranted.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000922	28174141	Case report	Advanced mucosal melanoma	Mucosal melanoma	MONDO:0000544	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	No clinical response	The most severe adverse events were categorised as CTCAE (common terminology criteria for adverse events) Grade 2.	N/A	N/A	N/A	N/A	N/A	 2017 Apr 1	 Checkpoint inhibition for advanced mucosal melanoma.	 Eur J Dermatol	 BACKGROUND: Whereas anti-PD-1 therapy has demonstrated a significant and durable   response against advanced cutaneous melanoma, conventional chemotherapies have  shown only minor benefit against advanced mucosal melanoma. OBJECTIVES: To  investigate the efficacy of anti-PD-1 therapy in a small cohort of patients with   mucosal melanoma of the head and neck. MATERIALS & METHODS: We analysed five  patients with mucosal melanoma of the head and neck who received nivolumab or  pembrolizumab, at an advanced stage. Expression of PD-L1 and PD-1 in all tumour  samples was evaluated immunohistochemically. RESULTS: All patients received at  least two cycles of nivolumab or pembrolizumab. The most severe adverse events  were categorised as CTCAE (common terminology criteria for adverse events) Grade   2. All patients showed progressive disease after restaging at three and six  months, and no partial or complete response was observed. Immunohistochemical  staining demonstrated PD-L1 expression in less than 5% of tumour cells.  CONCLUSION: Systemic therapy with either nivolumab or pembrolizumab showed no  clinical response, however, tumour progression was identified in all patients  using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and  immune-related response criteria (irRC) to evaluate tumour response.
CANIT0000923	28174141	Case report	Advanced mucosal melanoma	Mucosal melanoma	MONDO:0000544	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Case	No clinical response	The most severe adverse events were categorised as CTCAE (common terminology criteria for adverse events) Grade 2.	N/A	N/A	N/A	N/A	N/A	 2017 Apr 1	 Checkpoint inhibition for advanced mucosal melanoma.	 Eur J Dermatol	 BACKGROUND: Whereas anti-PD-1 therapy has demonstrated a significant and durable   response against advanced cutaneous melanoma, conventional chemotherapies have  shown only minor benefit against advanced mucosal melanoma. OBJECTIVES: To  investigate the efficacy of anti-PD-1 therapy in a small cohort of patients with   mucosal melanoma of the head and neck. MATERIALS & METHODS: We analysed five  patients with mucosal melanoma of the head and neck who received nivolumab or  pembrolizumab, at an advanced stage. Expression of PD-L1 and PD-1 in all tumour  samples was evaluated immunohistochemically. RESULTS: All patients received at  least two cycles of nivolumab or pembrolizumab. The most severe adverse events  were categorised as CTCAE (common terminology criteria for adverse events) Grade   2. All patients showed progressive disease after restaging at three and six  months, and no partial or complete response was observed. Immunohistochemical  staining demonstrated PD-L1 expression in less than 5% of tumour cells.  CONCLUSION: Systemic therapy with either nivolumab or pembrolizumab showed no  clinical response, however, tumour progression was identified in all patients  using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and  immune-related response criteria (irRC) to evaluate tumour response.
CANIT0000924	28188133	Clinical research	Relapsed or refractory NK/T-cell lymphoma failing l-asparaginase	Mature t-cell and nk-cell non-hodgkin lymphoma	MONDO:0000430	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	7	N/A	N/A	PD1 blockade with pembrolizumab was a potent strategy for NK/T-cell lymphomas failing l-asparaginase regimens.	The only adverse event was grade 2 skin graft-versus-host disease in one patient with previous allogeneic HSCT.	N/A	N/A	N/A	N/A	N/A	 2017 Apr 27	 PD1 blockade with pembrolizumab is highly effective in relapsed or refractory  NK/T-cell lymphoma failing l-asparaginase.	 Blood	 Natural killer (NK)/T-cell lymphomas failing L-asparaginse regimens have no known  salvage and are almost invariably fatal. Seven male patients with NK/T-cell  lymphoma (median age, 49 years; range, 31-68 years) for whom a median of 2  (range, 1-5) regimens (including l-asparaginase regimens and allogeneic  hematopoietic stem-cell transplantation [HSCT] in 2 cases) failed were treated  with the anti-programmed death 1 (PD1) antibody pembrolizumab. All patients  responded, according to various clinical, radiologic (positron emission  tomography), morphologic, and molecular (circulating Epstein-Barr virus [EBV]  DNA) criteria. Two patients achieved complete response (CR) in all parameters.  Three patients achieved clinical and radiologic CRs, with two having molecular  remission (undetectable EBV DNA) but minimal EBV-encoded RNA-positive cells in  lesions comprising predominantly CD3(+)CD4(+) and CD3(+)CD8(+) T cells (which  ultimately disappeared, suggesting they represented pseudoprogression) and one  having detectable EBV DNA despite morphologic CR. Two patients achieved partial  response (PR). After a median of 7 (range, 2-13) cycles of pembrolizumab and a  follow-up of a median of 6 (range, 2-10) months, all five CR patients were still   in remission. The only adverse event was grade 2 skin graft-versus-host disease  in one patient with previous allogeneic HSCT. Expression of the PD1 ligand was  strong in 4 patients (3 achieving CR) and weak in 1 (achieving PR). PD1 blockade   with pembrolizumab was a potent strategy for NK/T-cell lymphomas failing  l-asparaginase regimens.CI  - (c) 2017 by The American Society of Hematology.
CANIT0000925	28204866	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6	N/A	Case	Vedolizumab is an effective and well-tolerated therapy for steroid refractory and/or dependent enterocolitis caused by treatment with ipilimumab. 	Enterocolitis	N/A	N/A	N/A	N/A	N/A	 2017 May	 Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis.	 Cancer Immunol Immunother	 Immune checkpoint inhibitors (ICPI), such as ipilimumab [anti-cytotoxic  T-lymphocyte antigen-4 (CTLA-4) antibody] and nivolumab or pembrolizumab  [anti-programmed cell death protein-1 (PD-1) antibodies], improve survival in  several cancer types. Since inhibition of CTLA-4 or PD-1 leads to non-selective  activation of the immune system, immune-related adverse events (irAEs) are  frequent. Enterocolitis is a common irAE, currently managed with corticosteroids   and, if necessary, anti-tumor necrosis factor-alpha therapy. Such a regimen  carries a risk of serious side-effects including infections, and may potentially   imply impaired antitumor effects. Vedolizumab is an anti-integrin alpha4beta7  antibody with gut-specific immunosuppressive effects, approved for Crohn's  disease and ulcerative colitis. We report a case series of seven patients with  metastatic melanoma or lung cancer, treated with vedolizumab off-label for  ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October  2016. Clinical, laboratory, endoscopic, and histologic data were analyzed.  Patients initially received corticosteroids but were steroid-dependent and/or  partially refractory. One patient was administered infliximab but was refractory.  The median time from onset of enterocolitis to start of vedolizumab therapy was  79 days. Following vedolizumab therapy, all patients but one experienced  steroid-free enterocolitis remission, with normalized fecal calprotectin. This  was achieved after a median of 56 days from vedolizumab start, without any  vedolizumab-related side-effects noted. The patient in whom vedolizumab was not  successful, due to active ulcerative colitis, received vedolizumab  prophylactically. This is the first case series to suggest that vedolizumab is an  effective and well-tolerated therapeutic for steroid-dependent or partially  refractory ICPI-induced enterocolitis. A larger prospective study to evaluate  vedolizumab in this indication is warranted.
CANIT0000926	28204866	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Vedolizumab is an effective and well-tolerated therapy for steroid refractory and/or dependent enterocolitis caused by treatment with nivolumab. 	Enterocolitis	N/A	N/A	N/A	N/A	N/A	 2017 May	 Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis.	 Cancer Immunol Immunother	 Immune checkpoint inhibitors (ICPI), such as ipilimumab [anti-cytotoxic  T-lymphocyte antigen-4 (CTLA-4) antibody] and nivolumab or pembrolizumab  [anti-programmed cell death protein-1 (PD-1) antibodies], improve survival in  several cancer types. Since inhibition of CTLA-4 or PD-1 leads to non-selective  activation of the immune system, immune-related adverse events (irAEs) are  frequent. Enterocolitis is a common irAE, currently managed with corticosteroids   and, if necessary, anti-tumor necrosis factor-alpha therapy. Such a regimen  carries a risk of serious side-effects including infections, and may potentially   imply impaired antitumor effects. Vedolizumab is an anti-integrin alpha4beta7  antibody with gut-specific immunosuppressive effects, approved for Crohn's  disease and ulcerative colitis. We report a case series of seven patients with  metastatic melanoma or lung cancer, treated with vedolizumab off-label for  ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October  2016. Clinical, laboratory, endoscopic, and histologic data were analyzed.  Patients initially received corticosteroids but were steroid-dependent and/or  partially refractory. One patient was administered infliximab but was refractory.  The median time from onset of enterocolitis to start of vedolizumab therapy was  79 days. Following vedolizumab therapy, all patients but one experienced  steroid-free enterocolitis remission, with normalized fecal calprotectin. This  was achieved after a median of 56 days from vedolizumab start, without any  vedolizumab-related side-effects noted. The patient in whom vedolizumab was not  successful, due to active ulcerative colitis, received vedolizumab  prophylactically. This is the first case series to suggest that vedolizumab is an  effective and well-tolerated therapeutic for steroid-dependent or partially  refractory ICPI-induced enterocolitis. A larger prospective study to evaluate  vedolizumab in this indication is warranted.
CANIT0000927	28212992	Clinical research	Recurrent or advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	111	N/A	A phase II clinical trial	Although the risk factors for nivolumab-induced interstitial lung disease were not identified, careful monitoring including imaging examinations is important in preventing the worsening of ILD in patients receiving nivolumab.	Interstitial lung disease	N/A	N/A	N/A	N/A	N/A	 2017 Feb	 Nivolumab-induced interstitial lung disease analysis of two phase II studies  patients with recurrent or advanced non-small-cell lung cancer.	 Lung Cancer	 OBJECTIVES: Drug-induced interstitial lung disease (ILD) is often associated with  high mortality; however it is difficult to predict and manage. we examined the  clinical findings and imaging characteristics of nivolumab induced ILD reported  in the two phase II studies patients with recurrent or advanced non-small-cell  lung cancer. MATERIALS AND METHODS: We examined the clinical findings and imaging  characteristics of all cases of ILD reported in two phase II trials of nivolumab,  an anti-programmed death-1 antibody, in Japanese patients with recurrent or  advanced non-small-cell lung cancer. These studies are registered with the Japan   Pharmaceutical Information Center, numbers JapicCTI-132072, JapicCTI-132073.  RESULTS: Eight (7.2%; two with squamous cell carcinoma, six with non-squamous  cell carcinoma) of the 111 patients included in these two studies experienced  ILD, and a causal relationship with nivolumab could not be ruled out in any of  them. ILD of >/=grade 3 severity was found in four patients (3.6%), and ILD was  considered a serious treatment-related adverse event in seven patients (6.3%).  All of the patients who experienced ILD were male and had a history of smoking,  with a median age of 65 years (range 52-78 years). In seven of the eight patients  who experienced ILD, their events were rapidly resolving or resolved  spontaneously or with steroid therapy; one patient died of respiratory failure  without resolution of ILD, after docetaxel treatment was initiated following  nivolumab discontinuation. Chest computed tomography images for the seven  patients with resolving or resolution of ILD showed a pattern of organizing  pneumonia or nonspecific interstitial pneumonia without traction bronchiectasis,   while the patient who died had traction bronchiectasis. CONCLUSION: Although the   risk factors for nivolumab-induced ILD were not identified, careful monitoring  including imaging examinations is important in preventing the worsening of ILD in  patients receiving nivolumab.CI  - Copyright A(c) 2017 The Authors. Published by Elsevier B.V. All rights reserved.
CANIT0000928	28222797	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	13	N/A	N/A	PBMCs of patients treated with ipi secreted significantly more cytokines, chemokines and growth factors in response to NY-ESO-1 than to gp-100 or MART-1.	N/A	N/A	N/A	Peripheral blood mononuclear cells (NCIT:C12954); 	PBMCs secreted more cytokines	Gene expression signature in serum	 2017 Feb 21	 Melanoma antigen-specific effector T cell cytokine secretion patterns in patients  treated with ipilimumab.	 J Transl Med	 BACKGROUND: In a previously reported study, patients with regionally advanced  melanoma were treated with neoadjuvant ipilimumab (ipi) (Tarhini in PLoS ONE  9(2): e87705, 3). Significant changes in circulating myeloid derived suppressor  cells (MDSC), regulatory T cells (Treg) and peptide specific type I CD4(+) and  CD8(+) T cells were noted at week 6 that correlated with clinical outcome.  Characterization of antigen-specific effector T cell secreted cytokines may shed   insights into ipi associated T cell activation and function. METHODS: Patients  were treated with neoadjuvant ipi (10 mg/kg every 3 weeks x2) administered  intravenously before and after surgery. Peripheral blood mononuclear cells (PBMC)  that were collected at baseline and week 6 (after ipi) were tested here. Each  sample was divided into 5 groups and stimulated with controls or shared melanoma   antigen overlapping peptide pools (NY-ESO 1, gp-100, MART-1). Secreted cytokines,  chemokines and growth factors were assessed using Luminex. Cytokine expression  levels between the 3 antigen groups were compared using the Wilcox rank-sum test.  RESULTS: Seventeen cytokines were differentially expressed with stimulation by  each antigen at baseline (p value <0.05): IL1beta, MIP1beta, IL1RA, VEGF, IL13,  IL17, MIP1alpha, GM-CSF, MCP1, IL5, IL2R, IL4, IL10, IFNG, TNFalpha, IL8 and   IL2. At week 6, 15 cytokines were differentially expressed (p < 0.05): IL1beta,  VEGF, G-CSF, HGF, IL13, IL17, GM-CSF, MCP1, IL5, IL7, IL4, IL10, IFNG, IL8  and IL2. Patients were later clustered based on cytokine expression levels at  baseline and at week 6, and recurrence free survival (RFS) was compared. Clear  differences in RFS were noted based on cytokine level clustering both at baseline  and at week 6: Patients whose PBMCs secreted more cytokines in response to  NY-ESO-1 showed a trend towards better RFS. CONCLUSIONS: PBMCs of patients  treated with ipi secreted significantly more cytokines, chemokines and growth  factors in response to NY-ESO-1 than to gp-100 or MART-1. These cytokines  belonged to different functional groups, including inflammatory, type 1, type 2  and regulatory, that warrant further study. Patients whose PBMCs secreted more  cytokines (particularly in response to NY-ESO-1) tended to have better RFS,  supporting further exploration in terms of therapeutic predictive value.
CANIT0000929	28223062	Clinical research	Previously treated unresectable metastatic anal cancer	Anal cancer	EFO:1000081	Anus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	A single-arm, multicentre, phase II trial 	Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease.	Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported.	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a  multicentre, single-arm, phase 2 study.	 Lancet Oncol	 BACKGROUND: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy  associated with infection by human papillomavirus (HPV). No consensus treatment  approach exists for the treatment of metastatic disease. Because intratumoral HPV  oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade  immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab   for patients with metastatic SCCA. METHODS: We did this single-arm, multicentre,   phase 2 trial at ten academic centres in the USA. We enrolled patients with  treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3  mg/kg). The primary endpoint was response according to Response Evaluation  Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At  the time of data cutoff, the study was ongoing, with patients continuing to  receive treatment. The study is registered with ClinicalTrials.gov, number  NCT02314169. RESULTS: We screened 39 patients, of whom 37 were enrolled and  received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI  15-33]) had responses. There were two complete responses and seven partial  responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1),   and hypothyroidism (n=1). No serious adverse events were reported.  INTERPRETATION: To our knowledge, this is the first completed phase 2 trial of  immunotherapy for SCCA. Nivolumab is well tolerated and effective as a  monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears  to be a promising approach for patients with this orphan disease. FUNDING:  National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal  Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson   Moon Shots Program, and an anonymous philanthropic donor.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000930	28228279	Case report	Metastatic uterine leiomyosarcoma	Uterine leiomyosarcoma	EFO:1001974	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Anti-PD-1 monotherapy can induce complete tumor remission in uterine leiomyosarcoma. Biallelic PTEN loss is associated with resistance to PD-1 blockade in sarcoma	N/A	N/A	N/A	PTEN (P60484); 	Biallelic PTEN loss	Mutational status	 2017 Feb 21	 Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade  Therapy in Metastatic Uterine Leiomyosarcoma.	 Immunity	 Response to immune checkpoint blockade in mesenchymal tumors is poorly  characterized, but immunogenomic dissection of these cancers could inform  immunotherapy mediators. We identified a treatment-naive patient who has  metastatic uterine leiomyosarcoma and has experienced complete tumor remission  for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed the primary  tumor, the sole treatment-resistant metastasis, and germline tissue to explore  mechanisms of immunotherapy sensitivity and resistance. Both tumors stained  diffusely for PD-L2 and showed sparse PD-L1 staining. PD-1(+) cell infiltration  significantly decreased in the resistant tumor (p = 0.039). Genomically, the  treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced  expression of two neoantigens that demonstrated strong immunoreactivity with  patient T cells in vitro, suggesting long-lasting immunological memory. In this  near-complete response to PD-1 blockade in a mesenchymal tumor, we identified  PTEN mutations and reduced expression of genes encoding neoantigens as potential   mediators of resistance to immune checkpoint therapy.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0000931	28233446	Case report	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Development of de novo psoriasis	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Mar	 Development of de novo psoriasis during nivolumab therapy for metastatic renal  cell carcinoma: immunohistochemical analyses and clinical outcome.	 APMIS	Unable to provide
CANIT0000932	28239465	Case report	Relapsed classical Hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation	Classic hodgkin lymphoma	MONDO:0009348	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Case	Our case series demonstrates that anti-PD-1 therapy with nivolumab can be highly effective following allogeneic transplant for Hodgkin's lymphoma, but serious immune-related adverse events can occur, requiring very close monitoring and interruption of therapy.	Nivolumab was well-tolerated in two of the patients. However, nivolumab had to be discontinued in one patient due to development of immune-related polyarthritis requiring treatment with systemic corticosteroids and methotrexate.	N/A	N/A	N/A	N/A	N/A	2017	 PD-1 blockade induces remissions in relapsed classical Hodgkin lymphoma following  allogeneic hematopoietic stem cell transplantation.	 J Immunother Cancer	 BACKGROUND: Allogeneic hematopoietic stem cell transplantation and checkpoint  blockade therapy are immune-based therapies that have activity in selected  refractory hematologic malignancies. Interest has developed in combining these  treatments for high-risk hematologic diseases. However, there is concern that  checkpoint blockade could augment graft-versus-host disease, and very few studies  have evaluated the safety of checkpoint blockade in the post-allogeneic setting.   Here, we report the outcomes of three patients with relapsed classical Hodgkin's   lymphoma following allogeneic transplant that were treated with the anti-PD-1  antibody, nivolumab. CASE PRESENTATIONS: Three patients with Hodgkin's lymphoma  relapsed following allogeneic transplant received nivolumab therapy at our  institution. All patients were free of graft-versus-host disease and were off of   all systemic immunosuppressive medications at the time of nivolumab treatment.  Nivolumab was well-tolerated in two of the patients. However, nivolumab had to be  discontinued in one patient due to development of immune-related polyarthritis  requiring treatment with systemic corticosteroids and methotrexate. Objective  responses were observed in all three patients. CONCLUSIONS: Our case series  demonstrates that anti-PD-1 therapy with nivolumab can be highly effective  following allogeneic transplant for Hodgkin's lymphoma, but serious  immune-related adverse events can occur, requiring very close monitoring and  interruption of therapy.
CANIT0000933	28239466	Case report	Metastatic squamous cell carcinoma of lung	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Myxedema crisis	N/A	N/A	N/A	N/A	N/A	2017	 Nivolumab induced myxedema crisis.	 J Immunother Cancer	 BACKGROUND: Nivolumab is an anti-programmed cell death (anti-PD-1) monoclonal  antibody that is approved by Food and Drug Administration for treatment of  metastatic non-small cell lung cancer, metastatic melanoma, relapsed Hodgkin  lymphoma and advanced renal cell cancer. We report a rare case of myxedema crisis  induced by nivolumab in a patient with metastatic squamous cell carcinoma of  lung. CASE PRESENTATION: Fifty three-year old woman with metastatic squamous cell  carcinoma currently on treatment with nivolumab presented with diffuse facial and  tongue swelling, slurred speech, depressed mentation, fatigue and weakness.  Initial evaluation revealed severe hypothyroidism with thyroid stimulating  hormone of 237 micro Unit/mL (Normal Reference range: 0.27-4.20 micro unit/mL)  and undetectable free T4. Patient was diagnosed with nivolumab induced myxedema  crisis. She was treated successfully with levothyroxine with complete resolution   of her symptoms. Nivolumab was safely restarted once the symptoms of myxedema  resolved. CONCLUSION: Nivolumab can cause immune-mediated endocrinopathies  including thyroiditis, hypophysitis, adrenal insufficiency and type 1 diabetes  mellitus. High index of suspicion and periodic measurement of thyroid function  tests are recommended in patients receiving nivolumab therapy. Our case also  suggests that once the myxedema crisis is treated and symptoms are resolved,  nivolumab can be safely re-challenged.
CANIT0000934	28239468	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Initial investigations revealed severe anemia with appropriate reticulocytosis, severely elevated lactate dehydrogenase, undetectable haptoglobin level and positive direct coombs test. Patient was diagnosed with severe autoimmune hemolytic anemia secondary to ipilimumab and nivolumab. She was successfully treated with high dose steroids and rituximab.	N/A	N/A	N/A	N/A	N/A	2017	 Immunotherapy-associated autoimmune hemolytic anemia.	 J Immunother Cancer	 BACKGROUND: Immunotherapy has been widely used in the treatment of several solid   and hematologic malignancies. Checkpoint inhibitors have been the forefront of  cancer immunotherapy in recent years. Cytotoxic T-lymphocyte-associated protein 4  (CTLA-4) and programmed cell death 1 (PD-1) pathway are the prototypic checkpoint  targets for immunotherapy. When combined, CTLA-4 and PD-1 checkpoint inhibitors  work synergistically, but with increased probability of toxicity. The following  case represents an unusual adverse effect of combined treatment with ipilimumab  and nivolumab used for treatment of metastatic melanoma. CASE PRESENTATION: A  43-year-old woman with metastatic melanoma presented with severe generalized  weakness and fatigue. She has received two cycles of ipilimumab and nivolumab,  last administered 3 weeks prior to her presentation. Initial investigations  revealed severe anemia with appropriate reticulocytosis, severely elevated  lactate dehydrogenase, undetectable haptoglobin level and positive direct coombs   test. Patient was diagnosed with severe autoimmune hemolytic anemia secondary to   ipilimumab and nivolumab. She was successfully treated with high dose steroids  and rituximab. CONCLUSIONS: In our case, we present a rare but serious adverse  effect of immunotherapy. We illustrate the clinical presentation and management  of immunotherapy associated autoimmune hemolytic anemia. Immunotherapy has  revolutionized the treatment of many malignant conditions; therefore, it is  imperative for health care professionals caring for cancer patient to be familiar  with the adverse effects of immunotherapy, which allow for early recognition and   management of these potentially lethal side effects.
CANIT0000935	28242504	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	30	N/A	N/A	Patients with normal baseline levels of CD45RO+CD8+ T cells showed a significant longer overall survival when treated with ipilimumab but not pembrolizumab.	N/A	N/A	N/A	CD8 (P01732); CD45RO (P08575); T-Lymphocyte (NCIT:C12476); 	Baseline levels of CD45RO(+)CD8(+) T-cell 	Gene expression signature on/in immune cell	 2017 Apr	 The proportion of circulating CD45RO(+)CD8(+) memory T cells is correlated with  clinical response in melanoma patients treated with ipilimumab.	 Eur J Cancer	 BACKGROUND: Immune checkpoint blockade (ICB) has been a breakthrough in the  treatment of metastatic melanoma. But with only about 20-40% long-term responders  and severe side-effects in about 12-17%, finding predictive markers for treatment  response is of great interest. METHODS: We prospectively assessed clinical data,   haematologic parameters and freshly isolated peripheral blood mononuclear cells  of 30 patients treated with ipilimumab (n = 21) and pembrolizumab (n = 9) prior  to the first 4 cycles with ICB and before the first tumour assessment. RESULTS:  We discovered that the baseline levels of CD45RO(+)CD8(+) T cells significantly  differed among the patients. Thirteen (43%) of our patients had normal baseline  levels of CD45RO(+)CD8(+) T cells, whereas 17 (57%) patients were low on  CD45RO(+)CD8(+) T cells. The baseline levels of CD45RO(+)CD8(+) T cells  correlated significantly with the response to ipilimumab but not pembrolizumab.  Patients with baseline levels of lower/equal 25% of CD45RO(+)CD8(+) T cells did  not respond to treatment with ipilimumab. Phenotyping the CD8(+) T cells in  patients treated with ipilimumab revealed an activated HLA-DR(+)CD25(-)  phenotype, implying antigen non-specific stimulation. The levels of the  HLA-DR(+)CD25(-)CD8(+) T cells were significantly higher in patients with a  normal baseline of CD45RO(+)CD8(+) T cells and even increased significantly  during treatment. Furthermore, proliferation of melanoma antigen recognized by T   cells 1 (MART-1)-specific CD8(+) T cells was not observed. Patients with normal  baseline levels of CD45RO(+)CD8(+) T cells showed a significant longer overall  survival when treated with ipilimumab but not pembrolizumab. CONCLUSION: Patients  with normal baseline levels of CD45RO(+)CD8(+) T cells respond significantly more  frequently to treatment with ipilimumab and the CD8(+) T cells appear to be  antigen non-specifically activated. The baseline level of CD45RO(+)CD8(+) T cells  represents a promising factor as biomarker for the prediction of the response to   ipilimumab.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000936	28242504	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	30	N/A	N/A	Patients with normal baseline levels of CD45RO+CD8+ T cells showed a significant longer overall survival when treated with ipilimumab but not pembrolizumab.	N/A	N/A	N/A	CD8 (P01732); CD45RO (P08575); T-Lymphocyte (NCIT:C12476); 	Baseline levels of CD45RO(+)CD8(+) T-cell 	Gene expression signature on/in immune cell	 2017 Apr	 The proportion of circulating CD45RO(+)CD8(+) memory T cells is correlated with  clinical response in melanoma patients treated with ipilimumab.	 Eur J Cancer	 BACKGROUND: Immune checkpoint blockade (ICB) has been a breakthrough in the  treatment of metastatic melanoma. But with only about 20-40% long-term responders  and severe side-effects in about 12-17%, finding predictive markers for treatment  response is of great interest. METHODS: We prospectively assessed clinical data,   haematologic parameters and freshly isolated peripheral blood mononuclear cells  of 30 patients treated with ipilimumab (n = 21) and pembrolizumab (n = 9) prior  to the first 4 cycles with ICB and before the first tumour assessment. RESULTS:  We discovered that the baseline levels of CD45RO(+)CD8(+) T cells significantly  differed among the patients. Thirteen (43%) of our patients had normal baseline  levels of CD45RO(+)CD8(+) T cells, whereas 17 (57%) patients were low on  CD45RO(+)CD8(+) T cells. The baseline levels of CD45RO(+)CD8(+) T cells  correlated significantly with the response to ipilimumab but not pembrolizumab.  Patients with baseline levels of lower/equal 25% of CD45RO(+)CD8(+) T cells did  not respond to treatment with ipilimumab. Phenotyping the CD8(+) T cells in  patients treated with ipilimumab revealed an activated HLA-DR(+)CD25(-)  phenotype, implying antigen non-specific stimulation. The levels of the  HLA-DR(+)CD25(-)CD8(+) T cells were significantly higher in patients with a  normal baseline of CD45RO(+)CD8(+) T cells and even increased significantly  during treatment. Furthermore, proliferation of melanoma antigen recognized by T   cells 1 (MART-1)-specific CD8(+) T cells was not observed. Patients with normal  baseline levels of CD45RO(+)CD8(+) T cells showed a significant longer overall  survival when treated with ipilimumab but not pembrolizumab. CONCLUSION: Patients  with normal baseline levels of CD45RO(+)CD8(+) T cells respond significantly more  frequently to treatment with ipilimumab and the CD8(+) T cells appear to be  antigen non-specifically activated. The baseline level of CD45RO(+)CD8(+) T cells  represents a promising factor as biomarker for the prediction of the response to   ipilimumab.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000937	28245875	Case report	Refractory, metastatic lung squamous cell cancer	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Severe nivolumab-induced pneumonitis preceding durable clinical remission	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Feb 28	 Severe nivolumab-induced pneumonitis preceding durable clinical remission in a  patient with refractory, metastatic lung squamous cell cancer: a case report.	 J Hematol Oncol	 BACKGROUND: Programmed cell death 1 (PD-1) and its ligand 1 (PD-L1) inhibitors  have quickly become standard of care for patients with advanced non-small cell  lung cancer and increasing numbers of other cancer types. In this report, we  discuss the clinical history, pathological evaluation, and genomic findings in a   patient with metastatic lung squamous cell cancer (SCC) who developed severe  nivolumab-induced pneumonitis preceding durable clinical remission after three  doses of nivolumab. CASE PRESENTATION: A patient with chemotherapy-refractory,  metastatic lung SCC developed symptomatic pneumonitis by week 4 after nivolumab  treatment, concurrently with onset of a potent antitumor response. Despite  discontinuation of nivolumab after three doses and the use of high dose oral  corticosteroids for grade 3 pneumonitis, continued tumor response to a complete  remission by 3 months was evident by radiographic assessment. At the time of this  submission, the patient has remained in clinical remission for 14 months. High  PD-L1 expression by immunohistochemistry staining was seen in intra-alveolar  macrophages and viable tumor cells in the pneumonitis and recurrent tumor  specimens, respectively. Tumor genomic profiling by FoundationOne targeted exome   sequencing revealed a very high tumor mutation burden (TMB) corresponding to  95-96 percentile in lung SCC, i.e., 87.4-91.0 and 82.9 mut/Mb, respectively, in  pre- and post-nivolumab tumor specimens. Except for one, the 13 functional  genomic alterations remained the same in the diagnostic, recurrent, and  post-treatment, relapsed tumor specimens, suggesting that nivolumab reset the  patient's immune system against one or more preexisting tumor-associated antigens  (TAAs). One potential TAA candidate is telomerase reverse transcriptase (TERT) in  which an oncogenic promoter -146C>T mutation was detected. Human leukocyte  antigen (HLA) typing revealed HLA-A*0201 homozygosity, which is the prevalent HLA  class I allele that has been used to develop universal cancer vaccine targeting  TERT-derived peptides. CONCLUSIONS: Nivolumab could quickly reset and sustain  host immunity against preexisting TAA(s) in this chemotherapy-refractory lung SCC  patient. Further mechanistic studies are needed to characterize the effective  immune cells and define the HLA-restricted TAA(s) and the specific T cell  receptor clones responsible for the potent antitumor effect, with the aim of  developing precision immunotherapy with improved effectiveness and safety.
CANIT0000938	28248716	Case report	Widespread BRAFV600E mutant metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); ipilimumab (DB06186); 	1	N/A	Case	Feasible treatment option	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Intraepithelial Melanoma in the Stomach After Treatment With Immune Checkpoint  Blockade Therapy.	 Am J Dermatopathol	 Melanoma is the most common tumor to metastasize to the gastrointestinal tract,  commonly affecting the small intestine, colon, and anorectum. Primary mucosal  melanoma can arise in any gastrointestinal site, most frequently affecting  anorectal mucosa. Melanoma involving the gastric mucosa, specifically, is  exceedingly rare and carries a poor prognosis with a median survival of 5 months.  The presence of atypical melanocytes exclusively within gastric epithelium has  not been previously described. We report a case of a 52-year-old man with  widespread BRAFV600E mutant metastatic melanoma who was referred to our  institution for immune checkpoint antibody-blockade therapy. The patient had  previously been treated with BRAF inhibitors, and despite initial response to  therapy, developed resistance leading to disease progression and multiorgan  involvement including the liver, spleen, and axial skeleton. Immune checkpoint  antibody blockade with ipilimumab and pembrolizumab has been shown to induce  significant tumor regression in patients with melanoma by upregulating T-cell  activity and removing the natural check on the host immune response. After his  first dose of combination therapy, the patient underwent an upper  gastrointestinal tract endoscopy for severe nausea and was found to have 2  pigmented lesions within the gastric body, one of which was biopsied. The biopsy   showed gastric body-fundic type mucosa with melanophages and scattered atypical  intraepithelial melanocytes within the lamina propria, which were strongly  positive for S100, HMB45, SOX10, and MITF. A Fontana-Masson silver stain was  performed for confirmation. The finding of predominantly atypical intraepithelial  melanocytes associated with melanin pigment was interpreted as metastatic  melanoma to the stomach with some regression in response to immune checkpoint  blockade therapy.
CANIT0000939	28257394	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	8	N/A	Case	Our study suggests PD1i retreatment as a reasonable option for selected patients.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Reinduction of PD1-inhibitor therapy: first experience in eight patients with  metastatic melanoma.	 Melanoma Res	 Significant progress has been made in the treatment of metastatic melanoma during  the last years. Approval of immune-checkpoint inhibitors and targeted therapies  has been achieved recently. The sequencing of these therapies is an important  issue. Here, we report our experience with the treatment and retreatment with  PD1-inhibitors (PD1i) in eight patients. The patients (two female and seven male   with a median age of 70 years, all melanoma stage IV, M1c) underwent a first  treatment period with PD1i for a median of 5.5 months. Three (37.5%) patients had  a stable disease as best response, two (25%) showed progression, two (25%) showed  partial response, and one (12.5%) achieved complete remission. PD1i was  discontinued due to disease progression in seven patients and due to side effects  (pancreatitis) in one patient. Patients were subsequently treated with ipilimumab  (n=2), or chemotherapy (n=4), or no other medical treatment (n=2). All eight  patients were subsequently retreated with PD1i for a median of 2.5 months. One  (12.5%) developed a partial response, whereas in three patients (37.5%) the  disease was stabilized. PD1i have shown a high and durable response rate in the  first-line treatment of metastatic melanoma. Our study suggests PD1i retreatment   as a reasonable option for selected patients. Further investigations are needed  to verify the value of PD1i re-exposure and to identify subgroups of patients who  can benefit.
CANIT0000940	28257394	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	8	N/A	Case	Our study suggests PD1i retreatment as a reasonable option for selected patients.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Reinduction of PD1-inhibitor therapy: first experience in eight patients with  metastatic melanoma.	 Melanoma Res	 Significant progress has been made in the treatment of metastatic melanoma during  the last years. Approval of immune-checkpoint inhibitors and targeted therapies  has been achieved recently. The sequencing of these therapies is an important  issue. Here, we report our experience with the treatment and retreatment with  PD1-inhibitors (PD1i) in eight patients. The patients (two female and seven male   with a median age of 70 years, all melanoma stage IV, M1c) underwent a first  treatment period with PD1i for a median of 5.5 months. Three (37.5%) patients had  a stable disease as best response, two (25%) showed progression, two (25%) showed  partial response, and one (12.5%) achieved complete remission. PD1i was  discontinued due to disease progression in seven patients and due to side effects  (pancreatitis) in one patient. Patients were subsequently treated with ipilimumab  (n=2), or chemotherapy (n=4), or no other medical treatment (n=2). All eight  patients were subsequently retreated with PD1i for a median of 2.5 months. One  (12.5%) developed a partial response, whereas in three patients (37.5%) the  disease was stabilized. PD1i have shown a high and durable response rate in the  first-line treatment of metastatic melanoma. Our study suggests PD1i retreatment   as a reasonable option for selected patients. Further investigations are needed  to verify the value of PD1i re-exposure and to identify subgroups of patients who  can benefit.
CANIT0000941	28259107	Clinical research	Inoperable locally advanced cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	N/A	The favorable treatment response combined with significant involvement of PD-1 and PD ligands in cSCC lesions suggests that PD-1 blockade may be a viable therapeutic option for locally advanced cSCC and provides rationale for further investigation in future clinical trials.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD11 (P11215); T-Lymphocyte (NCIT:C12476); 	CD11c(+) T-cell 	Gene expression signature on/in immune cell	 2017 Apr 1	 Expression of Programmed Cell Death Ligand in Cutaneous Squamous Cell Carcinoma  and Treatment of Locally Advanced Disease With Pembrolizumab.	 JAMA Dermatol	 Importance: Limited therapies are available in patients with inoperable locally  advanced cutaneous squamous cell carcinoma (cSCC). Objective: To determine the  efficacy of programmed cell death 1 receptor (PD-1) inhibitors in locally  advanced cSCC. Design, Setting, and Participants: A single patient with locally  advanced cSCC who declined surgery and radiotherapy underwent treatment with  pembrolizumab, an anti-PD-1 antibody, at an academic dermatologic surgery section  and cancer center. The patient was followed up for clinical and radiologic  regression of cSCC. With the use of NanoString to amplify potential biomarkers,  immunohistochemistry, and immunofluorescence, the ex vivo expression of PD-1 and   a ligand (PD-L2) was assessed in 38 cSCC biopsy specimens from 24 patients with  cSCC. Expression of PD-L1 and PD-L2 in the cSCC microenvironment was defined.  Intervention: Pembrolizumab, 2 mg/kg every 3 weeks, for 4 cycles. Main Outcomes  and Measures: Expression of PD-L1 and PD-L2 in the cSCC microenvironment.  Results: In 1 patient with locally advanced cSCC who was treated with  pembrolizumab, nearly complete tumor regression was observed after 4 cycles of  therapy. The NanoString technology used in 38 cSCC biopsy specimens from 24  patients with cSCC (19 men and 5 women; mean [SD] age, 76.4 [12.2] years)  detected increased PD-1 and PD-L2 expression in high-risk cSCC.  Immunohistochemical analysis confirmed enhanced expression of PD-1 and its  ligands in cSCC with perineural invasion (mean [SEM] expression, 5.06 [1.27]; P =  .05), superficial cSCC (mean [SEM] expression, 3.58 [1.50]; P = .15), organ  transplant-associated cSCC (mean [SEM] expression, 3.01 [0.54]; P = .005), and  infiltrative cSCC (mean [SD] expression, 2.01 [0.30]; P = .006) compared with  normal skin specimens. In double-label immunofluorescence staining, CD11c+, a  marker of myeloid dendritic cells, colocalized with PD-L1 and PD-L2 in cSCC  lesions. Conclusions and Relevance: The favorable treatment response combined  with significant involvement of PD-1 and PD ligands in cSCC lesions suggests that  PD-1 blockade may be a viable therapeutic option for locally advanced cSCC and  provides rationale for further investigation in future clinical trials.
CANIT0000942	28262413	Clinical research	Advanced renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	Everolimus	Immune checkpoint therapy	Nivolumab (DB09035); everolimus (DB01590); 	410	411	A checkmate 025 randomized phase III study	The trend for OS and ORR benefit with nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC.	The incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower with nivolumab.	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and  Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma.	 Eur Urol	 BACKGROUND: The randomized, phase 3 CheckMate 025 study of nivolumab (n=410)  versus everolimus (n=411) in previously treated adults (75% male; 88% white) with  advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall   survival (OS) and objective response rate (ORR). OBJECTIVE: To investigate which   baseline factors were associated with OS and ORR benefit with nivolumab versus  everolimus. DESIGN, SETTING, AND PARTICIPANTS: Subgroup OS analyses were  performed using Kaplan-Meier methodology. Hazard ratios were estimated using the   Cox proportional hazards model. INTERVENTION: Nivolumab 3mg/kg every 2 wk or  everolimus 10mg once daily. RESULTS AND LIMITATIONS: The minimum follow-up was 14  mo. Baseline subgroup distributions were balanced between nivolumab and  everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus  across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and  International Metastatic Renal Cell Carcinoma Database Consortium risk groups;  age <65 and >/=65 yr; one and two or more sites of metastases; bone, liver, and  lung metastases; number of prior therapies; duration of prior therapy; and prior   sunitinib, pazopanib, or interleukin-2 therapy. The benefit with nivolumab versus  everolimus was noteworthy for patients with poor MSKCC risk (hazard ratio 0.48,  95% confidence interval 0.32-0.70). The mortality rate at 12 mo for all subgroups  was lower with nivolumab compared with everolimus. ORR also favored nivolumab.  The incidence of grade 3 or 4 treatment-related adverse events across subgroups  was lower with nivolumab. Limitations include the post hoc analysis and differing  sample sizes between groups. CONCLUSION: The trend for OS and ORR benefit with  nivolumab for multiple subgroups, without notable safety concerns, may help to  guide treatment decisions, and further supports nivolumab as the standard of care  in previously treated patients with aRCC. PATIENT SUMMARY: We investigated the  impact of demographic and pretreatment features on survival benefit and tumor  response with nivolumab versus everolimus in advanced renal cell carcinoma  (aRCC). Survival benefit and response were observed for multiple subgroups,  supporting the use of nivolumab as a new standard of care across a broad range of  patients with previously treated aRCC. The trial is registered on  ClinicalTrials.gov as NCT01668784.CI  - Copyright (c) 2017 European Association of Urology. Published by Elsevier B.V.  All rights reserved.
CANIT0000943	28266091	Clinical research	Advanced or recurrent squamous non-small cell lung cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	35	N/A	A multicenter phase II study	Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy.	Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or  discontinuation of nivolumab.	N/A	N/A	N/A	N/A	N/A	 2017 May	 Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent   squamous non-small cell lung cancer.	 Cancer Sci	 Limited treatment options are available for stage IIIB/IV non-small cell lung  cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor   antibody, has been shown to be effective for the treatment of NSCLC. The present   study investigated the effectiveness and safety of nivolumab in Japanese patients  with advanced or recurrent squamous NSCLC that progressed after  platinum-containing chemotherapy. In this multicenter phase II study, patients  were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive  disease or unacceptable toxicity was seen. Primary endpoint was overall response   rate (ORR) assessed by independent radiology review committee (IRC) and secondary  endpoints included a study site-assessed ORR, overall survival (OS),  progression-free survival (PFS), duration of response, time to response, best  overall response (BOR), and safety. The study included 35 patients from 17 sites   in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the  study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to   response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2  (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response,  stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients,   respectively. Treatment-related adverse events were reported in 24 patients  (68.6%), most of which resolved with appropriate treatment including steroid  therapy or discontinuation of nivolumab. Nivolumab was effective and well  tolerated in Japanese patients with advanced or recurrent squamous NSCLC that  progressed after platinum-containing chemotherapy. CLINICAL TRIAL REGISTRATION  NUMBER: JapicCTI-132072.CI  - (c) 2017 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0000944	28266140	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	35	N/A	A phase II, single-arm	Repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients. Pretreatment serum interferon-G was significantly higher in the patients with objective tumor responses than in those with tumor progression.	Grade 3-4 drug-related adverse events were observed in 31.4% of patients.	N/A	N/A	IFNG (P01579); 	Serum IFNG expression levels	Gene expression signature in serum	 2017 May	 Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a  phase 2 study for advanced melanoma.	 Cancer Sci	 Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor  antibody against the programmed death-1 protein, were suggested in previous phase  1 studies. The present phase 2, single-arm study (JAPIC-CTI #111681) evaluated  the antitumor activities of nivolumab and explored its predictive correlates in  advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg  was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from  December 2011 to May 2012 until they experienced unacceptable toxicity, disease  progression, or complete response. Primary endpoint was objective response rate.   Serum levels of immune modulators were assessed at multiple time points. As of 21  October 2014, median response duration, median progression-free survival, and  median overall survival were 463 days, 169 days, and 18.0 months, respectively.  The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and  42.9%, respectively. Thirteen patients remained alive at the end of the  observation period and no deaths were drug related. Grade 3-4 drug-related  adverse events were observed in 31.4% of patients. Pretreatment serum  interferon-gamma, and interleukin-6 and -10 levels were significantly higher in  the patients with objective tumor responses than in those with tumor progression.  In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor  effects and a manageable safety profile in advanced melanoma patients, strongly  suggesting the usefulness of nivolumab for advanced melanoma and the usefulness  of pretreatment serum cytokine profiles as correlates for predicting treatment  efficacy.CI  - (c) 2017 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0000945	28266140	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	35	N/A	A phase II, single-arm	Repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients. Pretreatment serum interleukin-10 levels was significantly higher in the patients with objective tumor responses than in those with tumor progression.	Grade 3-4 drug-related adverse events were observed in 31.4% of patients.	N/A	N/A	IL10 (P22301); 	Serum IL10 expression levels	Gene expression signature in serum	 2017 May	 Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a  phase 2 study for advanced melanoma.	 Cancer Sci	 Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor  antibody against the programmed death-1 protein, were suggested in previous phase  1 studies. The present phase 2, single-arm study (JAPIC-CTI #111681) evaluated  the antitumor activities of nivolumab and explored its predictive correlates in  advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg  was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from  December 2011 to May 2012 until they experienced unacceptable toxicity, disease  progression, or complete response. Primary endpoint was objective response rate.   Serum levels of immune modulators were assessed at multiple time points. As of 21  October 2014, median response duration, median progression-free survival, and  median overall survival were 463 days, 169 days, and 18.0 months, respectively.  The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and  42.9%, respectively. Thirteen patients remained alive at the end of the  observation period and no deaths were drug related. Grade 3-4 drug-related  adverse events were observed in 31.4% of patients. Pretreatment serum  interferon-gamma, and interleukin-6 and -10 levels were significantly higher in  the patients with objective tumor responses than in those with tumor progression.  In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor  effects and a manageable safety profile in advanced melanoma patients, strongly  suggesting the usefulness of nivolumab for advanced melanoma and the usefulness  of pretreatment serum cytokine profiles as correlates for predicting treatment  efficacy.CI  - (c) 2017 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0000946	28266140	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	35	N/A	A phase II, single-arm	Repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients. Pretreatment serum interleukin-6 was significantly higher in the patients with objective tumor responses than in those with tumor progression.	Grade 3-4 drug-related adverse events were observed in 31.4% of patients.	N/A	N/A	IL6 (P05231); 	Serum IL6 expression levels	Gene expression signature in serum	 2017 May	 Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a  phase 2 study for advanced melanoma.	 Cancer Sci	 Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor  antibody against the programmed death-1 protein, were suggested in previous phase  1 studies. The present phase 2, single-arm study (JAPIC-CTI #111681) evaluated  the antitumor activities of nivolumab and explored its predictive correlates in  advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg  was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from  December 2011 to May 2012 until they experienced unacceptable toxicity, disease  progression, or complete response. Primary endpoint was objective response rate.   Serum levels of immune modulators were assessed at multiple time points. As of 21  October 2014, median response duration, median progression-free survival, and  median overall survival were 463 days, 169 days, and 18.0 months, respectively.  The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and  42.9%, respectively. Thirteen patients remained alive at the end of the  observation period and no deaths were drug related. Grade 3-4 drug-related  adverse events were observed in 31.4% of patients. Pretreatment serum  interferon-gamma, and interleukin-6 and -10 levels were significantly higher in  the patients with objective tumor responses than in those with tumor progression.  In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor  effects and a manageable safety profile in advanced melanoma patients, strongly  suggesting the usefulness of nivolumab for advanced melanoma and the usefulness  of pretreatment serum cytokine profiles as correlates for predicting treatment  efficacy.CI  - (c) 2017 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0000947	28267244	Clinical research	Refractory/relapsed classical Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	17	N/A	A multicenter phase II study	Nivolumab is a potentially effective and tolerable treatment option for Japanese patients with relapsed/refractory classical Hodgkin lymphoma previously treated with brentuximab vedotin.	The most common adverse events (AE) were pyrexia (41.2%), pruritus (35.3%), rash (35.3%) and hypothyroidism (29.4%). Four patients (23.5%) experienced grade 3 or 4 AE, but most AE were of grade 1 or 2.	N/A	N/A	N/A	N/A	N/A	 2017 May	 Multicenter phase II study of nivolumab in Japanese patients with relapsed or  refractory classical Hodgkin lymphoma.	 Cancer Sci	 Overexpression of programmed death-1 (PD-1) ligands contributes to an  immunosuppressive microenvironment. Nivolumab is a PD-1-blocking antibody that  inhibits the PD-1 pathway and showed good efficacy in several types of  malignancy. This phase II study examined the efficacy and safety of nivolumab in   17 Japanese patients with refractory/relapsed classical Hodgkin lymphoma  previously treated with brentuximab vedotin. Sixteen patients were included in  efficacy analyses and 17 in safety analyses. The primary endpoint was the  centrally assessed objective response rate (ORR). The study was commenced in  March 2015. We report data obtained at a cutoff of 16 March 2016, at which time  11 patients were still receiving nivolumab. The median (range) duration of  treatment and follow-up were 7.0 (1.4-10.6) months and 9.8 (6.0-11.1) months,  respectively. All 17 patients had previously received brentuximab vedotin. The  ORR was 81.3% (95% confidence interval [CI]: 54.4-96.0%; 13/16 patients), with  complete remission and partial remission in 4 and 9 patients, respectively. The  overall survival (OS) and progression-free survival (PFS) rates at 6 months were   100 and 60.0% (95% CI: 31.8-79.7%), respectively; the median OS and PFS were not   reached. The most common adverse events (AE) were pyrexia (41.2%), pruritus  (35.3%), rash (35.3%) and hypothyroidism (29.4%). Four patients (23.5%)  experienced grade 3 or 4 AE, but most AE were of grade 1 or 2. In conclusion,  nivolumab is a potentially effective and tolerable treatment option for Japanese   patients with relapsed/refractory classical Hodgkin lymphoma previously treated  with brentuximab vedotin.CI  - (c) 2017 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0000948	28283736	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	42	N/A	A phase I clinical trial 	The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.	Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage).	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in  Japanese patients with advanced melanoma (KEYNOTE-041).	 Cancer Chemother Pharmacol	 PURPOSE: This phase I b study evaluated the safety and anti-tumor activity of  pembrolizumab in Japanese patients with advanced melanoma. METHODS: Pembrolizumab  (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed  progression or unacceptable toxicity. The tumor response was assessed as per the   Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both  investigator review and central review. RESULTS: Forty-two patients with advanced  melanoma received pembrolizumab. A primary cutaneous histology was observed in 34  patients (81.0%), while a primary mucosal histology was observed in 8 patients  (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse  events (AEs). The most common treatment-related AEs were pruritus, maculopapular   rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8   patients (19.0%). The only grade 3-5 treatment-related AE reported in at least  two patients was anemia. There were two treatment-related deaths (unknown cause  and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall   response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5)   for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The  responses were durable, and the median duration of response was not reached in  either population. The median overall survival (OS) was not reached, with a  12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma.  CONCLUSION: The safety profile of pembrolizumab in Japanese patients was similar   to that reported in the previous clinical studies. Pembrolizumab provided  promising anti-tumor activity in Japanese patients with advanced melanoma.
CANIT0000949	28284337	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Autoimmune limbic encephalitis with anti-contactin-associated protein-like 2 antibody	N/A	N/A	N/A	N/A	N/A	 2017 Apr 15	 Autoimmune limbic encephalitis with anti-contactin-associated protein-like 2  antibody secondary to pembrolizumab therapy.	 J Neuroimmunol	 Immune checkpoint inhibitors such as Pembrolizumab are used to restore antitumour  immune response. It is important to be vigilant of immune mediated adverse events  related to such therapy. We report a case of autoimmune limbic encephalitis with   Contactin-Associated Protein-like 2 (CASPR2) antibody secondary to Pembrolizumab   therapy for metastatic melanoma.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0000950	28285682	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	175	N/A	A retrospective cohort study	In a cohort of patients with NSCLC treated with nivolumab in routine practice, pretreatment NLR>/=5 was associated with inferior outcomes. It is unclear whether this marker is predictive or prognostic. Prospective studies are warranted to determine the utility of NLR in the context of other biomarkers of programmed death-1 (PD-1) therapy.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Apr	 Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in  nivolumab-treated patients with advanced non-small-cell lung cancer.	 Lung Cancer	 OBJECTIVES: Efficient use of nivolumab in non-small-cell lung cancer (NSCLC) has   been limited by the lack of a definitive predictive biomarker. In patients with  metastatic melanoma treated with ipilimumab, a pretreatment  neutrophil-to-lymphocyte ratio (NLR)<5 has been associated with improved  survival. This retrospective cohort study aimed to determine whether the  pretreatment NLR was associated with outcomes in NSCLC patients treated with  nivolumab. METHODS: We reviewed the medical records of all patients with  previously treated advanced NSCLC who received nivolumab between March 2015 and  March 2016 outside of a clinical trial at the University of Pennsylvania.  Patients were dichotomized according to pretreatment NLR<5 vs. >/=5.  Multivariable logistic regression and Cox proportional hazards models were used  to assess the impact of pretreatment NLR on overall survival (OS),  progression-free survival (PFS), and overall response rate (ORR). RESULTS: 175  patients were treated. Median age was 68 (range, 33-88); 54% were female.  Twenty-five percent of patients had an Eastern Cooperative Oncology Group  Performance Status (ECOG PS) >/=2; 46% had received >/=2 prior systemic  therapies. In multivariate analyses, pretreatment neutrophil-to-lymphocyte ratio   (NLR) >/=5 was independently associated with inferior OS (median 5.5 vs. 8.4  months; HR 2.07, 95% CI 1.3-3.3; p=0.002) and inferior PFS (median 1.9 vs. 2.8  months; HR 1.43, 95% CI 1.02-2.0; p=0.04). CONCLUSIONS: In a cohort of patients  with NSCLC treated with nivolumab in routine practice, pretreatment NLR>/=5 was  associated with inferior outcomes. It is unclear whether this marker is  predictive or prognostic. Prospective studies are warranted to determine the  utility of NLR in the context of other biomarkers of programmed death-1 (PD-1)  therapy.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0000951	28295515	Case report	Melanomas	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Melanomas paradoxically metastasizing to the intestinal tract	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Two cases of melanomas paradoxically metastasizing to the intestinal tract during  nivolumab therapy.	 J Dermatol	 We report two cases of melanomas in patients who developed intestinal metastasis   despite other metastatic sites responding to nivolumab and despite the patients  having favorable findings such as vitiligo and normal lactate dehydrogenase. The   first case is an 85-year-old man who had been administrated nivolumab for  lung/cutaneous metastases. After 22 courses of nivolumab therapy, fever and  anorexia had appeared and his bodyweight had decreased. An intussusception on the  ileocecal valve was revealed by computed tomography, and emergency surgery  revealed metastatic lesions on the colon. The second case is an 87-year-old woman  treated with nivolumab for lymph node metastases. After 10 courses, laboratory  tests had revealed anemia and positive fecal occult blood. Her bodyweight had  decreased. Capsule endoscopy showed scattered tumors and clots, indicating  metastases of melanoma. The frequency of symptomatic intestinal metastasis of  melanoma is very low. Further, intestinal metastasis of melanoma is difficult to   detect through routine examinations. Our cases suggest that fecal occult blood  test and decreased bodyweight are indications of intestinal metastases.CI  - (c) 2017 Japanese Dermatological Association.
CANIT0000952	28295542	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Unexpected recalcitrant course of drug-induced erythema multiforme-like eruption and interstitial pneumonia sequentially occurring	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Unexpected recalcitrant course of drug-induced erythema multiforme-like eruption   and interstitial pneumonia sequentially occurring after nivolumab therapy.	 J Dermatol	 Vemurafenib improves survival of melanoma patients. However, cutaneous  side-effects commonly occur in them. Nivolumab and ipilimumab are monoclonal  antibodies against programmed death 1 and cytotoxic T-lymphocyte-associated  antigen 4, both of which regulate excessive T-cell activation. Although these  agents induce antitumor immunity against melanoma, the modified immune condition   may result in an unexpected adverse reaction which has not been observed  previously. Herein, we report a case who manifested severe erythema  multiforme-like eruption with mucosal involvement associated with vemurafenib  following nivolumab. The patient also subsequently suffered from  ipilimumab-induced interstitial pneumonia with refractory course. Such a case has  never been reported. This case suggested that dermatologists should pay special  attention to unexpected adverse events of these drugs, and carefully observe  cutaneous and respiratory status of patients during the treatment of melanoma.CI  - (c) 2017 Japanese Dermatological Association.
CANIT0000953	28303763	Case report	Endometrial cancer	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The present report focuses on the computed tomography diagnostic features of nivolumab-related pneumonitis. The accumulation of knowledge regarding various types of antiprogrammed death-1-related pneumonitis will lead to appropriate treatment for this newly emerging adverse event.	Pneumonitis	N/A	N/A	N/A	N/A	N/A	 2017 Mar	 Case report of nivolumab-related pneumonitis.	 Immunotherapy	 We report a case with suggestive antiprogrammed death-1 inhibitor-related  pneumonitis in an endometrial cancer patient. This case presented with fever and   cough after three dosages of nivolumab. Computed tomography initially showed  centrilobular nodularities in a unilateral lung, which was compatible with  aspiration pneumonia. However, diffuse ground-glass opacities (GGO) rapidly  developed in the unilateral lung over 4 days despite the use of broad-spectrum  antibiotics. Development of GGO was considered to be related to a  nivolumab-mediated immune reaction. Corticosteroid was administered and the GGO  subsequently disappeared. The present report focuses on the computed tomography  diagnostic features of nivolumab-related pneumonitis. The accumulation of  knowledge regarding various types of antiprogrammed death-1-related pneumonitis  will lead to appropriate treatment for this newly emerging adverse event.
CANIT0000954	28303768	Case report	Metastatic lung squamous cell carcinoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Diffuse edema suggestive of cytokine release syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Mar	 Diffuse edema suggestive of cytokine release syndrome in a metastatic lung  carcinoma patient treated with pembrolizumab.	 Immunotherapy	 Immune checkpoint inhibitors (ICIs) are actually being indicated more commonly in  the management of chemoresistant cancer patients in view of their favorable  toxicity profile in comparison to cytotoxic chemotherapy. In this paper, we  report, to our knowledge, the first case suggestive of cytokine release syndrome   secondary to pembrolizumab in a patient with metastatic lung squamous cell  carcinoma. In view of the quick approvals of ICI and the absence of sufficient  knowledge of the corresponding toxicity profile, the occurrence of any clinical  or biological sign or symptom in patients receiving ICI requires further  investigation.
CANIT0000955	28314688	Clinical research	Oesophageal squamous-cell carcinoma	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	65	N/A	An open-label, single-arm, multicentre phase II	Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma.	Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%) patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse events that occurred during the study were lung infection (four [6%] patients), dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There were no treatment-related deaths.	N/A	N/A	N/A	N/A	N/A	 2017 May	 Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label,  multicentre, phase 2 trial.	 Lancet Oncol	 BACKGROUND: Nivolumab is a human monoclonal IgG4 antibody that inhibits  programmed cell death protein 1 (PD-1) expressed on activated T cells. We  investigated the safety and activity of nivolumab in patients with  treatment-refractory oesophageal cancer. METHODS: We did an open-label,  single-arm, multicentre phase 2 study. Eligible patients had advanced  squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the  oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based,  and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given  intravenously once every 2 weeks in 6-week cycles. The primary endpoint was  centrally assessed objective response (the proportion of patients whose best  response was complete or partial response), according to the Response Evaluation   Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related  adverse events (defined as events for which a causal relation to nivolumab could   not be ruled out) were monitored throughout the study. The safety analysis was  done in patients who received at least one dose of nivolumab, and drug activity  was assessed in patients who received at least one dose of nivolumab and had at  least one central assessment of tumour response. This study is registered with  clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients  is ongoing. FINDINGS: Between Feb 25 and Nov 14, 2014, 65 patients were enrolled,  all with squamous-cell carcinoma. 64 patients were assessable for the primary  endpoint as one patient was excluded due to having multiple primary cancers; all   patients were assessable for safety. Median follow-up was 10.8 months (IQR  4.9-14.3). 11 (17%, 95% CI 10-28) of 64 patients had a centrally assessed  objective response. Of the 65 patients assessed for adverse events, the most  common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%)  patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased  appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase  (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse  events that occurred during the study were lung infection (four [6%] patients),  dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia,   dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis,  gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There   were no treatment-related deaths. INTERPRETATION: Nivolumab showed promising  activity with a manageable safety profile. This drug could offer a potential new   treatment approach for patients with treatment-refractory advanced squamous-cell   carcinoma. FUNDING: Ono Pharmaceutical, Bristol-Myers Squibb.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0000956	28315636	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Rapid disease progression	Graft failure of renal transplant	N/A	N/A	N/A	N/A	N/A	 2017 Mar 19	 Pembrolizumab for metastatic melanoma in a renal allograft recipient with  subsequent graft rejection and treatment response failure: a case report.	 J Med Case Rep	 BACKGROUND: Transplant patients were excluded from the pivotal phase III trials  of checkpoint inhibitors in metastatic melanoma. The efficacy and toxicity  profiles of checkpoint inhibitors in this cohort of patients are not well  described. To the best of our knowledge, this is the first case report of a renal  transplant patient with stage IV melanoma treated with a programmed cell death  protein 1 checkpoint inhibitor that led to both treatment failure and renal graft  rejection. CASE PRESENTATION: We present a case of a 58-year-old white man with a  long-standing cadaveric renal transplant who was diagnosed with a B-Raf  Proto-Oncogene, Serine/Threonine Kinase wild-type metastatic melanoma. He was  treated with first-line pembrolizumab but experienced subsequent graft failure  and rapid disease progression. CONCLUSIONS: This case highlights the risks  associated with the administration of checkpoint inhibitors in patients with a  renal transplant and on immunosuppressive therapy. More specifically, it adds to   the literature indicating that, compared with the cytotoxic  T-lymphocyte-associated protein 4 inhibitor ipilimumab, anti-programmed cell  death protein 1 agents are more likely to lead to renal graft failure.  Additionally, these novel immunotherapeutics may be ineffective in transplant  patients; therefore, clinicians should be very aware of those risks and carefully  consider selection of agents and full disclosure of the risks to their patients.
CANIT0000957	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	315	N/A	N/A	Better outcome in female patients	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000958	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	315	N/A	N/A	Better outcome in female patients	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000959	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	315	N/A	N/A	Better outcome in patients with age <65 years	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000960	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	315	N/A	N/A	Better outcome in patients with age <65 years	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000961	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	315	N/A	N/A	Better outcome in patients with elevated LDH	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000962	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	315	N/A	N/A	Better outcome in patients with elevated LDH	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000963	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	315	N/A	N/A	Better outcome in patients with history of ipilimumab treatment	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	History of ipilimumab treatment	Exposure factors/status	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000964	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	315	N/A	N/A	Better outcome in patients with history of ipilimumab treatment	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	History of ipilimumab treatment	Exposure factors/status	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000965	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	315	N/A	N/A	Better outcome in patients with presence of liver metastasis	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000966	28324889	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	315	N/A	N/A	Better outcome in patients with presence of liver metastasis	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2017 Apr 25	 Evaluation of clinicopathological factors in PD-1 response: derivation and  validation of a prediction scale for response to PD-1 monotherapy.	 Br J Cancer	 BACKGROUND: Anti-PD-1 therapy has shown significant clinical activity in advanced  melanoma. We developed and validated a clinical prediction scale for response to   anti- PD-1 monotherapy. METHODS: A total of 315 patients with advanced melanoma  treated with pembrolizumab (2 or 10 mg kg(-1) Q2W or Q3W) or nivolumab (3 mg  kg(-1) Q2W) at four cancer centres between 2011 to 2013 served as the setting for  the present cohort study. Variables with significant association to response on a  univariate analysis were entered into a forward stepwise logistic regression  model and were given a score based on ORs to calculate a clinical prediction  scale. RESULTS: The developed clinical prediction scale included elevated LDH (1   point), age <65 years (1 point), female sex (1 point), history of ipilimumab  treatment (2 points) and the presence of liver metastasis (2 points). The scale  had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80)   in predicting response to therapy. The predictive performance of the score was  maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the  goodness-to-fit model demonstrated good calibration. CONCLUSIONS: Based on a  large cohort of patients, we developed and validated a simple five-factor  prediction scale for the clinical activity of PD-1 antibodies in advanced  melanoma patients. This scale can be used to stratify patients participating in  clinical trials.
CANIT0000967	28327969	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	86	N/A	N/A	Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting nivolumab plus ipilimumab	Metabolite	 2017 May 1	 Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic  melanoma.	 Ann Oncol	 Background: Programmed death 1 (PD1) inhibitors are now a foundation of medical  management of metastatic melanoma. This study sought to determine whether  circulating tumour DNA (ctDNA) provides useful early response and prognostic  information. Patients and methods: We evaluated the relationship between  pre-treatment and early on treatment ctDNA and outcome in melanoma patients  treated with PD1 inhibitors alone or in combination with ipilimumab. Results:  ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with  stage, LDH levels, disease volume and ECOG performance. RECIST response was 72%  (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B  (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6%  (1/18) in group C (elevated ctDNA at baseline and remained elevated during  treatment). The median PFS was not reached in groups A and B and was 2.7 months  for group C [hazard ratio (HR) 0.09; P < 0.001 for group A versus C, and 0.16; P   < 0.001 for group B versus C]. The median OS was not reached for groups A and B  and was 9.2 months for group C (HR 0.02; P < 0.001 for group A versus C and 0.14;  P < 0.001 for group B versus C). The poor outcome measures associated with group   C remained significant in multivariate analysis adjusted for LDH, performance  status, tumour stage and disease volume. The predictive value for ctDNA for  response was confirmed in a separate validation cohort (n = 29, P < 0.01).  Conclusion: Longitudinal assessment of ctDNA in metastatic melanoma patients  receiving treatment with PD1 inhibitors is an accurate predictor of tumour  response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy  had a poor prognosis, and this may guide combination and sequencing of subsequent  therapies.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000968	28327969	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	86	N/A	N/A	Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting pembrolizumab	Metabolite	 2017 May 1	 Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic  melanoma.	 Ann Oncol	 Background: Programmed death 1 (PD1) inhibitors are now a foundation of medical  management of metastatic melanoma. This study sought to determine whether  circulating tumour DNA (ctDNA) provides useful early response and prognostic  information. Patients and methods: We evaluated the relationship between  pre-treatment and early on treatment ctDNA and outcome in melanoma patients  treated with PD1 inhibitors alone or in combination with ipilimumab. Results:  ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with  stage, LDH levels, disease volume and ECOG performance. RECIST response was 72%  (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B  (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6%  (1/18) in group C (elevated ctDNA at baseline and remained elevated during  treatment). The median PFS was not reached in groups A and B and was 2.7 months  for group C [hazard ratio (HR) 0.09; P < 0.001 for group A versus C, and 0.16; P   < 0.001 for group B versus C]. The median OS was not reached for groups A and B  and was 9.2 months for group C (HR 0.02; P < 0.001 for group A versus C and 0.14;  P < 0.001 for group B versus C). The poor outcome measures associated with group   C remained significant in multivariate analysis adjusted for LDH, performance  status, tumour stage and disease volume. The predictive value for ctDNA for  response was confirmed in a separate validation cohort (n = 29, P < 0.01).  Conclusion: Longitudinal assessment of ctDNA in metastatic melanoma patients  receiving treatment with PD1 inhibitors is an accurate predictor of tumour  response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy  had a poor prognosis, and this may guide combination and sequencing of subsequent  therapies.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000969	28327969	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	86	N/A	N/A	Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting nivolumab	Metabolite	 2017 May 1	 Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic  melanoma.	 Ann Oncol	 Background: Programmed death 1 (PD1) inhibitors are now a foundation of medical  management of metastatic melanoma. This study sought to determine whether  circulating tumour DNA (ctDNA) provides useful early response and prognostic  information. Patients and methods: We evaluated the relationship between  pre-treatment and early on treatment ctDNA and outcome in melanoma patients  treated with PD1 inhibitors alone or in combination with ipilimumab. Results:  ctDNA was detected in 40/76 patients (53%) at baseline, and correlated with  stage, LDH levels, disease volume and ECOG performance. RECIST response was 72%  (26/36) in group A (undetectable ctDNA at baseline), 77% (17/22) in group B  (elevated ctDNA at baseline but undetectable within 12 weeks of therapy) and 6%  (1/18) in group C (elevated ctDNA at baseline and remained elevated during  treatment). The median PFS was not reached in groups A and B and was 2.7 months  for group C [hazard ratio (HR) 0.09; P < 0.001 for group A versus C, and 0.16; P   < 0.001 for group B versus C]. The median OS was not reached for groups A and B  and was 9.2 months for group C (HR 0.02; P < 0.001 for group A versus C and 0.14;  P < 0.001 for group B versus C). The poor outcome measures associated with group   C remained significant in multivariate analysis adjusted for LDH, performance  status, tumour stage and disease volume. The predictive value for ctDNA for  response was confirmed in a separate validation cohort (n = 29, P < 0.01).  Conclusion: Longitudinal assessment of ctDNA in metastatic melanoma patients  receiving treatment with PD1 inhibitors is an accurate predictor of tumour  response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy  had a poor prognosis, and this may guide combination and sequencing of subsequent  therapies.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000970	28328302	Clinical research	Platinum- and cetuximab-refractory head and neck cancer	Head and neck carcinoma	MONDO:0002038	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	171	N/A	A  multicenter, phase II, single-arm study	Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.	109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade  3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events.	N/A	N/A	N/A	N/A	N/A	 2017 May 10	 Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer:  Results From a Single-Arm, Phase II Study.	 J Clin Oncol	 Purpose There are no approved treatments for recurrent/metastatic head and neck  squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm,   phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti-programmed death   1 receptor antibody, in this platinum- and cetuximab-pretreated population with  poor prognosis. Methods Eligibility stipulated disease progression within 6  months of platinum and cetuximab treatment. Patients received pembrolizumab 200  mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points:  overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central  review) and safety. Efficacy was assessed in all dosed patients and in subgroups   on the basis of programmed death ligand 1 (PD-L1) expression and human  papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two  or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive,  and 22% were HPV positive. At the time of analysis, 109 patients (64%)  experienced a treatment-related adverse event; 26 patients (15%) experienced a  grade >/= 3 event. Seven patients (4%) discontinued treatment, and one died of  treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to  23%), with a median duration of response of 8 months (range, 2+ to 12+ months);  75% of responses were ongoing at the time of analysis. Response rates were  similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1   months, and median overall survival was 8 months. Conclusion Pembrolizumab  exhibited clinically meaningful antitumor activity and an acceptable safety  profile in recurrent/metastatic head and neck squamous cell carcinoma previously   treated with platinum and cetuximab.
CANIT0000971	28334791	Case report	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Isolated ACTH deficiency	N/A	N/A	N/A	N/A	N/A	 2017 May 1	 Isolated ACTH deficiency probably induced by autoimmune-related mechanism evoked   with nivolumab.	 Jpn J Clin Oncol	 Nivolumab, an anti-programmed death-1 antibody, is a breakthrough treatment for  several malignancies. Its specific adverse effects caused by autoimmunity are  termed immune-related adverse events, which involve several endocrine  dysfunctions. Herein, we report two cases of isolated adrenocorticotropic hormone  (ACTH) deficiency induced by nivolumab for the treatment of metastatic malignant   melanoma. Case 1 was a 39-year-old man and Case 2 was a 50-year-old woman, both  of whom presented with progressive melanoma. After 13 courses of nivolumab  administration, both cases were diagnosed with adrenal insufficiency. Despite  their basal serum ACTH and cortisol levels being low with little response to  corticotropin-releasing hormone loading, other anterior pituitary hormone levels   were preserved. Based on these endocrinological data, isolated ACTH deficiency  was diagnosed. Magnetic resonance imaging showed normal pituitary glands,  excluding hypophysitis. Finally, hydrocortisone replacement enabled the patients   to continue nivolumab treatment. Therefore, it is important to consider isolated   ACTH syndrome as a possible and potentially severe immune-related adverse event  of nivolumab, even when head magnetic resonance imaging of affected cases does  not show enlargement. We should not misdiagnose hidden immune-related adverse  events behind general complaints of malignancies such as general malaise and  appetite loss, to allow successful treatment using this beneficial immune  checkpoint inhibitor.CI  - (c) The Author 2017. Published by Oxford University Press. All rights reserved.  For permissions, please e-mail: journals.permissions@oup.com.
CANIT0000972	28342215	Clinical research	Previously untreated advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A single-arm, open-label, multicenter, phase II study	Nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations.	Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment.	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2017 Jun	 Efficacy and safety of nivolumab in Japanese patients with previously untreated  advanced melanoma: A phase II study.	 Cancer Sci	 Treating advanced or recurrent melanoma remains a challenge. Cancer cells can  evade the immune system by blocking T-cell activation through overexpression of  the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitor  nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune  resistance of cancer cells. Nivolumab has shown promising anticancer activity in   various cancers. We carried out a single-arm, open-label, multicenter, phase II  study to investigate the efficacy and safety of nivolumab in previously untreated  Japanese patients with advanced melanoma. Twenty-four patients with stage III/IV   or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2  weeks until disease progression or unacceptable toxicity. The primary endpoint  was overall response rate evaluated by an independent radiology review committee.  The independent radiology review committee-assessed overall response rate was  34.8% (90% confidence interval, 20.8-51.9), and the overall survival rate at 18  months was 56.5% (90% confidence interval, 38.0-71.4). Treatment-related adverse   events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two  patients discontinued nivolumab because of AEs, but all AEs were considered  manageable by early diagnosis and appropriate treatment. Subgroup analyses showed  that nivolumab was clinically beneficial and tolerable regardless of BRAF  genotype, and that patients with treatment-related select AEs and with vitiligo  showed tendency for better survival. In conclusion, nivolumab showed favorable  efficacy and safety profiles in Japanese patients with advanced or recurrent  melanoma, with or without BRAF mutations. (Trial registration no.  JapicCTI-142533.).CI  - (c) 2017 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0000973	28342816	Case report	Thymic epithelial tumor	Thymic epithelial neoplasm	MONDO:0018079	Thymus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Antineutrophil cytoplasmic antibody-associated rapid progressive glomerulonephritis	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Antineutrophil Cytoplasmic Antibody-Associated Rapid Progressive  Glomerulonephritis after Pembrolizumab Treatment in Thymic Epithelial Tumor: A  Case Report.	 J Thorac Oncol	Unable to provide
CANIT0000974	28344807	Case report	Stage III melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Thrombotic thrombocytopenic purpura	N/A	N/A	N/A	N/A	N/A	2017	 Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP).	 J Immunother Cancer	 BACKGROUND: CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) was the first  immune checkpoint receptor clinically targeted for use in cancer treatment. It is  expressed exclusively on T-cells where its primary role is to regulate the  amplitude of the early stages of T-cell activation.1 Ipilimumab, a CTLA-4  blocking antibody, has been widely used for the treatment of patients with high  risk and metastatic melanoma. Given its mechanism of action and consequent immune  activation, the side effect profile of this drug greatly differs from that of  standard cytotoxic chemotherapy. Adverse events are from the most part  immune-mediated, ranging from the more common, such as rash and fatigue, to the  less common, such as immune endocrinopathy and colitis. CASE PRESENTATION: We  describe a case of immune-mediated thrombotic thrombocytopenic purpura (TTP) in a  68 year-old woman with high risk, stage III melanoma occurring after 3 cycles of   adjuvant treatment with ipilimumab as part of a clinical trial. CONCLUSION: The  range of immune-mediated adverse events during treatment with ipilimumab is wide   and varied and clinicians should have a high degree of suspicion when managing  these patients.
CANIT0000975	28346412	Basic research	Prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Basic research	VISTA represents another compensatory inhibitory pathway in prostate tumors after ipilimumab therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2017 May	 VISTA is an inhibitory immune checkpoint that is increased after ipilimumab  therapy in patients with prostate cancer.	 Nat Med	 To date, anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) monotherapy has not  been demonstrated to be of substantial clinical benefit in patients with prostate  cancer. To identify additional immune-inhibitory pathways in the prostate-tumor  microenvironment, we evaluated untreated and ipilimumab-treated tumors from  patients in a presurgical clinical trial. Levels of the PD-L1 and VISTA  inhibitory molecules increased on independent subsets of macrophages in treated  tumors. Our data suggest that VISTA represents another compensatory inhibitory  pathway in prostate tumors after ipilimumab therapy.
CANIT0000976	28356222	Clinical research	Unresectable stage III or IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	197	N/A	N/A	A high neutrophil to lymphocyte ratio (NLR), whether measured prior to or during treatment with IPI, is associated with worse OS, PFS, and clinical response in patients with advanced melanoma. An increasing NLR from baseline during treatment was correlated with worse OS and PFS in IPI-treated patients.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Apr	 Neutrophil to Lymphocyte Ratio is Associated With Outcome During Ipilimumab  Treatment.	 EBioMedicine	 BACKGROUND: Ipilimumab (IPI) and BRAF inhibitors (BRAFi) improve survival in  melanoma, but not all patients will benefit and toxicity can be significant.  Pretreatment neutrophil to lymphocyte ratio (NLR) has been associated with  outcome in IPI-treated patients, but has not been studied during treatment or in   BRAFi-treated patients. METHODS: Using a prospectively maintained database,  patients with unresectable stage III or IV melanoma treated with IPI or a BRAFi  (vemurafenib or dabrafenib as monotherapy) from 2006 to 2011 were identified. NLR  was calculated before treatment and at 3-week intervals after treatment  initiation until 9weeks. Baseline NLR was tested for association with overall  survival (OS), progression free survival (PFS), and clinical response to  treatment. On-treatment NLRs were tested for association with the same outcomes  using landmark survival analyses and time-dependent Cox regression models. The  association of relative change of NLR from baseline with outcomes was also  examined. A multivariate model tested the association of NLR and OS/PFS with  additional clinical factors. RESULTS: There were 197 IPI patients and 65 BRAFi  patients. In multivariable analysis adjusting for M stage, and disease type (in  OS)/gender (in PFS), an NLR value of 5 or above at every timepoint was associated  with worse OS (HR 2.03-3.37, p<0.001), PFS (HR 1.81-2.51, p<0.001), and response   to therapy (OR 3.92-9.18, p<0.007), in the IPI cohort. In addition, a >30%  increase in NLR above baseline at any timepoint was associated with a worse OS  and PFS (HR 1.81 and 1.66, p<0.004). In BRAFi patients, NLR was not consistently   associated with outcomes. CONCLUSIONS: A high NLR, whether measured prior to or  during treatment with IPI, is associated with worse OS, PFS, and clinical  response in patients with advanced melanoma. An increasing NLR from baseline  during treatment was correlated with worse OS and PFS in IPI-treated patients. In  comparison, as NLR was not associated with outcomes in BRAFi patients, NLR may  have a uniquely predictive value in patients treated with immunotherapy.CI  - Copyright (c) 2017 The Authors. Published by Elsevier B.V. All rights reserved.
CANIT0000977	28356247	Case report	Relapsed/refractory primary central nervous system and testicular lymphoma	Central nervous system lymphoma	EFO:1000157	Nervous system	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	Good outcome in in relapsed/refractory PCNSL and PTL	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jun 8	 PD-1 blockade with nivolumab in relapsed/refractory primary central nervous  system and testicular lymphoma.	 Blood	 Primary central nervous system (CNS) lymphoma (PCNSL) and primary testicular  lymphoma (PTL) are rare extranodal large B-cell lymphomas with similar genetic  signatures. There are no standard-of-care treatment options for patients with  relapsed and refractory PCNSL and PTL, and the overall prognosis is poor. PCNSLs   and PTLs exhibit frequent 9p24.1 copy-number alterations and infrequent  translocations of 9p24.1 and associated increased expression of the programmed  cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. The activity of PD-1  blockade in other lymphomas with 9p24.1 alterations prompted us to test the  efficacy of the anti-PD1 antibody, nivolumab, in 4 patients with  relapsed/refractory PCNSL and 1 patient with CNS relapse of PTL. All 5 patients  had clinical and radiographic responses to PD-1 blockade, and 3 patients remain  progression-free at 13(+) to 17(+) months. Our data suggest that nivolumab is  active in relapsed/refractory PCNSL and PTL and support further investigation of   PD-1 blockade in these diseases.CI  - (c) 2017 by The American Society of Hematology.
CANIT0000978	28356247	Case report	Relapsed/refractory primary central nervous system and testicular lymphoma	Testicular lymphoma	EFO:0004281	Testis	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	Good outcome in in relapsed/refractory PCNSL and PTL	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jun 8	 PD-1 blockade with nivolumab in relapsed/refractory primary central nervous  system and testicular lymphoma.	 Blood	 Primary central nervous system (CNS) lymphoma (PCNSL) and primary testicular  lymphoma (PTL) are rare extranodal large B-cell lymphomas with similar genetic  signatures. There are no standard-of-care treatment options for patients with  relapsed and refractory PCNSL and PTL, and the overall prognosis is poor. PCNSLs   and PTLs exhibit frequent 9p24.1 copy-number alterations and infrequent  translocations of 9p24.1 and associated increased expression of the programmed  cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. The activity of PD-1  blockade in other lymphomas with 9p24.1 alterations prompted us to test the  efficacy of the anti-PD1 antibody, nivolumab, in 4 patients with  relapsed/refractory PCNSL and 1 patient with CNS relapse of PTL. All 5 patients  had clinical and radiographic responses to PD-1 blockade, and 3 patients remain  progression-free at 13(+) to 17(+) months. Our data suggest that nivolumab is  active in relapsed/refractory PCNSL and PTL and support further investigation of   PD-1 blockade in these diseases.CI  - (c) 2017 by The American Society of Hematology.
CANIT0000979	28363614	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Acute symptomatic hypocalcemia	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Acute symptomatic hypocalcemia from immune checkpoint therapy-induced  hypoparathyroidism.	 Am J Emerg Med	 BACKGROUND: Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a  humanized antibody against PD-1) target these immune checkpoint pathways and are   used for treatment of melanoma and an increasing number of other cancers.  However, they may cause immune-related adverse effects (IRAEs). Although many  endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe  hypocalcemia has never been reported. This is the first case of  hypoparathyroidism as an IRAE presenting to an Emergency Department with acute  hypocalcemia. CASE DESCRIPTION: A 73-year-old man with metastatic melanoma  presented to the Emergency Department for the chief complaints of imbalance,  general muscle weakness, abdominal pain and tingling in extremities. He had wide   spread metastasis, and begun immunotherapy with concurrent ipilimumab and  nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands  and feet, and abdominal cramping. Magnetic resonance imaging of the brain was  unremarkable. He was found to be hypocalcemic with undetectable plasma  parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia  and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had  thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of  primary hypothyroidism. At 4months after the Emergency Department visit, his  parathyroid function and thyroid function had not recovered, and required  continued thyroid hormone replacement and calcium and vitamin D treatment for  hypocalcemia. CONCLUSIONS: Primary hypoparathyroidism caused by ipilimumab and  nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care  providers should be aware of hypoparathyroidism as a new IRAE in this new era of   immuno-oncology.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0000980	28366756	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	N/A	Nearly half of the veterans exhibited durable clinical benefit (DCB) and pembrolizumab therapy was well tolerated. An increase in ALC from baseline and occurrence of autoimmune phenomena might be associated with DCB.	There were no CTCAE Grade > 3 adverse events. All immune-related adverse events occurred in patients with DCB.	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Clinical Determinants of Durable Clinical Benefit of Pembrolizumab in Veterans  With Advanced Non-Small-Cell Lung Cancer.	 Clin Lung Cancer	 BACKGROUND: Because of the prevalence of smoking in the veteran population,  non-small-cell lung cancer (NSCLC) remains a significant cause of morbidity and  mortality. The objectives of our study were to evaluate the extent of durable  clinical benefit (DCB) to pembrolizumab in veterans with metastatic NSCLC and to   identify clinical determinants of DCB. MATERIALS AND METHODS: Prospective  clinical data on veterans receiving pembrolizumab were collected. Duration of  response was calculated from the first date of infusion until date of disease  progression on computed tomography scans, defined according to Response  Evaluation Criteria in Solid Tumors version 1.1 (CTCAE). RESULTS: As of the  censor date, 25 veterans consented and 24 were evaluable. The response rate was  25% (6 of 24 patients), with all achieving a partial response. Four patients  received palliative radiation because of focal progression and continued to  receive pembrolizumab, leading to a DCB rate of 41% (10 of 24 patients). The mean  duration of response at the censor date was 12.9 months (95% confidence interval   [CI], 9.9-15.9) and 2.7 months (95% CI, 1.9-4.3) for those with and without DCB,   respectively. Patients without DCB had a higher pack-year smoking history (P =  .007). An increase in peripheral blood absolute lymphocyte count (ALC) during  therapy was seen in patients with DCB (P = .073). There were no CTCAE Grade > 3  adverse events. All immune-related adverse events occurred in patients with DCB.   CONCLUSION: Nearly half of the veterans exhibited DCB and pembrolizumab therapy  was well tolerated. An increase in ALC from baseline and occurrence of autoimmune  phenomena might be associated with DCB. Immunotherapy with pembrolizumab is a  promising therapeutic strategy in veterans with advanced NSCLC.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0000981	28368440	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	146	N/A	A retrospective cohort study	Prior radiotherapy does not predict nivolumab response in non-small-cell lung cancer.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Previous radiotherapy	Exposure factors/status	 2017 Jun 1	 Prior radiotherapy does not predict nivolumab response in non-small-cell lung  cancer: a retrospective cohort study.	 Ann Oncol	Unable to provide
CANIT0000982	28373217	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	303	N/A	A retrospective cohort study	We conclude that CT is a fast, reliable, and noninvasive mode of diagnosing colitis, whereas colonoscopy and biopsy may not be needed to establish that diagnosis.	Ninety nine (33%) of 303 patients developed diarrhea during therapy, and 46 patients (15%) received corticosteroids for colitis. Of the patients with diarrhea, 48 (48%) underwent colonoscopy and 46 (46%) underwent both CT and colonoscopy. In the 34 patients (34%) with a CT and biopsy, CT was highly predictive of colitis on biopsy (positive predictive value 96%), and the absence of CT findings was predictive of a negative biopsy (negative likelihood ratio 0.2). In patients who had symptoms and CT evaluation, CT was highly predictive of the need for steroids to reach resolution of symptoms (positive predictive value 92%, positive likelihood ratio 7.3).	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Diagnostic Comparison of CT Scans and Colonoscopy for Immune-Related Colitis in  Ipilimumab-Treated Advanced Melanoma Patients.	 Cancer Immunol Res	 Colitis can be a life-threatening toxicity for patients treated with immune  checkpoint blockade antibodies. With the anticipated widespread use of these  reagents, the timely and accurate diagnosis of immune-related colitis becomes  increasingly important. To better understand the clinical presentation of colitis  from ipilimumab and to assess the use of CT scans of the abdomen/pelvis as a  diagnostic tool, we retrospectively analyzed patients with advanced melanoma who   received ipilimumab at our institution. Ninety nine (33%) of 303 patients  developed diarrhea during therapy, and 46 patients (15%) received corticosteroids  for colitis. Of the patients with diarrhea, 48 (48%) underwent colonoscopy and 46  (46%) underwent both CT and colonoscopy. In the 34 patients (34%) with a CT and  biopsy, CT was highly predictive of colitis on biopsy (positive predictive value   96%), and the absence of CT findings was predictive of a negative biopsy  (negative likelihood ratio 0.2). In patients who had symptoms and CT evaluation,   CT was highly predictive of the need for steroids to reach resolution of symptoms  (positive predictive value 92%, positive likelihood ratio 7.3). We conclude that   CT is a fast, reliable, and noninvasive mode of diagnosing colitis, whereas  colonoscopy and biopsy may not be needed to establish that diagnosis. Cancer  Immunol Res; 5(4); 286-91. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0000983	28373768	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	114	N/A	A retrospective cohort study	Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis.	A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients (14%) developed  grade 2 diarrhea. All patients were treated with high-dose corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Colonic ulcerations	Disease status	 2017 Mar 21	 Colonic ulcerations may predict steroid-refractory course in patients with  ipilimumab-mediated enterocolitis.	 World J Gastroenterol	 AIM: To investigate management of patients who develop ipilimumab-mediated  enterocolitis, including association of endoscopic findings with  steroid-refractory symptoms and utility of infliximab as second-line therapy.  METHODS: We retrospectively reviewed all patients at our center with metastatic  melanoma who were treated with ipilimumab between March 2011 and May 2014. All  patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk  for four doses or until therapy was stopped due to toxicity or disease  progression. Basic demographic and clinical data were collected on all patients.   For patients who developed grade 2 or worse diarrhea (increase of 4 bowel  movements per day), additional data were collected regarding details of  gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive   statistics were used. RESULTS: A total of 114 patients were treated with  ipilimumab during the study period and all were included. Sixteen patients (14%)   developed >/= grade 2 diarrhea. All patients were treated with high-dose  corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients  (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory  patients received one dose of intravenous infliximab at 5 mg/kg, and all but one   had brisk resolution of diarrhea. Fourteen of the patients underwent either  colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild  erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by  sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory  symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse  events associated with prednisone or infliximab were reported. CONCLUSION: In  patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers  on endoscopy was associated with a steroid-refractory course.
CANIT0000984	28381841	Case report	Metastatic hepatocellular carcinoma	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus sorafenib	N/A	Immune checkpoint therapy plus Target therapy	Sorafenib (DB00398); pembrolizumab (DB09037); 	1	N/A	Case	Complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Apr	 Complete Response to the Combination of Pembrolizumab and Sorafenib for  Metastatic Hepatocellular Carcinoma: A Case Report.	 Am J Gastroenterol	Unable to provide
CANIT0000985	28382561	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	50	N/A	A retrospective cohort study	Multivariate logistic regression identified response to the treatment immediately before nivolumab monotherapy as independently associated with response to nivolumab monotherapy.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Response to the treatment immediately before nivolumab monotherapy	Exposure factors/status	 2017 Aug	 Response to the treatment immediately before nivolumab monotherapy may predict  clinical response to nivolumab in patients with non-small cell lung cancer.	 Int J Clin Oncol	 BACKGROUND: Currently, no markers predictive of response to nivolumab monotherapy  in patients with advanced non-small cell lung cancer (NSCLC) are currently  recognized in Japan. The present study was undertaken to identify such markers.  MATERIALS AND METHODS: Medical records of 50 patients with advanced NSCLC and  treated with nivolumab monotherapy at Shizuoka Cancer Center between December  2015 and April 2016 were retrospectively reviewed. The parameters studied were  age, sex, Eastern Cooperative Oncology Group performance status, smoking history,  histological diagnosis, epidermal growth factor receptor or anaplastic lymphoma  kinase status, therapeutic line of nivolumab, efficacy of treatment immediately  before nivolumab monotherapy, and time since previous therapy. RESULTS: The  objective response rate to nivolumab monotherapy was 18% [95% confidence interval  (CI) 10-31]. Multivariate logistic regression identified squamous histology  [odds ratio (OR) 0.00054; 95% CI 0-0.27] and response to the treatment  immediately before nivolumab monotherapy (OR 0.0011; 95% CI 0-0.092) as  independently associated with response to nivolumab monotherapy. CONCLUSION:  Response to the treatment immediately before nivolumab monotherapy might be a  predictive marker of response to nivolumab in patients with advanced NSCLC.
CANIT0000986	28382561	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	50	N/A	A retrospective cohort study	Multivariate logistic regression identified squamous histology as independently associated with response to nivolumab monotherapy.	N/A	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	 2017 Aug	 Response to the treatment immediately before nivolumab monotherapy may predict  clinical response to nivolumab in patients with non-small cell lung cancer.	 Int J Clin Oncol	 BACKGROUND: Currently, no markers predictive of response to nivolumab monotherapy  in patients with advanced non-small cell lung cancer (NSCLC) are currently  recognized in Japan. The present study was undertaken to identify such markers.  MATERIALS AND METHODS: Medical records of 50 patients with advanced NSCLC and  treated with nivolumab monotherapy at Shizuoka Cancer Center between December  2015 and April 2016 were retrospectively reviewed. The parameters studied were  age, sex, Eastern Cooperative Oncology Group performance status, smoking history,  histological diagnosis, epidermal growth factor receptor or anaplastic lymphoma  kinase status, therapeutic line of nivolumab, efficacy of treatment immediately  before nivolumab monotherapy, and time since previous therapy. RESULTS: The  objective response rate to nivolumab monotherapy was 18% [95% confidence interval  (CI) 10-31]. Multivariate logistic regression identified squamous histology  [odds ratio (OR) 0.00054; 95% CI 0-0.27] and response to the treatment  immediately before nivolumab monotherapy (OR 0.0011; 95% CI 0-0.092) as  independently associated with response to nivolumab monotherapy. CONCLUSION:  Response to the treatment immediately before nivolumab monotherapy might be a  predictive marker of response to nivolumab in patients with advanced NSCLC.
CANIT0000987	28387913	Basic research	Platinum-resistant ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	The combined treatment with nivolumab and cisplatin effectively inhibited PROC cells via induction of cell apoptosis and inhibition of ADAM17 expression.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2017 Mar	 Nivolumab effectively inhibit platinum-resistant ovarian cancer cells via  induction of cell apoptosis and inhibition of ADAM17 expression.	 Eur Rev Med Pharmacol Sci	 OBJECTIVE: Nivolumab is an anti-PD-1 (anti-programmed death-1) monoclonal  antibody. It has achieved an overall response rate of 17% in Phase 1 clinical  trial for patient with platinum-resistant ovarian cancer (PROC). However, its  underlying mechanism has not been fully explored yet. The aim of the study is to   investigate the efficiency of nivolumab to inhibit PROC cells and its possible  mechanism. MATERIALS AND METHODS: Firstly, methylthiazolyl tetrazolium bromide  (MTT) assay was performed to determine the IC50 values of cisplatin in  cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. The results  showed that IC50 (half maximal inhibitory concentration) values of cisplatin were  significantly decreased in a time-dependent manner in A2780, A2780/DDP, SKOV3,  and SKOV3/DDP cells. Secondly, MMT assay was used once again to measure  anti-tumor effects of nivolumab in A2780/DDP cells. The results showed that  anti-tumor effects of nivolumab increased in a dose- and time-dependent manner.  Thirdly, A2780/DDP cells were treated with nivolumab in combination with  cisplatin for 48 h. RESULTS: The results demonstrated that nivolumab increased  the anti-tumor effects of cisplatin in A2780/DDP cells. Notably, the combined  treatment effectively reversed cisplatin resistance in PROC cells. Also,  nivolumab induced cell apoptosis and cell-cycle arrest in G0/G1 phase in PROC  cells. FACS and Western blot were performed to measure cell apoptosis and Bcl-2  and Bax expression respectively. The results showed that combined treatment  significantly increased cell apoptosis rate, down-regulated Bcl-2, and  unregulated Bax expression in PROC cells. Additionally, the expression levels of   ADAM17 were significantly decreased in a dose-dependent manner in PROC cells,  which were treated with nivolumab. CONCLUSIONS: Therefore, all the results  demonstrated that the combined treatment with nivolumab and cisplatin effectively  inhibited PROC cells via induction of cell apoptosis and inhibition of ADAM17  expression.
CANIT0000988	28388966	Clinical research	Pancreatic cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	DENDRITIC CELL (N/A); TLR3 (O15455); 	DENDRITIC CELL; TLR3	Vaccination with peptide-pulsed dendritic cells plus with poly-ICLC	N/A	Tumor vaccine	Poly-ICLC (NCIT:C1198); dendritic cell vaccine (NCIT:C28310); 	12	N/A	N/A	Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Apr 7	 Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in  patients with pancreatic cancer.	 J Hematol Oncol	 BACKGROUND: Dendritic cells (DCs) enhance the quality of anti-tumor immune  response in patients with cancer. Thus, we posit that DC-based immunotherapy, in   conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising  approach for harnessing immunity against metastatic or locally advanced  unresectable pancreatic cancer (PC). METHODS: We generated autologous DCs from  the peripheral blood of HLA-A2(+) patients with PC. DCs were pulsed with three  distinct A2-restricted peptides: 1) human telomerase reverse transcriptase  (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin  (SRV.A2). Patients received four intradermal injections of 1 x 10(7)  peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently,  patients received intramuscular administration of Poly-ICLC at 30 mug/Kg on  vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31,  37, and 45. Our key objective was to assess safety and feasibility. The effect of  DC vaccination on immune response was measured at each DC injection time point by  enumerating the phenotype and function of patient T cells. RESULTS: Twelve  patients underwent apheresis: nine patients with metastatic disease, and three  patients with locally advanced unresectable disease. Vaccines were successfully  manufactured from all individuals. We found that this treatment was  well-tolerated, with the most common symptoms being fatigue and/or self-limiting   flu-like symptoms. Among the eight patients who underwent imaging on day 56, four  patients experienced stable disease while four patients had disease progression.   The median overall survival was 7.7 months. One patient survived for 28 months  post leukapheresis. MHC class I -tetramer analysis before and after vaccination  revealed effective generation of antigen-specific T cells in three patients with   stable disease. CONCLUSION: Vaccination with peptide-pulsed DCs in combination  with poly-ICLC is safe and induces a measurable tumor specific T cell population   in patients with advanced PC. TRIAL REGISTRATION: NCT01410968 ; Name of registry:  clinicaltrials.gov; Date of registration: 08/04/2011).
CANIT0000989	28396509	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	488	N/A	A retrospective cohort study	Acquired resistance to anti-PD-1 was frequently associated with excellent clinical outcomes and often presented as isolated progression amenable to localized therapy (surgery or radiation) or systemic progression sensitive to therapy resumption.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 May	 Clinical Features of Acquired Resistance to Anti-PD-1 Therapy in Advanced  Melanoma.	 Cancer Immunol Res	 Anti-PD-1 therapy has improved clinical outcomes in advanced melanoma, but most  patients experience intrinsic resistance. Responding patients can develop  acquired resistance to anti-PD-1. We retrospectively reviewed 488 patients  treated with anti-PD-1 from three academic centers and identified 36 patients  with acquired resistance, defined as disease progression following objective  response. The incidence, timing, disease sites, post-progression survival (PPS),   and outcomes were evaluated descriptively. The acquired resistance cohort  consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated   LDH, or brain metastasis), and 67% had previously received ipilimumab. Partial  and complete responses were achieved in 89% (n = 32) and 11% (n = 4) of patients,  respectively, and median time to resistance (progression-free survival; PFS) was   11.1 months (range 4.3-32.8 months). Most progression was isolated (78% of  patients, n = 28) and occurred while receiving therapy (78%, n = 28). The median   PPS was 12.8 months (range 0.1-51.8 months), and the median overall survival was   33.7 months. Among isolated progressors, 15 received localized therapy (12 with  surgery, 3 with radiation). Patients with isolated versus systemic progression  exhibited a trend for improved PPS (P = 0.081), and patients with an initial PFS   >/= 15 months showed significant PPS improvement (P = 0.036). Two patients  experienced subsequent responses to anti-PD-1 resumption. In conclusion, acquired  resistance to anti-PD-1 was frequently associated with excellent clinical  outcomes and often presented as isolated progression amenable to localized  therapy (surgery or radiation) or systemic progression sensitive to therapy  resumption. Cancer Immunol Res; 5(5); 357-62. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0000990	28396509	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	488	N/A	A retrospective cohort study	Acquired resistance to anti-PD-1 was frequently associated with excellent clinical outcomes and often presented as isolated progression amenable to localized therapy (surgery or radiation) or systemic progression sensitive to therapy resumption.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 May	 Clinical Features of Acquired Resistance to Anti-PD-1 Therapy in Advanced  Melanoma.	 Cancer Immunol Res	 Anti-PD-1 therapy has improved clinical outcomes in advanced melanoma, but most  patients experience intrinsic resistance. Responding patients can develop  acquired resistance to anti-PD-1. We retrospectively reviewed 488 patients  treated with anti-PD-1 from three academic centers and identified 36 patients  with acquired resistance, defined as disease progression following objective  response. The incidence, timing, disease sites, post-progression survival (PPS),   and outcomes were evaluated descriptively. The acquired resistance cohort  consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated   LDH, or brain metastasis), and 67% had previously received ipilimumab. Partial  and complete responses were achieved in 89% (n = 32) and 11% (n = 4) of patients,  respectively, and median time to resistance (progression-free survival; PFS) was   11.1 months (range 4.3-32.8 months). Most progression was isolated (78% of  patients, n = 28) and occurred while receiving therapy (78%, n = 28). The median   PPS was 12.8 months (range 0.1-51.8 months), and the median overall survival was   33.7 months. Among isolated progressors, 15 received localized therapy (12 with  surgery, 3 with radiation). Patients with isolated versus systemic progression  exhibited a trend for improved PPS (P = 0.081), and patients with an initial PFS   >/= 15 months showed significant PPS improvement (P = 0.036). Two patients  experienced subsequent responses to anti-PD-1 resumption. In conclusion, acquired  resistance to anti-PD-1 was frequently associated with excellent clinical  outcomes and often presented as isolated progression amenable to localized  therapy (surgery or radiation) or systemic progression sensitive to therapy  resumption. Cancer Immunol Res; 5(5); 357-62. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0000991	28396974	Clinical research	Melanoma 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	68	N/A	A retrospective cohort study	Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.	Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI  25 kg/m2 and 11 (16%) a BMI  30, while 13 (19%) had both sarcopenia and a BMI  25 kg/m2. For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m2; p = 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Occurrence of early acute limiting toxicity	Disease status	 2017 Aug	 Sarcopenic overweight is associated with early acute limiting toxicity of  anti-PD1 checkpoint inhibitors in melanoma patients.	 Invest New Drugs	 Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors.  Sarcopenic obesity is associated with increased acute toxicity of cytotoxic  agents and targeted therapies. We explored whether body composition also  influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in  melanoma patients. This is a monocentric, retrospective study analyzing toxicity   outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab.  Various parameters linked to the patient or the disease status have been  analysed. Body mass index (BMI; kg/m(2)) and muscle mass using CT were measured  prior to treatment initiation. Chi-squared test and Mann-Whitney's tests were  used for the comparison of categorical and continuous variables respectively.  Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21  nivolumab), 38 (56%) patients had a BMI >/= 25 kg/m(2) and 11 (16%) a BMI >/= 30,  while 13 (19%) had both sarcopenia and a BMI >/= 25 kg/m(2). For the 11 (16%)  patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7  kg/m(2); p = 0.04). Among the 32 female patients, sarcopenic overweight patients   had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic  overweight is associated with more early ALT of anti-PD1 in melanoma patients.
CANIT0000992	28396974	Clinical research	Melanoma 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	68	N/A	A retrospective cohort study	Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.	Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI  25 kg/m2 and 11 (16%) a BMI  30, while 13 (19%) had both sarcopenia and a BMI  25 kg/m2. For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m2; p = 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Occurrence of early acute limiting toxicity	Disease status	 2017 Aug	 Sarcopenic overweight is associated with early acute limiting toxicity of  anti-PD1 checkpoint inhibitors in melanoma patients.	 Invest New Drugs	 Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors.  Sarcopenic obesity is associated with increased acute toxicity of cytotoxic  agents and targeted therapies. We explored whether body composition also  influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in  melanoma patients. This is a monocentric, retrospective study analyzing toxicity   outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab.  Various parameters linked to the patient or the disease status have been  analysed. Body mass index (BMI; kg/m(2)) and muscle mass using CT were measured  prior to treatment initiation. Chi-squared test and Mann-Whitney's tests were  used for the comparison of categorical and continuous variables respectively.  Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21  nivolumab), 38 (56%) patients had a BMI >/= 25 kg/m(2) and 11 (16%) a BMI >/= 30,  while 13 (19%) had both sarcopenia and a BMI >/= 25 kg/m(2). For the 11 (16%)  patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7  kg/m(2); p = 0.04). Among the 32 female patients, sarcopenic overweight patients   had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic  overweight is associated with more early ALT of anti-PD1 in melanoma patients.
CANIT0000993	28397508	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Autoimmune haemolytic anaemia	N/A	N/A	N/A	N/A	N/A	 Spring 2017	 An Autoimmune Haemolytic Anaemia Secondary to Ipilimumab Treatment.	 Klin Onkol	 BACKGROUND: Melanoma is one of the fastest growing neoplasms worldwide. Treatment  of metastatic disease has swiftly shifted in the last decade from generally  ineffective chemotherapy regimens to highly effective targeted treatments or  immunotherapy, with a range of side effects that differ completely from those of   previous treatments for this disease. CASE: We present a case of a 71-year-old  man with diagnosis metastatic melanoma. This patient was treated with anti-CTLA-4  antibody ipilimumab. Despite minor skin toxicity, the regimen was well tolerated   until he developed hemolytic anemia, an autoimmune side effect of ipilimumab. The  treatment was withdrawn and steroids were administered until the issue was  resolved. CONCLUSION: Immunotherapy has become the standard of care for many  tumors, and its side effects are completely different from those of chemotherapy,  meaning that oncologists must be aware of this to avoid a potentially  life-threatening situation and arrive at an early diagnosis and implement prompt   treatment.Key words: anemia - autoimmune event - anti-CTLA-4.
CANIT0000994	28398170	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	418	N/A	Case	A longer OS was found in patients who completed all four therapy cycles (p < 0.001).	Adverse events of any grade were reported for 66% of patients (mainly cutaneous and gastrointestinal), but most were low grade and easily managed. Adverse events of grades 3-4 were observed in 13% of patients. This study confirmed the efficacy and safety of this treatment in real practice.	N/A	N/A	Therapy cycles (); 	Therapy cycles	Exposure factors/status	 2017 Aug	 Ipilimumab in real-world clinical practice: efficacy and safety data from a  multicenter observational study.	 J Chemother	 In patients with metastatic melanoma, ipilimumab has been shown to improve  long-term survival. This observational multicenter study reports clinical  outcomes of 418 patients treated with second-line ipilimumab from February 2013  to August 2014. Median overall survival (OS) was 6.43 months (95%CI: 5.45-7.42; n  = 300), while median progression-free survival (PFS) was 3.7 months (95%CI:  3.23-4.17; n = 188). Demographic factors, such as sex or number of previous  therapies did not affect OS. Survival was shorter in patients with ECOG > 0  (Eastern Cooperative Oncology Group, Performance Status) (p < 0.001), while a  longer OS was found in patients who completed all four therapy cycles (p <  0.001). Adverse events of any grade were reported for 66% of patients (mainly  cutaneous and gastrointestinal), but most were low grade and easily managed.  Adverse events of grades 3-4 were observed in 13% of patients. This study  confirmed the efficacy and safety of this treatment in real practice.
CANIT0000995	28398170	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	418	N/A	Case	Survival was shorter in patients with ECOG > 0 (Eastern Cooperative Oncology Group, Performance Status) (p < 0.001).	Adverse events of any grade were reported for 66% of patients (mainly cutaneous and gastrointestinal), but most were low grade and easily managed. Adverse events of grades 3-4 were observed in 13% of patients. This study confirmed the efficacy and safety of this treatment in real practice.	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2017 Aug	 Ipilimumab in real-world clinical practice: efficacy and safety data from a  multicenter observational study.	 J Chemother	 In patients with metastatic melanoma, ipilimumab has been shown to improve  long-term survival. This observational multicenter study reports clinical  outcomes of 418 patients treated with second-line ipilimumab from February 2013  to August 2014. Median overall survival (OS) was 6.43 months (95%CI: 5.45-7.42; n  = 300), while median progression-free survival (PFS) was 3.7 months (95%CI:  3.23-4.17; n = 188). Demographic factors, such as sex or number of previous  therapies did not affect OS. Survival was shorter in patients with ECOG > 0  (Eastern Cooperative Oncology Group, Performance Status) (p < 0.001), while a  longer OS was found in patients who completed all four therapy cycles (p <  0.001). Adverse events of any grade were reported for 66% of patients (mainly  cutaneous and gastrointestinal), but most were low grade and easily managed.  Adverse events of grades 3-4 were observed in 13% of patients. This study  confirmed the efficacy and safety of this treatment in real practice.
CANIT0000996	28407039	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	25	N/A	A retrospective cohort study	T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.	N/A	N/A	N/A	EGFR (P00533); 	EGFR T790M mutation	Mutational status	 2017 Jul 1	 Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive  non-small-cell lung cancer based on T790M status after disease progression during  EGFR-TKI treatment.	 Ann Oncol	 Background: The efficacy of programmed death-1 blockade in epidermal growth  factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC)   patients with different mechanisms of acquired resistance to EGFR tyrosine kinase  inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and  immune-related factors in such patients according to their status for the T790M  resistance mutation of EGFR. Patients and methods: We identified 25 patients with  EGFR mutation-positive NSCLC who were treated with nivolumab after disease  progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1  (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor  specimens obtained after acquisition of EGFR-TKI resistance were determined by  immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to  identify gene alterations. The relation of T790M status to PD-L1 expression or  TIL density was also examined in an independent cohort of 60 patients (cohort B).  Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3  months for T790M-negative and T790M-positive patients, respectively (P = 0.099;  hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was  2.1 and 1.3 months for patients with a PD-L1 expression level of >/=1% or <1%,  respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of  0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with  cutoff values of >/=10% and >/=50%. The proportion of tumors with a PD-L1 level  of >/=10% or >/=50% was higher among T790M-negative patients than among  T790M-positive patients of both cohorts A and B. Nivolumab responders had a  significantly higher CD8+ TIL density and nonsynonymous mutation burden.  Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more  likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result  of a higher PD-L1 expression level, than are T790M-positive patients.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0000997	28407622	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	26	N/A	N/A	Hyperprolactinemia in mNSCLC patients treated with NIVO could potentially represent a negative early predictive factor for poor clinical outcomes, thus anticipating PD shown by CT scan.	N/A	N/A	N/A	Prolactin (NCIT:C778); 	Serum prolactin levels	Gene expression signature in serum	2017	 Prolactin as a Potential Early Predictive Factor in Metastatic Non-Small Cell  Lung Cancer Patients Treated with Nivolumab.	 Oncology	 BACKGROUND/AIMS: Prolactin (PRL) is a peptide hormone and several studies have  demonstrated its role as a cytokine in human T cell-mediated immunity. We are  unaware if PRL is a positive or negative immunomodulator, but its effects on the   regulation of T cells could inhibit the antitumor activity elicited by nivolumab   (NIVO). We aimed to assess whether the occurrence of hyperprolactinemia in  metastatic non-small cell lung cancer (mNSCLC) patients treated with NIVO is  associated with poor clinical outcomes. METHODS: We evaluated 26 mNSCLC patients   treated with NIVO. Blood samples were collected in every patient to evaluate PRL   basal levels before starting the therapy with NIVO and before each following  administration of NIVO. All patients underwent a conventional CT to investigate  the effect of therapy according to Immune-related Response Evaluation Criteria in  Solid Tumors (IrRECIST). RESULTS: Twenty patients (77%) developed  hyperprolactinemia during the treatment, whereas 6 patients (23%) had stable  levels of PRL during the therapy (p = 0.001). A total of 95% of the 20 patients  with hyperprolactinemia had progressive disease (PD), according to CT results,  whereas only 2 patients (33%) out of 6 with stable PRL levels had PD (p = 0.004).  CONCLUSIONS: Hyperprolactinemia in mNSCLC patients treated with NIVO could  potentially represent a negative early predictive factor for poor clinical  outcomes, thus anticipating PD shown by CT scan.CI  - (c) 2017 S. Karger AG, Basel.
CANIT0000998	28410865	Clinical research	Advanced renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	406	N/A	A phase III CheckMate 025 study	A subset of patients with advanced renal cell carcinoma and RECIST progression experienced tumor reduction postprogression with nivolumab, and had an acceptable safety profile. Clinical judgment remains essential when switching therapy.	Incidence of treatment-related adverse events in patients TBP was lower after (59%) versus before (71%) progression.	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma  Treated with Nivolumab in CheckMate 025.	 Eur Urol	 BACKGROUND: Response patterns to nivolumab differ from those seen with other  approved targeted therapies. OBJECTIVE: To investigate the efficacy of nivolumab   in previously treated patients with advanced renal cell carcinoma who were  treated beyond (Response Evaluation Criteria In Solid Tumors) RECIST progression.  DESIGN, SETTING, AND PARTICIPANTS: This was a subgroup analysis of patients  treated with nivolumab in the phase 3 CheckMate 025 study. Patients continuing to  tolerate therapy and exhibiting investigator-assessed clinical benefit were  eligible to be treated beyond RECIST progression (TBP) and received therapy for  >/=4 wk after first progression; patients not treated beyond RECIST progression  (NTBP) received 0 wk to <4 wk of therapy after progression. INTERVENTIONS:  Nivolumab 3mg/kg intravenously every 2 wk. RESULTS AND LIMITATIONS: Of 406  nivolumab-treated patients, 316 (78%) progressed by RECIST criteria. Of those who  progressed, 48% were TBP, 52% were NTBP. Before being TBP, objective response  rate (95% confidence interval) was 20% (14-28) and 14% (9-21) in patients TBP and  NTBP, respectively. Differences in clinical characteristics assessed at first  progression between patients TBP versus NTBP included better Karnofsky  performance status, less deterioration in Karnofsky performance status, shorter  time to response, lower incidence of new bone lesions, and improved quality of  life. Postprogression, 13% of all patients TBP (20/153) had >/=30% tumor burden  reduction including patients with preprogression and postprogression tumor  measurements (n=142) and complete/partial response (28%, 8/29), stable disease  (6%, 3/47), and progressive disease (14%, 9/66) as their best response before  being TBP. Incidence of treatment-related adverse events in patients TBP was  lower after (59%) versus before (71%) progression. Limitations included potential  bias from the nonrandomized nature of the analysis. CONCLUSIONS: A subset of  patients with advanced renal cell carcinoma and RECIST progression experienced  tumor reduction postprogression with nivolumab, and had an acceptable safety  profile. Clinical judgment remains essential when switching therapy.  ClinicalTrials.gov Identifier: NCT01668784. PATIENT SUMMARY: A subset of patients  with advanced renal cell carcinoma and disease progression may continue to  benefit from nivolumab treatment beyond progression as evidenced by tumor  reduction postprogression and an acceptable safety profile.CI  - Copyright (c) 2017 European Association of Urology. Published by Elsevier B.V.  All rights reserved.
CANIT0000999	28411193	Clinical research	Melanoma or lung cancer 	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	336	N/A	A retrospective cohort study	Liver metastatic patients with melanoma or NSCLC that had been  treated with pembrolizumab were associated with reduced responses and PFS, and  liver metastases were associated with reduced marginal CD8(+) T-cell  infiltration, providing a potential mechanism for this outcome.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2017 May	 Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in  Patients with Melanoma and NSCLC.	 Cancer Immunol Res	 We explored the association between liver metastases, tumor CD8(+) T-cell count,   and response in patients with melanoma or lung cancer treated with the anti-PD-1   antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I  Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote   002, 006, and EAP trials and the non-small cell lung cancer (NSCLC) cohort from  Keynote 001. Liver metastasis was associated with reduced response and shortened   progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS,  5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median  PFS, 20.1 months) P </= 0.0001, and confirmed in the validation cohort (P =  0.0006). The presence of liver metastasis significantly increased the likelihood   of progression (OR, 1.852; P < 0.0001). In a subset of biopsied patients (n =  62), liver metastasis was associated with reduced CD8(+) T-cell density at the  invasive tumor margin (liver metastasis(+) group, n = 547 +/- 164.8; liver  metastasis(-) group, n = 1,441 +/- 250.7; P < 0.016). A reduced response rate and  shortened PFS was also observed in NSCLC patients with liver metastasis [median  PFS, 1.8 months; 95% confidence interval (CI), 1.4-2.0], compared with those  without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1-5.1), P =   0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been  treated with pembrolizumab were associated with reduced responses and PFS, and  liver metastases were associated with reduced marginal CD8(+) T-cell  infiltration, providing a potential mechanism for this outcome. Cancer Immunol  Res; 5(5); 417-24. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001000	28416753	Basic research	Mouse model of renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Anti-CTLA-4 9H10 plus lycorine hydrochloride	N/A	Immune checkpoint therapy plus Chemotherapy	Lycorine hydrochloride (NCIT:C29363); anti-CTLA-4 9H10 (NCIT:C128036); 	Cell lines/ animal models	N/A	Basic research	We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2017 Mar 28	 Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the  growth inhibitor lycorine in a mouse model of renal cell carcinoma.	 Oncotarget	 Renal cell carcinoma (RCC) management has undergone a major transformation over  the past decade; immune checkpoint inhibitors are currently undergoing clinical  trials and show promising results. However, the effectiveness of immune  checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited.  Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is  touted as a potential anti-cancer drug because of its demonstrative growth  inhibition capacity (induction of cell cycle arrest and inhibition of  vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy  with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4)  has improved outcomes in cancer patients. However, the anti-tumor efficacy of  combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated   a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine  RCC model. As a means of in vitro confirmation, we found that lycorine  hydrochloride inhibited the viability of various RCC cell lines. Furthermore,  luciferase-expressing Renca cells were implanted in the left kidney and the lung   of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride  and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and  luciferin-staining in tumor images. Importantly, the observed anti-tumor effects   of this combination were dependent on significantly suppressing regulatory T  cells while upregulating effector T cells; a decrease in regulatory T cells by  31.43% but an increase in effector T cells by 31.59% were observed in the  combination group compared with those in the control group). We suggest that a  combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic  option for RCC patients.
CANIT0001001	28419059	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Pneumonitis and multiple immune-related adverse events	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Late-onset nivolumab-mediated pneumonitis in a patient with melanoma and multiple  immune-related adverse events.	 Melanoma Res	 Immune-related adverse effects (AEs) of PD-1 inhibitors can affect almost every  organ, but the skin, intestine, lung, eye, and liver are the most commonly  affected organs. Here, we present the case of a 62-year-old female patient with  stage IIIc melanoma treated with nivolumab in an adjuvant setting who  sequentially developed hyperthyroidism, hypothyroidism, acute hepatitis, and  pneumonitis. Six months before the emergence of pneumonitis, the patient had  discontinued treatment with nivolumab because of acute hepatitis. Information on   pneumonitis after nivolumab discontinuation in the literature is scarce, whereas   most of the cases emerge during the first 2.5 months of treatment. Patients with   multiple immune-related AEs comprise a group of special interest as the  identification of factors affecting the susceptibility of patients to  immune-related AEs of PD-1 inhibitors may lead to a more rational use of these  drugs. Human leukocyte antigen haplotype and Fcgamma receptor polymorphisms are  possible targets of the relevant research.
CANIT0001002	28419181	Clinical research	Recurrent and/or metastatic head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	34	N/A	A retrospective cohort study	Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional  recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.	N/A	N/A	N/A	Hyperprogression (NCIT:C158754); 	Hyperprogression	Disease status	 2017 Jul 1	 Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or  metastatic head and neck squamous cell carcinoma.	 Ann Oncol	 Background: Pembrolizumab and nivolumab are immune checkpoint inhibitors  targeting PD-1 that have recently been approved in pretreated recurrent and/or  metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the  clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents  but rather to experience an acceleration of tumor growth kinetics (TGK). Patients  and methods: We retrospectively compared TGK on immunotherapy and TGK on last  treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four  French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before  treatment and the slope of tumor growth on treatment) was calculated.  Hyperprogression was defined as a TGKR >/= 2. Results: From September 2012 to  September 2015, 34 patients were identified. Patterns of recurrence included  exclusive loco-regional recurrence in 14 patients, exclusive distant metastases  in 11 patients, and both in 9 patients. No pseudo-progression was observed.  Hyperprogression was observed in 10 patients (29%), including 9 patients with at   least a locoregional recurrence, and only 1 patient with exclusively distant  metastases. Hyperprogression significantly correlated with a regional recurrence   (TGKR >/= 2: 90% versus TGKR < 2: 37%, P = 0.008), but not with local or distant   recurrence. Hyperprogression was associated with a shorter progression-free  survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not  with overall survival (P = 0.77). Conclusions: Hyperprogression was observed in  29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated  with a shorter PFS. It occurred in 39% of patients with at least a locoregional  recurrence and 9% of patients with exclusively distant metastases. No  pseudo-progressions were reported. Mechanisms and causality of hyperprogression  should further be assessed through prospective controlled studies.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001003	28419181	Clinical research	Recurrent and/or metastatic head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	34	N/A	A retrospective cohort study	Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional  recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.	N/A	N/A	N/A	Hyperprogression (NCIT:C158754); 	Hyperprogression	Disease status	 2017 Jul 1	 Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or  metastatic head and neck squamous cell carcinoma.	 Ann Oncol	 Background: Pembrolizumab and nivolumab are immune checkpoint inhibitors  targeting PD-1 that have recently been approved in pretreated recurrent and/or  metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the  clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents  but rather to experience an acceleration of tumor growth kinetics (TGK). Patients  and methods: We retrospectively compared TGK on immunotherapy and TGK on last  treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four  French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before  treatment and the slope of tumor growth on treatment) was calculated.  Hyperprogression was defined as a TGKR >/= 2. Results: From September 2012 to  September 2015, 34 patients were identified. Patterns of recurrence included  exclusive loco-regional recurrence in 14 patients, exclusive distant metastases  in 11 patients, and both in 9 patients. No pseudo-progression was observed.  Hyperprogression was observed in 10 patients (29%), including 9 patients with at   least a locoregional recurrence, and only 1 patient with exclusively distant  metastases. Hyperprogression significantly correlated with a regional recurrence   (TGKR >/= 2: 90% versus TGKR < 2: 37%, P = 0.008), but not with local or distant   recurrence. Hyperprogression was associated with a shorter progression-free  survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not  with overall survival (P = 0.77). Conclusions: Hyperprogression was observed in  29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated  with a shorter PFS. It occurred in 39% of patients with at least a locoregional  recurrence and 9% of patients with exclusively distant metastases. No  pseudo-progressions were reported. Mechanisms and causality of hyperprogression  should further be assessed through prospective controlled studies.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001004	28419248	Clinical research	Advanced renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	Everolimus	Immune checkpoint therapy	Nivolumab (DB09035); everolimus (DB01590); 	410	411	A retrospective cohort study	With >2 years of follow-up, Japanese patients had a higher response rate with nivolumab versus everolimus that was more pronounced yet consistent with the global population, with median OS not reached, and a favorable safety profile.	In Japanese patients, any-grade treatment-related adverse events (AEs) occurred in 78% (Grade 3-4, 19%; most common, anemia [5%]) treated with nivolumab and 100% (Grade 3-4, 58%; most common, hypertriglyceridemia [12%]) treated with everolimus; the most common with nivolumab was diarrhea (19%) and with everolimus was stomatitis (77%). Quality of life was stable in the nivolumab arm.	N/A	N/A	N/A	N/A	N/A	 2017 Jul 1	 Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup  analysis from the CheckMate 025 study.	 Jpn J Clin Oncol	 Background: Nivolumab improved overall survival (OS) and objective response rate   (ORR) versus everolimus in previously treated patients with advanced renal cell  carcinoma in the phase III CheckMate 025 study (minimum follow-up: 14 months). We  report efficacy and safety in the global and Japanese populations (minimum  follow-up: 26 months). Methods: Patients were randomized 1:1 to receive nivolumab  3 mg/kg intravenously every 2 weeks or everolimus 10-mg tablet orally once daily.  Primary endpoint: OS, key secondary endpoints: ORR, progression-free survival and  safety. Results: Of 410 (nivolumab) and 411 (everolimus) patients, 37 (9%) and 26  (6%), respectively, were Japanese. Median OS for the global population was 26.0  months (nivolumab) and 19.7 months (everolimus; hazard ratio 0.73 [95% confidence  interval [CI]: 0.61-0.88]; P = 0.0006), with medians not reached for Japanese  patients. ORR for the global population was 26% (nivolumab) versus 5%  (everolimus; odds ratio 6.13; 95% CI: 3.77-9.95); ORR for Japanese patients: 43%   versus 8% (odds ratio 9.14; 95% CI: 1.76-88.33). In Japanese patients, any-grade   treatment-related adverse events (AEs) occurred in 78% (Grade 3-4, 19%; most  common, anemia [5%]) treated with nivolumab and 100% (Grade 3-4, 58%; most  common, hypertriglyceridemia [12%]) treated with everolimus; the most common with  nivolumab was diarrhea (19%) and with everolimus was stomatitis (77%). Quality of  life was stable in the nivolumab arm. Conclusions: With >2 years of follow-up,  Japanese patients had a higher response rate with nivolumab versus everolimus  that was more pronounced yet consistent with the global population, with median  OS not reached, and a favorable safety profile.CI  - (c) The Author 2017. Published by Oxford University Press.
CANIT0001005	28423487	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	43	N/A	N/A	These data show that a clinical response to ipilimumab not only requires reshaping T cell populations, but additionally involves a reduction in suppressive cells such as monocytic MDSCs.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2017 Mar 28	 Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory   T cells in long-term survivors with advanced melanoma.	 Oncotarget	 Ipilimumab has revolutionized malignant melanoma therapy, but a better  understanding of the mechanisms behind treatment response and adverse effects is   needed. In this work, the immune system of ipilimumab treated patients was  monitored to investigate potential mechanisms of action that may correlate with  treatment outcome. Blood samples from 43 advanced melanoma patients were taken  before, during and at the end of treatment. Hematological parameters were  measured and flow cytometry analysis was performed in fresh samples within two  hours of sample collection. Strong differences in markers CD45RA, CCR7, HLA-DR  and CD15 between fresh and cryopreserved samples were observed. Ipilimumab  treatment increased absolute lymphocyte counts, eosinophils, effector T cells and  their activation status, whilst diminishing the suppressive side of the immune  response, acting on regulatory T cells and myeloid derived suppressor cells  (MDSCs). These effects were visible after one ipilimumab infusion and, regarding   eosinophil counts, correlated with onset of adverse events. Monocytic MDSCs were   decreased in response to treatment only in patients with clinical benefit;  additionally, patients with a lower frequency of these cells after the first  ipilimumab infusion experienced increased overall survival. CD8 effector memory T  cell frequencies at the end of treatment were higher in patients with clinical  benefit and positively correlated with survival. These data show that a clinical   response to ipilimumab not only requires reshaping T cell populations, but  additionally involves a reduction in suppressive cells such as monocytic MDSCs.  Our work could provide insight on predicting treatment outcome, assisting  clinicians in offering the best personalized therapeutic approach.
CANIT0001006	28424162	Clinical research	Chronic lymphocytic leukemia and Richter transformation	Chronic lymphocytic leukemia	EFO:0000095	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	A phase II clinical trial	Pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT, and could change the landscape of therapy for RT patients if further validated.	Treatment-related grade 3 or above adverse events were reported in 15 (60%) patients and were manageable.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 29	 Pembrolizumab in patients with CLL and Richter transformation or with relapsed  CLL.	 Blood	 Chronic lymphocytic leukemia (CLL) patients progressed early on ibrutinib often  develop Richter transformation (RT) with a short survival of about 4 months.  Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to  inhibit immune surveillance in CLL. This phase 2 study was designed to test the  efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a  dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five  patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell  lymphoma) patients were enrolled, and 60% received prior ibrutinib. Objective  responses were observed in 4 out of 9 RT patients (44%) and in 0 out of 16 CLL  patients (0%). All responses were observed in RT patients who had progression  after prior therapy with ibrutinib. After a median follow-up time of 11 months,  the median overall survival in the RT cohort was 10.7 months, but was not reached  in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or  above adverse events were reported in 15 (60%) patients and were manageable.  Analyses of pretreatment tumor specimens from available patients revealed  increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression  in PD-1 in the tumor microenvironment in patients who had confirmed responses.  Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The   results of this study are the first to demonstrate the benefit of PD-1 blockade  in CLL patients with RT, and could change the landscape of therapy for RT  patients if further validated. This trial was registered at  www.clinicaltrials.gov as #NCT02332980.CI  - (c) 2017 by The American Society of Hematology.
CANIT0001007	28428880	Case report	Metastatic castrate-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	2	N/A	Case	Long-term complete remission	N/A	N/A	N/A	N/A	N/A	N/A	2017	 Long-term complete remission with Ipilimumab in metastatic castrate-resistant  prostate cancer: case report of two patients.	 J Immunother Cancer	 BACKGROUND: Prostate cancer is one of the most common cancers in men and the  fourth leading cause of cancer mortality worldwide. Although major progress has  been achieved in the last years for patients with metastatic castrate-resistant  prostate cancer (mCRPC), thanks to next-generation androgen receptor axis  targeted drugs, taxanes, and bone-targeted agents, immunotherapy has not been  widely approved and used for the treatment of prostate cancer. Two large studies   with ipilimumab, an anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibody  reported improved progression-free survival, but not statistically improved  overall survival at the primary analysis (CA184 043 and CA184 095). CASE  PRESENTATION: Here, we report on two patients who received ipilimumab in these  trials and are still in long-term complete remission with a follow-up of 64 and  52 months respectively after the initiation of ipilimumab. Immunohistochemical  staining for hMLH1, hMSH2, hMSH6 and PMS2 was performed on archival prostate  biopsy samples from one of the two patients; they exhibited normal protein  expression. Interestingly for this patient, a high CD3+ and CD8+ T cell  infiltration was observed on archival prostate biopsies as well as Treg FoxP3+ T   cells. CONCLUSION: Ipilimumab produces clinical activity in patients with CRPC,  including very long responders with no detectable residual disease.
CANIT0001008	28434018	Case report	Refractory classical Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Low-dose nivolumab induced remission in refractory classical Hodgkin lymphoma.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Low-dose nivolumab induced remission in refractory classical Hodgkin lymphoma.	 Ann Hematol	Unable to provide
CANIT0001009	28434031	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	118	77	N/A	FKBP51s-based immunophenotyping of melanoma patients revealed several profiles related to a negative immune regulatory control and identified an unknown Treg subset.	N/A	N/A	N/A	FKBP51 (Q13451); 	FKBP51s expression levels in regulatory T-cell 	Gene expression signature on/in immune cell	 2017 Sep	 FKBP51s signature in peripheral blood mononuclear cells of melanoma patients as a  possible predictive factor for immunotherapy.	 Cancer Immunol Immunother	 The inhibitory immune checkpoint PD-L1/PD1 promotes the alternative splicing of  the FKBP5 gene, resulting in increased expression of its variant 4 in the  peripheral blood mononuclear cells of melanoma patients. The variant 4 transcript  is translated into the truncated FKBP51s protein. Given the importance of  co-inhibitory signalling in tumour immune escape, here we tested the potential  for using FKBP51s expression to predict immunotherapy outcomes. To do this, we  immunophenotyped PBMCs from 118 melanoma patients and 77 age- and sex-matched  healthy controls. Blood samples were collected before patients underwent  ipilimumab treatment. In 64 of the 118 patients, FKBP51s expression was also  assessed in regulatory T cells (Tregs). We found that each PBMC subset analysed  contained an FKBP51s(pos) fraction, and that this fraction was greater in the  melanoma patients than healthy controls. In CD4 T lymphocytes, the FKBP51s(neg)  fraction was significantly impaired. Tregs count was increased in melanoma  patients, which is in line with previous studies. Also, by analyses of FKBP51s in  Tregs, we identified a subgroup of ipilimumab nonresponder patients (p = 0.002).   In conclusion, FKBP51s-based immunophenotyping of melanoma patients revealed  several profiles related to a negative immune regulatory control and identified  an unknown Treg subset. These findings are likely to be useful in the selection  of the patients that are candidate for immunotherapy.
CANIT0001010	28434516	Case report	Nonsquamous metastatic nonCsmall cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Long-lasting response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 May	 Long-Lasting Response to Nivolumab and Immune-Related Adverse Events in a  Nonsquamous Metastatic Non-Small Cell Lung Cancer Patient.	 J Thorac Oncol	Unable to provide
CANIT0001011	28434648	Clinical research	Advanced hepatocellular carcinoma	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	262	N/A	A phase I/II, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) 	Nivolumab had a manageable safety  profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma.	Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy).	N/A	N/A	N/A	N/A	N/A	 2017 Jun 24	 Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an   open-label, non-comparative, phase 1/2 dose escalation and expansion trial.	 Lancet	 BACKGROUND: For patients with advanced hepatocellular carcinoma, sorafenib is the  only approved drug worldwide, and outcomes remain poor. We aimed to assess the  safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune  checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or   without chronic viral hepatitis. METHODS: We did a phase 1/2, open-label,  non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab  in adults (>/=18 years) with histologically confirmed advanced hepatocellular  carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous  sorafenib treatment was allowed. A dose-escalation phase was conducted at seven  hospitals or academic centres in four countries or territories (USA, Spain, Hong   Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39  sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan).  At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A   or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the  dose-expansion phase, and an Eastern Cooperative Oncology Group performance  status of 1 or less. Patients with HBV infection had to be receiving effective  antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for  patients with HCV infection. We excluded patients previously treated with an  agent targeting T-cell costimulation or checkpoint pathways. Patients received  intravenous nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase  (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion  phase to patients in four cohorts: sorafenib untreated or intolerant without  viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and   HBV infected. Primary endpoints were safety and tolerability for the escalation  phase and objective response rate (Response Evaluation Criteria In Solid Tumors  version 1.1) for the expansion phase. This study is registered with  ClinicalTrials.gov, number NCT01658878. FINDINGS: Between Nov 26, 2012, and Aug  8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation  phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have  completed treatment and follow-up is ongoing. During dose escalation, nivolumab  showed a manageable safety profile, including acceptable tolerability. In this  phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease  progression. Incidence of treatment-related adverse events did not seem to be  associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48  patients had grade 3/4 treatment-related adverse events. Three (6%) patients had   treatment-related serious adverse events (pemphigoid, adrenal insufficiency,  liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not  determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for   dose expansion. The objective response rate was 20% (95% CI 15-26) in patients  treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28)   in the dose-escalation phase. INTERPRETATION: Nivolumab had a manageable safety  profile and no new signals were observed in patients with advanced hepatocellular  carcinoma. Durable objective responses show the potential of nivolumab for  treatment of advanced hepatocellular carcinoma. FUNDING: Bristol-Myers Squibb.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001012	28438383	Case report	Stage IV BRAF-wild type and NRAS exon 2-mutated melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome   induced by nivolumab.	 Semin Arthritis Rheum	 INTRODUCTION: A new articular syndrome described as immunrelated side effect of  immunotherapy: PD-1 inhibitors have revolutionized the treatment of advanced  melanoma but are responsible for immune-related toxicity. We report a case of  remitting seronegative symetrical synovitis with pitting edema (RS3PE) syndrome  induced by nivolumab. CASE REPORT: A 80 year-old man with stage IV BRAF-wild type  and NRAS exon 2-mutated melanoma was treated first line by nivolumab 3mg/kg every  2 weeks. At week 4, before the 3rd infusion, he presented with inflammatory  arthralgia, synovitis of proximal interphalangeal, wrist and ankle joints, and  edema of both hands and forearms. Laboratory tests showed inflammatory syndrome  (CRP = 8.4mg/dL), negative rheumatoid factor, and anti-CCP antibodies.  Radiographs did not show any joint erosion but joint ultrasound displayed  intra-articular effusion and tenosynovitis. PET/CT performed 6 and 3 months  before treatment for melanoma work-up showed an isolated hypermetabolism of the  shoulder girdle. The diagnosis of RS3PE was retained. A systemic corticosteroid  treatment (0.5mg/kg/d) was initiated; nivolumab was hold during 4 weeks leading  to remission of clinical symptoms within 10 days, CRP level normalization and  without relapse when nivolumab was resumed. Corticosteroids were progressively  tapered and stopped after 9 months. After 5 months, anti-PD1 was definitively  stopped because of disease progression. CONCLUSION: With this atypical case,  clinicians should remain alert on a whole range of autoimmune diseases  susceptible to be induced.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001013	28438440	Case report	Metastatic nasopharyngeal carcinoma	Nasopharyngeal squamous cell carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Stevens-Johnson syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients.	 Eur J Cancer	Unable to provide
CANIT0001014	28438440	Case report	Metastatic sarcomatoid renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Stevens-Johnson syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients.	 Eur J Cancer	Unable to provide
CANIT0001015	28440953	Clinical research	Advanced leiomyosarcoma of the uterus	Uterine leiomyosarcoma	EFO:1001974	Uterus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	12	N/A	A phase II clinical trial	Single-agent nivolumab did not demonstrate a benefit in this cohort of previously treated advanced ULMS patients.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Sep 1	 Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the  uterus: Results of a phase 2 study.	 Cancer	 BACKGROUND: Immunotherapy has changed the therapeutic landscape in oncology.  Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most  cases, and despite new drug approvals, improvements in overall survival have been  modest at best. The goal of this study was to evaluate programmed-death 1 (PD-1)   inhibition with nivolumab in this patient population. METHODS: This single-center  phase 2 trial completed enrollment between May and October 2015. Patients  received 3 mg/kg of intravenous nivolumab on day 1 of each 2-week cycle until  disease progression or unacceptable toxicity. The primary endpoint was objective   response rate. We assessed PD-1, PD-ligand 1 (PD-L1), and PD-L2 expression in  archival tumor samples and variations in immune-phenotyping of circulating immune  cells during treatment. RESULTS: Twelve patients were enrolled in the first stage  of the 2-stage design. A median of 5 (range, 2-6) 2-week cycles of nivolumab were  administered. Of the 12 patients, none responded to treatment. The overall median  progression-free survival was 1.8 months (95% confidence interval, 0.8-unknown).   The study did not open the second stage due to lack of benefit as defined by the   statistical plan. Archival samples were available for 83% of patients. PD-1 (>3%   of cells), PD-L1, and PD-L2 (>5% and >10% of tumor cells, respectively)  expression were observed in 20%, 20%, and 90% of samples, respectively. No  significant differences were observed between pre- and posttreatment cell  phenotypes. CONCLUSION: Single-agent nivolumab did not demonstrate a benefit in  this cohort of previously treated advanced ULMS patients. Further  biomarker-driven approaches and studies evaluating combined immune  checkpoint-modulators should be considered. Cancer 2017;123:3285-90. (c) 2017  American Cancer Society.CI  - (c) 2017 American Cancer Society.
CANIT0001016	28441111	Clinical research	Relapsed or refractory classic Hodgkin lymphoma	Classic hodgkin lymphoma	MONDO:0009348	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	210	N/A	A single-arm phase II	Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease.	The safety profile was largely consistent with previous pembrolizumab studies. 	N/A	N/A	N/A	N/A	N/A	 2017 Jul 1	 Phase II Study of the Efficacy and Safety of Pembrolizumab for  Relapsed/Refractory Classic Hodgkin Lymphoma.	 J Clin Oncol	 Purpose Hodgkin Reed-Sternberg cells harbor alterations in chromosome 9p24.1,  leading to overexpression of programmed death-ligand 1 (PD-L1) and PD-L2.  Pembrolizumab, a programmed death 1-blocking antibody, demonstrated a high  overall response rate (ORR) in patients with relapsed or refractory classic  Hodgkin lymphoma (rrHL) in phase I testing. Methods KEYNOTE-087 (  ClinicalTrials.gov identifier, NCT02453594) was a single-arm phase II study of  pembrolizumab in three cohorts of patients with rrHL, defined on the basis of  lymphoma progression after (1) autologous stem cell transplantation (ASCT) and  subsequent brentuximab vedotin (BV); (2) salvage chemotherapy and BV, and thus,  ineligible for ASCT because of chemoresistant disease; and (3) ASCT, but without   BV after transplantation. Patients received pembrolizumab 200 mg once every 3  weeks. Response was assessed every 12 weeks. The primary end points were ORR by  central review and safety. Results A total of 210 patients were enrolled and  treated (69 in cohort 1, 81 in cohort 2, and 60 in cohort 3). At the time of  analysis, patients received a median of 13 treatment cycles. Per central review,   the ORR was 69.0% (95% CI, 62.3% to 75.2%), and the complete response rate was  22.4% (95% CI, 16.9% to 28.6%). By cohort, ORRs were 73.9% for cohort 1, 64.2%  for cohort 2, and 70.0% for cohort 3. Thirty-one patients had a response >/= 6  months. The safety profile was largely consistent with previous pembrolizumab  studies. Conclusion Pembrolizumab was associated with high response rates and an   acceptable safety profile in patients with rrHL, offering a new treatment  paradigm for this disease.
CANIT0001017	28444424	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Pembrolizumab-based therapy resulted in meaningful efficacy and good tolerability in Chinese patients with melanoma, including those with acral and mucosal types.	The incidences of grade 3-4 adverse events were 14% in the two monotherapy groups and 30% in the combined therapy group. The most frequent adverse events were elevation of aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue. Treatment-related rash or vitiligo was associated with a better prognosis.	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 The experience of immune checkpoint inhibitors in Chinese patients with  metastatic melanoma: a retrospective case series.	 Cancer Immunol Immunother	 Melanomas in Chinese patients show relatively higher rates of acral and mucosal  types than in other populations. However, the efficacy of checkpoint inhibitor  therapies against these melanoma subtypes is not well defined. We analyzed 52  patients treated with ipilimumab, pembrolizumab, or a combination of both to  evaluate the efficacy and safety of checkpoint inhibitors in Chinese patients  with advanced melanoma, particularly those with acral and mucosal types. The  objective response rates (ORRs) were 0, 25, and 20% for ipilimumab,  pembrolizumab, and pembrolizumab plus ipilimumab, respectively. Pembrolizumab  contained therapy was as effective in acral and mucosal melanoma patients (ORR  26.7 and 20%, respectively) as in non-acral cutaneous melanoma patients (ORR  26.7%). Baseline lactate dehydrogenase levels and relative lymphocyte counts were  independent prognostic factors for PFS and OS. The incidences of grade 3-4  adverse events were 14% in the two monotherapy groups and 30% in the combined  therapy group. The most frequent adverse events were elevation of  aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue.  Treatment-related rash or vitiligo was associated with a better prognosis. In  summary, pembrolizumab-based therapy resulted in meaningful efficacy and good  tolerability in Chinese patients with melanoma, including those with acral and  mucosal types.
CANIT0001018	28444424	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	52	N/A	N/A	Pembrolizumab-based therapy resulted in meaningful efficacy and good tolerability in Chinese patients with melanoma, including those with acral and mucosal types.	The incidences of grade 3-4 adverse events were 14% in the two monotherapy groups and 30% in the combined therapy group. The most frequent adverse events were elevation of aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue. Treatment-related rash or vitiligo was associated with a better prognosis.	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 The experience of immune checkpoint inhibitors in Chinese patients with  metastatic melanoma: a retrospective case series.	 Cancer Immunol Immunother	 Melanomas in Chinese patients show relatively higher rates of acral and mucosal  types than in other populations. However, the efficacy of checkpoint inhibitor  therapies against these melanoma subtypes is not well defined. We analyzed 52  patients treated with ipilimumab, pembrolizumab, or a combination of both to  evaluate the efficacy and safety of checkpoint inhibitors in Chinese patients  with advanced melanoma, particularly those with acral and mucosal types. The  objective response rates (ORRs) were 0, 25, and 20% for ipilimumab,  pembrolizumab, and pembrolizumab plus ipilimumab, respectively. Pembrolizumab  contained therapy was as effective in acral and mucosal melanoma patients (ORR  26.7 and 20%, respectively) as in non-acral cutaneous melanoma patients (ORR  26.7%). Baseline lactate dehydrogenase levels and relative lymphocyte counts were  independent prognostic factors for PFS and OS. The incidences of grade 3-4  adverse events were 14% in the two monotherapy groups and 30% in the combined  therapy group. The most frequent adverse events were elevation of  aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue.  Treatment-related rash or vitiligo was associated with a better prognosis. In  summary, pembrolizumab-based therapy resulted in meaningful efficacy and good  tolerability in Chinese patients with melanoma, including those with acral and  mucosal types.
CANIT0001019	28452169	Case report	Melanoma with multiple lung metastases 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Partial response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Melanoma patient response to nivolumab treatment for metastatic lung lesions:  Multi-OMICS analysis in Project HOPE.	 J Dermatol	 A 70-year-old woman was diagnosed with a malignant melanoma of the occipital skin  which was resected; however, multiple lung metastases were detected. Nivolumab  therapy was initiated and partial response was obtained. However, the patient was  diagnosed with grade 2 interstitial pneumonitis. Prednisolone administration was   initiated and the interstitial pneumonitis shadow disappeared. However, then a  right rib metastasis was noticed and given radiation therapy. After progressive  disease was obtained, the metastatic lesion was resected, and no relapse occurred  until skeletal muscle metastasis was found. According to whole-exome sequencing  and gene expression profiling, the rib and skeletal muscle metastatic lesions  showed an upregulated expression of programmed death-ligand 1 mRNA and a high  single-nucleotide variant (SNV) number. The current melanoma case is  representative of a patient who responded to nivolumab therapy, and showed  typical immunological markers for responders such as high PD-L1 expression and  high SNV.CI  - (c) 2017 Japanese Dermatological Association.
CANIT0001020	28452849	Case report	Resected stage III melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Guillain-Barr syndrome presenting as dysautonomia	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Ipilimumab-induced Guillain-Barre Syndrome Presenting as Dysautonomia: An Unusual  Presentation of a Rare Complication of Immunotherapy.	 J Immunother	 Immune-related adverse events are common and well-documented in patients treated   with ipilimumab, a cytotoxic T-lymphocyte antigen-4 monoclonal antibody approved   for the treatment of metastatic and stage III melanoma. Neurological  complications are rare, but widely variable and potentially devastating. Here, we  discuss a case of a patient who was treated with a single dose of ipilimumab for   resected stage III melanoma. She subsequently developed pandysautonomia that  manifested as a tonically dilated pupil, gastrointestinal dysmotility, urinary  retention, and profound orthostatic hypotension. Guillain-Barre syndrome was  diagnosed on electromyography. She was treated with intravenous immunoglobulin,  droxidopa, and supportive care, with prolonged but eventual recovery. Given the  broadening use of ipilimumab in the treatment of advanced and metastatic  melanoma, awareness and recognition of its profound immune-mediated adverse  effects are essential.
CANIT0001021	28459940	Case report	Metastatic kidney cancer	Renal carcinoma	EFO:0002890	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Tumor-infiltrating lymphocyte-mediated pleuritis	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Tumor-infiltrating lymphocyte-mediated pleuritis followed by marked shrinkage of   metastatic kidney cancer of the chest wall during nivolumab treatment.	 Ann Oncol	Unable to provide
CANIT0001022	28459943	Clinical research	10 nonsmall cell lung cancer, 3 uveal melanoma, or 2 microsatellite-instable colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	15	N/A	N/A	Quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting nivolumab	Metabolite	 2017 Aug 1	 Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a  proof-of-concept study.	 Ann Oncol	 Background: Recent clinical results support the use of new immune checkpoint  blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and  anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is   challenging due to tumor immune infiltration. Changes of circulating tumor DNA  (ctDNA) levels during therapy could be a promising tool for very accurate  monitoring of treatment efficacy, but data are lacking with ICB. Patients and  methods: This prospective pilot study was conducted in patients with nonsmall  cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer  treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels  were assessed at baseline and after 8 weeks (w8) by bidirectional  pyrophosphorolysis-activated polymerization, droplet digital PCR or  next-generation sequencing depending on the mutation type. Radiological  evaluation of efficacy of treatment was carried out by using immune-related  response criteria. Results: ctDNA was detected at baseline in 10 out of 15  patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed  between synchronous changes in ctDNA levels and tumor size. Patients in whom  ctDNA levels became undetectable at w8 presented a marked and lasting response to  therapy. ctDNA detection at w8 was also a significant prognostic factor in terms   of progression-free survival (hazard ratio = 10.2; 95% confidence interval  2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence  interval 2.5-94.9, P = 0.004). Conclusion: This proof-of-principle study is the  first to demonstrate that quantitative ctDNA monitoring is a valuable tool to  assess tumor response in patients treated with anti-PD-1 drugs.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001023	28459943	Clinical research	10 nonsmall cell lung cancer, 3 uveal melanoma, or 2 microsatellite-instable colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	15	N/A	N/A	Quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting pembrolizumab	Metabolite	 2017 Aug 1	 Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a  proof-of-concept study.	 Ann Oncol	 Background: Recent clinical results support the use of new immune checkpoint  blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and  anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is   challenging due to tumor immune infiltration. Changes of circulating tumor DNA  (ctDNA) levels during therapy could be a promising tool for very accurate  monitoring of treatment efficacy, but data are lacking with ICB. Patients and  methods: This prospective pilot study was conducted in patients with nonsmall  cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer  treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels  were assessed at baseline and after 8 weeks (w8) by bidirectional  pyrophosphorolysis-activated polymerization, droplet digital PCR or  next-generation sequencing depending on the mutation type. Radiological  evaluation of efficacy of treatment was carried out by using immune-related  response criteria. Results: ctDNA was detected at baseline in 10 out of 15  patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed  between synchronous changes in ctDNA levels and tumor size. Patients in whom  ctDNA levels became undetectable at w8 presented a marked and lasting response to  therapy. ctDNA detection at w8 was also a significant prognostic factor in terms   of progression-free survival (hazard ratio = 10.2; 95% confidence interval  2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence  interval 2.5-94.9, P = 0.004). Conclusion: This proof-of-principle study is the  first to demonstrate that quantitative ctDNA monitoring is a valuable tool to  assess tumor response in patients treated with anti-PD-1 drugs.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001024	28459943	Clinical research	10 nonsmall cell lung cancer, 3 uveal melanoma, or 2 microsatellite-instable colorectal cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	15	N/A	N/A	Quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting nivolumab	Metabolite	 2017 Aug 1	 Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a  proof-of-concept study.	 Ann Oncol	 Background: Recent clinical results support the use of new immune checkpoint  blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and  anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is   challenging due to tumor immune infiltration. Changes of circulating tumor DNA  (ctDNA) levels during therapy could be a promising tool for very accurate  monitoring of treatment efficacy, but data are lacking with ICB. Patients and  methods: This prospective pilot study was conducted in patients with nonsmall  cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer  treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels  were assessed at baseline and after 8 weeks (w8) by bidirectional  pyrophosphorolysis-activated polymerization, droplet digital PCR or  next-generation sequencing depending on the mutation type. Radiological  evaluation of efficacy of treatment was carried out by using immune-related  response criteria. Results: ctDNA was detected at baseline in 10 out of 15  patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed  between synchronous changes in ctDNA levels and tumor size. Patients in whom  ctDNA levels became undetectable at w8 presented a marked and lasting response to  therapy. ctDNA detection at w8 was also a significant prognostic factor in terms   of progression-free survival (hazard ratio = 10.2; 95% confidence interval  2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence  interval 2.5-94.9, P = 0.004). Conclusion: This proof-of-principle study is the  first to demonstrate that quantitative ctDNA monitoring is a valuable tool to  assess tumor response in patients treated with anti-PD-1 drugs.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001025	28459943	Clinical research	10 nonsmall cell lung cancer, 3 uveal melanoma, or 2 microsatellite-instable colorectal cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	15	N/A	N/A	Quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting pembrolizumab	Metabolite	 2017 Aug 1	 Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a  proof-of-concept study.	 Ann Oncol	 Background: Recent clinical results support the use of new immune checkpoint  blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and  anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is   challenging due to tumor immune infiltration. Changes of circulating tumor DNA  (ctDNA) levels during therapy could be a promising tool for very accurate  monitoring of treatment efficacy, but data are lacking with ICB. Patients and  methods: This prospective pilot study was conducted in patients with nonsmall  cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer  treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels  were assessed at baseline and after 8 weeks (w8) by bidirectional  pyrophosphorolysis-activated polymerization, droplet digital PCR or  next-generation sequencing depending on the mutation type. Radiological  evaluation of efficacy of treatment was carried out by using immune-related  response criteria. Results: ctDNA was detected at baseline in 10 out of 15  patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed  between synchronous changes in ctDNA levels and tumor size. Patients in whom  ctDNA levels became undetectable at w8 presented a marked and lasting response to  therapy. ctDNA detection at w8 was also a significant prognostic factor in terms   of progression-free survival (hazard ratio = 10.2; 95% confidence interval  2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence  interval 2.5-94.9, P = 0.004). Conclusion: This proof-of-principle study is the  first to demonstrate that quantitative ctDNA monitoring is a valuable tool to  assess tumor response in patients treated with anti-PD-1 drugs.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001026	28459943	Clinical research	10 nonsmall cell lung cancer, 3 uveal melanoma, or 2 microsatellite-instable colorectal cancer	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	15	N/A	N/A	Quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting pembrolizumab	Metabolite	 2017 Aug 1	 Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a  proof-of-concept study.	 Ann Oncol	 Background: Recent clinical results support the use of new immune checkpoint  blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and  anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is   challenging due to tumor immune infiltration. Changes of circulating tumor DNA  (ctDNA) levels during therapy could be a promising tool for very accurate  monitoring of treatment efficacy, but data are lacking with ICB. Patients and  methods: This prospective pilot study was conducted in patients with nonsmall  cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer  treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels  were assessed at baseline and after 8 weeks (w8) by bidirectional  pyrophosphorolysis-activated polymerization, droplet digital PCR or  next-generation sequencing depending on the mutation type. Radiological  evaluation of efficacy of treatment was carried out by using immune-related  response criteria. Results: ctDNA was detected at baseline in 10 out of 15  patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed  between synchronous changes in ctDNA levels and tumor size. Patients in whom  ctDNA levels became undetectable at w8 presented a marked and lasting response to  therapy. ctDNA detection at w8 was also a significant prognostic factor in terms   of progression-free survival (hazard ratio = 10.2; 95% confidence interval  2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence  interval 2.5-94.9, P = 0.004). Conclusion: This proof-of-principle study is the  first to demonstrate that quantitative ctDNA monitoring is a valuable tool to  assess tumor response in patients treated with anti-PD-1 drugs.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001027	28459943	Clinical research	10 nonsmall cell lung cancer, 3 uveal melanoma, or 2 microsatellite-instable colorectal cancer	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	15	N/A	N/A	Quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting pembrolizumab	Metabolite	 2017 Aug 1	 Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a  proof-of-concept study.	 Ann Oncol	 Background: Recent clinical results support the use of new immune checkpoint  blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and  anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is   challenging due to tumor immune infiltration. Changes of circulating tumor DNA  (ctDNA) levels during therapy could be a promising tool for very accurate  monitoring of treatment efficacy, but data are lacking with ICB. Patients and  methods: This prospective pilot study was conducted in patients with nonsmall  cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer  treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels  were assessed at baseline and after 8 weeks (w8) by bidirectional  pyrophosphorolysis-activated polymerization, droplet digital PCR or  next-generation sequencing depending on the mutation type. Radiological  evaluation of efficacy of treatment was carried out by using immune-related  response criteria. Results: ctDNA was detected at baseline in 10 out of 15  patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed  between synchronous changes in ctDNA levels and tumor size. Patients in whom  ctDNA levels became undetectable at w8 presented a marked and lasting response to  therapy. ctDNA detection at w8 was also a significant prognostic factor in terms   of progression-free survival (hazard ratio = 10.2; 95% confidence interval  2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence  interval 2.5-94.9, P = 0.004). Conclusion: This proof-of-principle study is the  first to demonstrate that quantitative ctDNA monitoring is a valuable tool to  assess tumor response in patients treated with anti-PD-1 drugs.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001028	28463153	Clinical research	71 metastatic non-small cell lung cancer, 52 melanoma, or 10 renal cell cancer 	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); radiotherapy (NCIT:C15696); 	133	N/A	A retrospective cohort study	Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated.	Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 1	 Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and  CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To analyze immune-related adverse events (ir-AEs) in patients treated  with radiation and immune checkpoint blockade. METHODS AND MATERIALS: We  retrospectively reviewed records from patients with metastatic non-small cell  lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a  CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined  using Common Terminology Criteria for Adverse Events version 4.0, were tabulated   in relation to treatment variables, and associations with sequencing and timing  were assessed. RESULTS: We identified 133 patients, of whom 28 received a CTLA-4   inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes  of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six  patients received radiation within 14 days of an immune checkpoint inhibitor.  Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both   CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with  either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of  patients in whom radiation was administered within 14 days of immunotherapy,  compared with 23% of other patients (P=.06) and more often in patients who  received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However,  most toxicities were mild. There were no associations between site irradiated and  specific ir-AEs. CONCLUSIONS: Our data suggest the combination of focal  palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with  manageable ir-AEs that did not seem to be associated with the particular site  irradiated. Although conclusions are limited by the heterogeneity of patients and  treatments, and future confirmatory studies are needed, this information can help  guide clinical practice for patients receiving immune checkpoint therapy who  require palliative radiation therapy.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001029	28463153	Clinical research	71 metastatic non-small cell lung cancer, 52 melanoma, or 10 renal cell cancer 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15696); 	133	N/A	A retrospective cohort study	Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated.	Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 1	 Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and  CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To analyze immune-related adverse events (ir-AEs) in patients treated  with radiation and immune checkpoint blockade. METHODS AND MATERIALS: We  retrospectively reviewed records from patients with metastatic non-small cell  lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a  CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined  using Common Terminology Criteria for Adverse Events version 4.0, were tabulated   in relation to treatment variables, and associations with sequencing and timing  were assessed. RESULTS: We identified 133 patients, of whom 28 received a CTLA-4   inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes  of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six  patients received radiation within 14 days of an immune checkpoint inhibitor.  Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both   CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with  either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of  patients in whom radiation was administered within 14 days of immunotherapy,  compared with 23% of other patients (P=.06) and more often in patients who  received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However,  most toxicities were mild. There were no associations between site irradiated and  specific ir-AEs. CONCLUSIONS: Our data suggest the combination of focal  palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with  manageable ir-AEs that did not seem to be associated with the particular site  irradiated. Although conclusions are limited by the heterogeneity of patients and  treatments, and future confirmatory studies are needed, this information can help  guide clinical practice for patients receiving immune checkpoint therapy who  require palliative radiation therapy.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001030	28463153	Clinical research	71 metastatic non-small cell lung cancer, 52 melanoma, or 10 renal cell cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); radiotherapy (NCIT:C15696); 	133	N/A	A retrospective cohort study	Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated.	Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 1	 Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and  CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To analyze immune-related adverse events (ir-AEs) in patients treated  with radiation and immune checkpoint blockade. METHODS AND MATERIALS: We  retrospectively reviewed records from patients with metastatic non-small cell  lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a  CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined  using Common Terminology Criteria for Adverse Events version 4.0, were tabulated   in relation to treatment variables, and associations with sequencing and timing  were assessed. RESULTS: We identified 133 patients, of whom 28 received a CTLA-4   inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes  of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six  patients received radiation within 14 days of an immune checkpoint inhibitor.  Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both   CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with  either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of  patients in whom radiation was administered within 14 days of immunotherapy,  compared with 23% of other patients (P=.06) and more often in patients who  received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However,  most toxicities were mild. There were no associations between site irradiated and  specific ir-AEs. CONCLUSIONS: Our data suggest the combination of focal  palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with  manageable ir-AEs that did not seem to be associated with the particular site  irradiated. Although conclusions are limited by the heterogeneity of patients and  treatments, and future confirmatory studies are needed, this information can help  guide clinical practice for patients receiving immune checkpoint therapy who  require palliative radiation therapy.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001031	28463153	Clinical research	71 metastatic non-small cell lung cancer, 52 melanoma, or 10 renal cell cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15696); 	133	N/A	A retrospective cohort study	Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated.	Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 1	 Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and  CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To analyze immune-related adverse events (ir-AEs) in patients treated  with radiation and immune checkpoint blockade. METHODS AND MATERIALS: We  retrospectively reviewed records from patients with metastatic non-small cell  lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a  CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined  using Common Terminology Criteria for Adverse Events version 4.0, were tabulated   in relation to treatment variables, and associations with sequencing and timing  were assessed. RESULTS: We identified 133 patients, of whom 28 received a CTLA-4   inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes  of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six  patients received radiation within 14 days of an immune checkpoint inhibitor.  Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both   CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with  either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of  patients in whom radiation was administered within 14 days of immunotherapy,  compared with 23% of other patients (P=.06) and more often in patients who  received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However,  most toxicities were mild. There were no associations between site irradiated and  specific ir-AEs. CONCLUSIONS: Our data suggest the combination of focal  palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with  manageable ir-AEs that did not seem to be associated with the particular site  irradiated. Although conclusions are limited by the heterogeneity of patients and  treatments, and future confirmatory studies are needed, this information can help  guide clinical practice for patients receiving immune checkpoint therapy who  require palliative radiation therapy.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001032	28463153	Clinical research	71 metastatic non-small cell lung cancer, 52 melanoma, or 10 renal cell cancer 	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); radiotherapy (NCIT:C15696); 	133	N/A	A retrospective cohort study	Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated.	Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 1	 Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and  CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To analyze immune-related adverse events (ir-AEs) in patients treated  with radiation and immune checkpoint blockade. METHODS AND MATERIALS: We  retrospectively reviewed records from patients with metastatic non-small cell  lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a  CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined  using Common Terminology Criteria for Adverse Events version 4.0, were tabulated   in relation to treatment variables, and associations with sequencing and timing  were assessed. RESULTS: We identified 133 patients, of whom 28 received a CTLA-4   inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes  of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six  patients received radiation within 14 days of an immune checkpoint inhibitor.  Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both   CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with  either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of  patients in whom radiation was administered within 14 days of immunotherapy,  compared with 23% of other patients (P=.06) and more often in patients who  received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However,  most toxicities were mild. There were no associations between site irradiated and  specific ir-AEs. CONCLUSIONS: Our data suggest the combination of focal  palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with  manageable ir-AEs that did not seem to be associated with the particular site  irradiated. Although conclusions are limited by the heterogeneity of patients and  treatments, and future confirmatory studies are needed, this information can help  guide clinical practice for patients receiving immune checkpoint therapy who  require palliative radiation therapy.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001033	28463153	Clinical research	71 metastatic non-small cell lung cancer, 52 melanoma, or 10 renal cell cancer 	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15696); 	133	N/A	A retrospective cohort study	Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated.	Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 1	 Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and  CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To analyze immune-related adverse events (ir-AEs) in patients treated  with radiation and immune checkpoint blockade. METHODS AND MATERIALS: We  retrospectively reviewed records from patients with metastatic non-small cell  lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a  CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined  using Common Terminology Criteria for Adverse Events version 4.0, were tabulated   in relation to treatment variables, and associations with sequencing and timing  were assessed. RESULTS: We identified 133 patients, of whom 28 received a CTLA-4   inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes  of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six  patients received radiation within 14 days of an immune checkpoint inhibitor.  Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both   CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with  either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of  patients in whom radiation was administered within 14 days of immunotherapy,  compared with 23% of other patients (P=.06) and more often in patients who  received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However,  most toxicities were mild. There were no associations between site irradiated and  specific ir-AEs. CONCLUSIONS: Our data suggest the combination of focal  palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with  manageable ir-AEs that did not seem to be associated with the particular site  irradiated. Although conclusions are limited by the heterogeneity of patients and  treatments, and future confirmatory studies are needed, this information can help  guide clinical practice for patients receiving immune checkpoint therapy who  require palliative radiation therapy.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001034	28465048	Case report	Nonseminomatous germ cell tumor	Extragonadal nonseminomatous germ cell tumor	MONDO:0003578	Testis	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Durable response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Durable Response to Immune Checkpoint Blockade in a Platinum-Refractory Patient  With Nonseminomatous Germ Cell Tumor.	 Clin Genitourin Cancer	Unable to provide
CANIT0001035	28466250	Clinical research	Non-small cell lung cancer brain metastases	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus stereotactic radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); stereotactic ablative radiotherapy (NCIT:C157991); 	17	N/A	A retrospective cohort study	Stereotactic radiation to NSCLC brain metastases was well tolerated in patients who received anti-PD-1/PD-L1 therapy.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Karnofsky performance status	Disease status	 2017 Jun	 Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation  for patients with non-small cell lung cancer brain metastases.	 J Neurooncol	 Anti-PD-1/PD-L1 therapies have demonstrated activity in patients with advanced  stage non-small cell lung cancer (NSCLC). However, little is known about the  safety and feasibility of patients receiving anti-PD-1/PD-L1 therapy and  stereotactic radiation for the treatment of brain metastases. Data were analyzed   retrospectively from NSCLC patients treated with stereotactic radiation either  before, during or after anti-PD-1/PD-L1 therapy with nivolumab (anti-PD-1) or  durvalumab (anti-PD-L1). Seventeen patients treated with stereotactic  radiosurgery (SRS) or fractionated stereotactic radiation therapy (FSRT) to 49  brain metastases over 21 sessions were identified. Radiation was administered  prior to, during and after anti-PD-1/PD-L1 therapy in 22 lesions (45%), 13  lesions (27%), and 14 lesions (29%), respectively. The 6 months Kaplan-Meier (KM)  distant brain control rate was 48% following stereotactic radiation. Six and 12  month KM rates of OS from the date of stereotactic radiation and the date of  cranial metastases diagnosis were 48/41% and 81/51%, respectively. The 6 month  rate of distant brain control following stereotactic radiation for patients  treated with stereotactic radiation during or prior to anti-PD-1/PD-L1 therapy  was 57% compared to 0% among patients who received anti-PD-1/PD-L1 therapy before  stereotactic radiation (p = 0.05). A Karnofsky Performance Status (KPS) of <90  was found to be predictive of worse OS following radiation treatment on both  univariate and multivariate analyses (MVA, p = 0.01). In our series, stereotactic  radiation to NSCLC brain metastases was well tolerated in patients who received  anti-PD-1/PD-L1 therapy. Prospective evaluation to determine how these two  modalities can be used synergistically to improve distant brain control and OS is  warranted.
CANIT0001036	28466250	Clinical research	Non-small cell lung cancer brain metastases	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab plus stereotactic radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Durvalumab (DB11714); stereotactic ablative radiotherapy (NCIT:C157991); 	17	N/A	A retrospective cohort study	Stereotactic radiation to NSCLC brain metastases was well tolerated in patients who received anti-PD-1/PD-L1 therapy.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Karnofsky performance status	Disease status	 2017 Jun	 Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation  for patients with non-small cell lung cancer brain metastases.	 J Neurooncol	 Anti-PD-1/PD-L1 therapies have demonstrated activity in patients with advanced  stage non-small cell lung cancer (NSCLC). However, little is known about the  safety and feasibility of patients receiving anti-PD-1/PD-L1 therapy and  stereotactic radiation for the treatment of brain metastases. Data were analyzed   retrospectively from NSCLC patients treated with stereotactic radiation either  before, during or after anti-PD-1/PD-L1 therapy with nivolumab (anti-PD-1) or  durvalumab (anti-PD-L1). Seventeen patients treated with stereotactic  radiosurgery (SRS) or fractionated stereotactic radiation therapy (FSRT) to 49  brain metastases over 21 sessions were identified. Radiation was administered  prior to, during and after anti-PD-1/PD-L1 therapy in 22 lesions (45%), 13  lesions (27%), and 14 lesions (29%), respectively. The 6 months Kaplan-Meier (KM)  distant brain control rate was 48% following stereotactic radiation. Six and 12  month KM rates of OS from the date of stereotactic radiation and the date of  cranial metastases diagnosis were 48/41% and 81/51%, respectively. The 6 month  rate of distant brain control following stereotactic radiation for patients  treated with stereotactic radiation during or prior to anti-PD-1/PD-L1 therapy  was 57% compared to 0% among patients who received anti-PD-1/PD-L1 therapy before  stereotactic radiation (p = 0.05). A Karnofsky Performance Status (KPS) of <90  was found to be predictive of worse OS following radiation treatment on both  univariate and multivariate analyses (MVA, p = 0.01). In our series, stereotactic  radiation to NSCLC brain metastases was well tolerated in patients who received  anti-PD-1/PD-L1 therapy. Prospective evaluation to determine how these two  modalities can be used synergistically to improve distant brain control and OS is  warranted.
CANIT0001037	28466375	Case report	Metastatic type 2 papillary renal cell carcinoma	Papillary renal cell carcinoma	EFO:0000640	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Impressive and durable response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Impressive and durable response to nivolumab in a patient with metastatic type 2   papillary renal cell carcinoma: On-label but without evidence.	 Invest New Drugs	 Nivolumab is a treatment option for patients with metastatic renal cell carcinoma  (RCC) previously treated with targeted antiangiogenic therapy. Papillary renal  cell carcinoma (PRCC) comprises 10-15% of RCC cases but non-clear cell subtypes  were excluded from the immunotherapy trials. We report the case of a woman with  recurrent metastatic PRCC who had an impressive therapeutic response to nivolumab  with no significant adverse events. She had previously been treated with  sunitinib and pazopanib with no response. She showed a remarkable clinical  improvement after only the first 2 immunotherapy cycles and subsequent  radiographic studies demonstrated a marked decrease in tumor burden. At present,   she continues to show a durable benefit after 8 months of treatment. Her tumor  had <1% positivity for PD-L1 staining and a low tumor mutational burden with no  actionable mutations on genomic sequencing. Considering its high genetic  variation, checkpoint blockade immunotherapies (CBIs) are attractive treatment  options in PRCC. This is the third case that reports objective responses of  nivolumab in PRCC. We believe our patient's experience supports the inclusion of   non-clear cell RCC on clinical trials using CBIs. PD-L1 status and TMB may not  serve as predictive biomarkers for response.
CANIT0001038	28466377	Case report	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	This case report suggests that even if patients receive nivolumab therapy, a long interval from the last administration of nivolumab may reduce the risk of osimertinib-induced interstitial lung disease (ILD).	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Successful osimertinib rechallenge in a patient with advanced non-small cell lung  cancer following osimertinib-induced interstitial lung disease after treatment  with nivolumab.	 Invest New Drugs	Unable to provide
CANIT0001039	28467522	Case report	2 metastatic melanoma, 1 metastatic squamous cell carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Case	Eruptive keratoacanthomas	Three consecutive patients with cancer, 2 men and 1 woman (median age, 83 years; range 77-91 years), experienced pembrolizumab-associated eruptive KAs. All patients presented with a sudden onset of multiple lesions on sun-exposed areas of their extremities after a median of 13 months (range, 4-18 months) of pembrolizumab therapy. On lesional biopsy, a lichenoid infiltrate was observed in the underlying dermis, predominantly composed of CD3+ T cells, scattered CD20+ B cells, and relatively few PD-1+ (programmed cell death 1-positive) T cells, an immunophenotypic pattern also observed in other cases of anti-PD-1-induced lichenoid dermatitis. Patients were treated with clobetasol ointment and intralesional triamcinolone, alone or in combination with open superficial cryosurgery. All KAs resolved in all patients, and no new lesions occurred during close follow-up. Pembrolizumab treatment was continued without disruption in all 3 cases, and all patients had complete responses of their primary cancers.	N/A	N/A	N/A	N/A	N/A	 2017 Jul 1	 Eruptive Keratoacanthomas Associated With Pembrolizumab Therapy.	 JAMA Dermatol	 Importance: To our knowledge, there have been no previous reports of eruptive  keratoacanthomas (KAs) in patients receiving pembrolizumab. Objective: To report   the cases of 3 consecutive patients with pembrolizumab-induced eruptive KAs and  their management. Design, Setting, and Participants: Case report study of 3  patients from 2 centers with pembrolizumab-treated cancer who all developed  eruptive KAs. Interventions: All 3 patients had AK treatment with clobetasol  ointment and intralesional triamcinolone; 2 patients also underwent open  superficial cryosurgery. Results: Three consecutive patients with cancer, 2 men  and 1 woman (median age, 83 years; range 77-91 years), experienced  pembrolizumab-associated eruptive KAs. All patients presented with a sudden onset  of multiple lesions on sun-exposed areas of their extremities after a median of  13 months (range, 4-18 months) of pembrolizumab therapy. On lesional biopsy, a  lichenoid infiltrate was observed in the underlying dermis, predominantly  composed of CD3+ T cells, scattered CD20+ B cells, and relatively few PD-1+  (programmed cell death 1-positive) T cells, an immunophenotypic pattern also  observed in other cases of anti-PD-1-induced lichenoid dermatitis. Patients were   treated with clobetasol ointment and intralesional triamcinolone, alone or in  combination with open superficial cryosurgery. All KAs resolved in all patients,   and no new lesions occurred during close follow-up. Pembrolizumab treatment was  continued without disruption in all 3 cases, and all patients had complete  responses of their primary cancers. Conclusions and Relevance: Pembrolizumab is  used in advanced melanoma, advanced non-small-cell lung cancer, and in head and  neck cancer. A variety of dermatologic immune-related adverse events including  maculopapular eruption, lichenoid reactions, pruritus, and vitiligo have been  described. This case series demonstrates that pembrolizumab therapy may also be  associated with eruptive KAs with characteristic dermal inflammation, which  improved with corticosteroid treatment (topical and intralesional) alone or in  combination with cryosurgery, allowing patients to continue therapy with  pembrolizumab.
CANIT0001040	28467522	Case report	2 metastatic melanoma, 1 metastatic squamous cell carcinoma	Squamous cell carcinoma	EFO:0000707	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Case	Eruptive keratoacanthomas	Three consecutive patients with cancer, 2 men and 1 woman (median age, 83 years; range 77-91 years), experienced pembrolizumab-associated eruptive KAs. All patients presented with a sudden onset of multiple lesions on sun-exposed areas of their extremities after a median of 13 months (range, 4-18 months) of pembrolizumab therapy. On lesional biopsy, a lichenoid infiltrate was observed in the underlying dermis, predominantly composed of CD3+ T cells, scattered CD20+ B cells, and relatively few PD-1+ (programmed cell death 1-positive) T cells, an immunophenotypic pattern also observed in other cases of anti-PD-1-induced lichenoid dermatitis. Patients were treated with clobetasol ointment and intralesional triamcinolone, alone or in combination with open superficial cryosurgery. All KAs resolved in all patients, and no new lesions occurred during close follow-up. Pembrolizumab treatment was continued without disruption in all 3 cases, and all patients had complete responses of their primary cancers.	N/A	N/A	N/A	N/A	N/A	 2017 Jul 1	 Eruptive Keratoacanthomas Associated With Pembrolizumab Therapy.	 JAMA Dermatol	 Importance: To our knowledge, there have been no previous reports of eruptive  keratoacanthomas (KAs) in patients receiving pembrolizumab. Objective: To report   the cases of 3 consecutive patients with pembrolizumab-induced eruptive KAs and  their management. Design, Setting, and Participants: Case report study of 3  patients from 2 centers with pembrolizumab-treated cancer who all developed  eruptive KAs. Interventions: All 3 patients had AK treatment with clobetasol  ointment and intralesional triamcinolone; 2 patients also underwent open  superficial cryosurgery. Results: Three consecutive patients with cancer, 2 men  and 1 woman (median age, 83 years; range 77-91 years), experienced  pembrolizumab-associated eruptive KAs. All patients presented with a sudden onset  of multiple lesions on sun-exposed areas of their extremities after a median of  13 months (range, 4-18 months) of pembrolizumab therapy. On lesional biopsy, a  lichenoid infiltrate was observed in the underlying dermis, predominantly  composed of CD3+ T cells, scattered CD20+ B cells, and relatively few PD-1+  (programmed cell death 1-positive) T cells, an immunophenotypic pattern also  observed in other cases of anti-PD-1-induced lichenoid dermatitis. Patients were   treated with clobetasol ointment and intralesional triamcinolone, alone or in  combination with open superficial cryosurgery. All KAs resolved in all patients,   and no new lesions occurred during close follow-up. Pembrolizumab treatment was  continued without disruption in all 3 cases, and all patients had complete  responses of their primary cancers. Conclusions and Relevance: Pembrolizumab is  used in advanced melanoma, advanced non-small-cell lung cancer, and in head and  neck cancer. A variety of dermatologic immune-related adverse events including  maculopapular eruption, lichenoid reactions, pruritus, and vitiligo have been  described. This case series demonstrates that pembrolizumab therapy may also be  associated with eruptive KAs with characteristic dermal inflammation, which  improved with corticosteroid treatment (topical and intralesional) alone or in  combination with cryosurgery, allowing patients to continue therapy with  pembrolizumab.
CANIT0001041	28471570	Case report	Advanced prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Distal esophageal dissection	N/A	N/A	N/A	N/A	N/A	 2016 Jul	 Ipilimumab Treatment-Induced Distal Esophageal Dissection in a Patient with  Advanced Prostate Cancer.	 Isr Med Assoc J	Unable to provide
CANIT0001042	28473314	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); VEGF (P15692); 	CTLA-4; VEGF	Ipilimumab plus bevacizumab	N/A	Immune checkpoint therapy plus Target therapy	Ipilimumab (DB06186); bevacizumab (DB00112); 	43	N/A	N/A	Humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti-CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking anti-angiogenesis and immune checkpoint blockade.	N/A	N/A	N/A	Galectin-1 (P09382); 	Serum galectin-1 protein levels	Gene expression signature in serum	 2017 Jun	 Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1  Which Is Associated with Favorable Clinical Outcomes.	 Cancer Immunol Res	 The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint  anti-CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial  activation and immune cell infiltration that were associated with favorable  clinical outcomes in patients with metastatic melanoma. To identify potential  immune targets responsible for these observations, posttreatment plasma from  long-term responding patients were used to screen human protein arrays. We  reported that ipilimumab plus bevacizumab therapy elicited humoral immune  responses to galectin-1 (Gal-1), which exhibits protumor, proangiogenesis, and  immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies  purified from posttreatment plasma suppressed the binding of Gal-1 to CD45, a  T-cell surface receptor that transduces apoptotic signals upon binding to  extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in  the group of patients with therapeutic responses and correlated with improved  overall survival. In contrast, another subgroup of treated patients had increased  circulating Gal-1 protein instead, and they had reduced overall survival. Our  findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of  anti-VEGF and anti-CTLA-4 combination therapy. Gal-1 may offer an additional  therapeutic target linking anti-angiogenesis and immune checkpoint blockade.  Cancer Immunol Res; 5(6); 446-54. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001043	28480561	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	3	N/A	Case	N/A	Sarcoidosis	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1  checkpoint inhibitors: Case series and immunophenotypic analysis.	 Int J Rheum Dis	 AIM: Sarcoidosis is a multisystem granulomatous disease. This condition has a  documented association with the diagnosis of melanoma and can be induced in  melanoma patients receiving anti-neoplastic therapy. We evaluated a case series  of melanoma patients who developed immunotherapy-induced sarcoidosis. METHODS:  Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated  with anti-programmed cell death (PD)-1 antibody therapy at two institutions  developed biopsy-proven sarcoidosis. We used mass cytometry to determine  expression of the relevant chemokine receptors (CR) by peripheral blood  mononuclear cells for two of the three patients who developed sarcoidosis and 13   melanoma patients who did not. Blood samples were collected before receiving PD-1  checkpoint inhibitor therapy. RESULTS: Immunophenotypic analysis demonstrated  abnormally high numbers of circulating Th17.1 (CCR6(+) CCR4(-) CXCR3(+) CCR10(-)   ) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15  melanoma patients, including both the patients who developed sarcoidosis during  the course of therapy. CONCLUSION: Our findings support prior literature  implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we  demonstrate these findings in patients with melanoma prior to administration of  checkpoint therapy and before the onset of clinically symptomatic sarcoidosis.  The identification of elevated Th17.1 cells in melanoma patients who have not  developed sarcoidosis may reflect the established association between melanoma  and sarcoidosis. With some patients receiving these agents over a prolonged  period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.CI  - (c) 2017 Asia Pacific League of Associations for Rheumatology and John Wiley &  Sons Australia, Ltd.
CANIT0001044	28480561	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Case	N/A	Sarcoidosis	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1  checkpoint inhibitors: Case series and immunophenotypic analysis.	 Int J Rheum Dis	 AIM: Sarcoidosis is a multisystem granulomatous disease. This condition has a  documented association with the diagnosis of melanoma and can be induced in  melanoma patients receiving anti-neoplastic therapy. We evaluated a case series  of melanoma patients who developed immunotherapy-induced sarcoidosis. METHODS:  Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated  with anti-programmed cell death (PD)-1 antibody therapy at two institutions  developed biopsy-proven sarcoidosis. We used mass cytometry to determine  expression of the relevant chemokine receptors (CR) by peripheral blood  mononuclear cells for two of the three patients who developed sarcoidosis and 13   melanoma patients who did not. Blood samples were collected before receiving PD-1  checkpoint inhibitor therapy. RESULTS: Immunophenotypic analysis demonstrated  abnormally high numbers of circulating Th17.1 (CCR6(+) CCR4(-) CXCR3(+) CCR10(-)   ) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15  melanoma patients, including both the patients who developed sarcoidosis during  the course of therapy. CONCLUSION: Our findings support prior literature  implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we  demonstrate these findings in patients with melanoma prior to administration of  checkpoint therapy and before the onset of clinically symptomatic sarcoidosis.  The identification of elevated Th17.1 cells in melanoma patients who have not  developed sarcoidosis may reflect the established association between melanoma  and sarcoidosis. With some patients receiving these agents over a prolonged  period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.CI  - (c) 2017 Asia Pacific League of Associations for Rheumatology and John Wiley &  Sons Australia, Ltd.
CANIT0001045	28480561	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Case	N/A	Sarcoidosis	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Immunotherapy-induced sarcoidosis in patients with melanoma treated with PD-1  checkpoint inhibitors: Case series and immunophenotypic analysis.	 Int J Rheum Dis	 AIM: Sarcoidosis is a multisystem granulomatous disease. This condition has a  documented association with the diagnosis of melanoma and can be induced in  melanoma patients receiving anti-neoplastic therapy. We evaluated a case series  of melanoma patients who developed immunotherapy-induced sarcoidosis. METHODS:  Three patients with melanoma (n = 1 resected Stage III, n = 2 metastatic) treated  with anti-programmed cell death (PD)-1 antibody therapy at two institutions  developed biopsy-proven sarcoidosis. We used mass cytometry to determine  expression of the relevant chemokine receptors (CR) by peripheral blood  mononuclear cells for two of the three patients who developed sarcoidosis and 13   melanoma patients who did not. Blood samples were collected before receiving PD-1  checkpoint inhibitor therapy. RESULTS: Immunophenotypic analysis demonstrated  abnormally high numbers of circulating Th17.1 (CCR6(+) CCR4(-) CXCR3(+) CCR10(-)   ) cells prior to commencing PD-1 checkpoint inhibitor therapy in five of 15  melanoma patients, including both the patients who developed sarcoidosis during  the course of therapy. CONCLUSION: Our findings support prior literature  implicating Th17.1 cells in the pathogenesis of sarcoidosis. However, we  demonstrate these findings in patients with melanoma prior to administration of  checkpoint therapy and before the onset of clinically symptomatic sarcoidosis.  The identification of elevated Th17.1 cells in melanoma patients who have not  developed sarcoidosis may reflect the established association between melanoma  and sarcoidosis. With some patients receiving these agents over a prolonged  period, the clinical course of immunotherapy-induced sarcoidosis is uncertain.CI  - (c) 2017 Asia Pacific League of Associations for Rheumatology and John Wiley &  Sons Australia, Ltd.
CANIT0001046	28481677	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Talimogene laherparepvec followed by nivolumab	N/A	Tumor vaccine followed by Immune checkpoint therapy	Nivolumab (DB09035); talimogene laherparepvec (DB13896); 	1	N/A	Case	Effective and well tolerated	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Metastatic melanoma in a 95 years old patient responding to treatment with  talimogene laherparepvec followed by nivolumab.	 Acta Oncol	Unable to provide
CANIT0001047	28489510	Clinical research	Advanced endometrial cancer	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A multicohort phase Ib KEYNOTE-028 (NCT02054806) study 	Pembrolizumab demonstrated a favorable safety profile and durable antitumor activity in a subgroup of patients with heavily pretreated advanced PD-L1-positive endometrial cancer.	Thirteen patients (54.2%) experienced treatment-related adverse events (AEs), with fatigue (20.8%), pruritus (16.7%), pyrexia (12.5%), and decreased appetite (12.5%) occurring in  10% of patients. Grade 3 treatment-related AEs were reported in four patients. No patient experienced a grade 4 AE, and no patient discontinued treatment because of an AE.	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death  Ligand 1-Positive Endometrial Cancer: Results From the KEYNOTE-028 Study.	 J Clin Oncol	 Purpose The multicohort phase Ib KEYNOTE-028 (NCT02054806) study was designed to   evaluate the safety and efficacy of pembrolizumab, an anti-programmed death 1  monoclonal antibody, in patients with programmed death ligand 1 (PD-L1) -positive  advanced solid tumors. The results from the advanced endometrial cancer cohort  are reported. Patients and Methods Female patients with locally advanced or  metastatic PD-L1-positive endometrial cancer who had experienced progression  after standard therapy were eligible. Patients received pembrolizumab 10 mg/kg  every 2 weeks for up to 24 months or until progression or unacceptable toxicity.   Primary efficacy end point was objective response rate by RECIST (version 1.1).  Secondary end points included safety, duration of response (DOR),  progression-free survival, and overall survival. The data cutoff was February 17,  2016. Results Of 75 patients screened, 36 (48.0%) had PD-L1-positive tumors, and   24 (32.0%) were enrolled. Fifteen (62.5%) of these 24 patients had received at  least two previous lines of therapy for advanced disease. Three patients (13.0%)   achieved confirmed partial response (95% CI, 2.8% to 33.6%); the median DOR was  not reached. Two patients were still receiving treatment and exhibiting continued  response at time of data cutoff. Three additional patients (13.0%) achieved  stable disease, with a median duration of 24.6 weeks. One patient who achieved  partial response had a polymerase E mutation. Thirteen patients (54.2%)  experienced treatment-related adverse events (AEs), with fatigue (20.8%),  pruritus (16.7%), pyrexia (12.5%), and decreased appetite (12.5%) occurring in  >/= 10% of patients. Grade 3 treatment-related AEs were reported in four  patients. No patient experienced a grade 4 AE, and no patient discontinued  treatment because of an AE. Conclusion Pembrolizumab demonstrated a favorable  safety profile and durable antitumor activity in a subgroup of patients with  heavily pretreated advanced PD-L1-positive endometrial cancer.
CANIT0001048	28489616	Case report	Massive skin metastasis from melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Complete response to anti-PD-1 nivolumab in massive skin metastasis from  melanoma: efficacy and tolerability in an elderly patient.	 Anticancer Drugs	 The advent of immune checkpoint inhibitors anti-PD-1/PD-L1 has delivered new and   effective treatment options with proven clinical benefits for patients affected  by metastatic melanoma. The 30-40% of treated patients experience an objective  tumour regression, with a significantly prolonged survival and an improved  quality of life. Here, we report a case of a 75-year-old Caucasian woman affected  by a massive cutaneous metastasis from a BRAF wild-type melanoma who experienced   multiple relapses after surgery and repeated electrochemotherapy treatments. A  poor response was observed after systemic therapy with ipilimumab, whereas a  marked reduction in the lesion size was obtained during the treatment with  nivolumab, with an objectively complete response after 6 months. Therapy was well  tolerated, without immune-related side effects. During treatment, LDH levels  decreased up to the standard values. Our experience confirms the good efficacy  and the safety of anti-PD-1 nivolumab for the treatment of relapsed or refractory  massive skin lesions, also in elderly patients.
CANIT0001049	28490569	Clinical research	Relapsed/refractory primary mediastinal large B-cell lymphoma	Primary mediastinal b-cell lymphoma	MONDO:0004021	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	18	N/A	A multicohort phase 1b  trial	These results in heavily pretreated rrPMBCL patients demonstrate that PD-1 blockade with pembrolizumab has a manageable safety profile and promising antitumor activity.	Eleven patients (61%) experienced drug-related adverse events (mostly grade 1-2); none discontinued treatment due to adverse events.	N/A	N/A	N/A	N/A	N/A	 2017 Jul 20	 Safety and tolerability of pembrolizumab in patients with relapsed/refractory  primary mediastinal large B-cell lymphoma.	 Blood	 Treatment options for relapsed/refractory primary mediastinal large B-cell  lymphoma (rrPMBCL) are limited, and prognosis is generally poor (overall response  rate [ORR] 0% to 25%; 2-year overall survival 15%). PMBCL frequently involves  PD-1 ligand overexpression, potentially making PMBCL particularly susceptible to   PD-1 blockade. We evaluated safety and antitumor activity of pembrolizumab, an  anti-PD-1 antibody, in rrPMBCL as part of the KEYNOTE-013 multicohort phase 1b  trial. At time of data cutoff, 18 patients (median age 30 years; median 3 prior  lines of therapy) had been enrolled and treated, of whom 17 were included in the   efficacy analyses. Eleven patients (61%) experienced drug-related adverse events   (mostly grade 1-2); none discontinued treatment due to adverse events. ORR was  41% (7/17); 6 additional patients (35%) had stable disease. Of patients evaluable  by imaging, 13 out of 16 (81%) had decreases in target lesions. With a median  follow-up of 11.3 months, median duration of response was not reached. Two  patients reached the maximum 2-year treatment duration and remain in remission.  Median overall survival was not reached for treated patients overall; all  responders were still alive at data cutoff. These results in heavily pretreated  rrPMBCL patients demonstrate that PD-1 blockade with pembrolizumab has a  manageable safety profile and promising antitumor activity. This trial was  registered at www.clinicaltrials.gov as #NCT01953692.CI  - (c) 2017 by The American Society of Hematology.
CANIT0001050	28492864	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Induction of immune reaction in benign melanocytic Nnevi without halo	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Induction of Immune Reaction in Benign Melanocytic Nevi Without Halo During  Nivolumab Therapy in a Patient With Melanoma.	 JAMA Dermatol	Unable to provide
CANIT0001051	28497158	Case report	Unresectable mucosal melanoma refractory to nivolumab	Mucosal melanoma	MONDO:0000544	Soft tissue	IL2R (A2N4P8); 	IL2R; 	IL2	N/A	Immune cytokine	IL2 (NCIT:C24498); 	1	N/A	Case	Intralesional IL-2 may represent a tolerable, effective, and cost-effcient therapy option.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Intralesional interleukin-2 for unresectable mucosal melanoma refractory to  nivolumab.	 Cancer Immunol Immunother	Unable to provide
CANIT0001052	28499411	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Paraneoplastic acral vascular syndrome	N/A	N/A	N/A	N/A	N/A	 2017 May 12	 Paraneoplastic acral vascular syndrome in a patient with metastatic melanoma  under immune checkpoint blockade.	 BMC Cancer	 BACKGROUND: Paraneoplastic acral vascular syndrome (PAVS) is a rare phenomenon  which is observed in patients with adenocarcinomas and other malignancies.  Various potential pathogenic mechanisms such as tumour invasion of sympathetic  nerves, hyperviscosity, hypercoagulability, vasoactive tumour-secreted  substances, and immunological mechanisms have been suggested. CASE PRESENTATION:   We report a 60-year-old Caucasian male attended our hospital with a bulky lymph  node mass in the right axilla. Extirpation of a lymph node conglomerate revealed   5 melanoma lymph node metastases. Computed tomography showed a liver metastasis  (diameter: 3.8 cm), several retroperitoneal metastases, bilateral metastases in  the lung hilus, and prepectoral subcutaneous metastases (Stage IV; pTx, N3, M1c).  Lactate dehydrogenase and S100B were slightly elevated. Combination therapy of  nivolumab (1 mg/kg BW) and ipilimumab (3 mg/kg BW) was started. Three weeks after  the first combination therapy he developed progressive erythema, paraesthesia and  pain on the fingertips of both hands. Both cold and warmth was not well tolerated  by the patient. Complete work-up excluded associated conditions or factors such  as haematological disorders, rheumatologic disorders, hypertension, diabetes or  smoking. Treatment was initiated with prostacyclin 20 mug twice daily and oral  prednisolone 50 mg in tapering dosage. However, prostacyclin was stopped after  the first applications because the pain increased during infusion. The second  course of nivolumab and ipilimumab was administered. About 2 weeks later, the  patient presented with increased pain and small subungual necrosis. We treated  the patient with oral analgetics and intravenous prednisolone 500 mg in tapering   dosage. On digital substraction angiography occlusion of all arteries of the  fingers was demonstrated. Further rheologic and anti-melanoma treatments were  refused by the patient. About 2 months after the second course of nivolumab and  ipilimumab combination therapy several fingers showed severe gangrene which  finally led to amputations of end phalanges of several fingers. Histopathology  did not reveal evidence for vasculitis or other primary vascular pathologies.  During the following 2 months the patient experienced dramatic progress of his  metastatic disease and finally died at multi-organ failure. CONCLUSION: Presence   of rapidly progressive digital ischemia in an elderly patient with cancer should   always raise clinical suspicion of a paraneoplastic phenomenon when other  possible causes have been excluded. In patients treated with immune checkpoint  inhibitors such as CTLA-4 and PD-L1 blockers PVAS-like events have not been  reported so far. However, it is debatable whether immune checkpoint blockade may   play a pathogenetic role in the development of PAVS in patients with  malignancies.
CANIT0001053	28500114	Case report	Stage IV lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Pseudoprogression	N/A	N/A	N/A	N/A	N/A	N/A	2017 May	Pseudoprogression in lung adenocarcinoma during treatment with nivolumab.	BMJ Case Rep	Unable to provide
CANIT0001054	28500627	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Widespread biphasic amyloidosis	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Widespread biphasic amyloidosis related to ipilimumab treatment for metastatic  melanoma.	 Int J Dermatol	Unable to provide
CANIT0001055	28515940	Case report	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Autoimmune diabetes mellitus presenting as diabetic ketoacidosis	N/A	N/A	N/A	N/A	N/A	2017	 Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic  ketoacidosis in a patient with metastatic lung cancer.	 J Immunother Cancer	 BACKGROUND: Advances in cancer immunotherapy have generated encouraging results  in multiple malignancies refractory to standard chemotherapies. As the use of  immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side  effects associated with these agents, termed immune related adverse events  (irAE), is expected to increase. The frequency of significant irAE in ICI treated  patients is about 10-20% and early recognition is critical to prevent serious  morbidity and even mortality. New onset autoimmune diabetes mellitus (DM)  associated with immune checkpoint inhibitor treatment is extremely rare,  occurring in less than 1% of patients. Autoimmune DM often presents as diabetic  ketoacidosis, a medical emergency requiring immediate treatment. We describe the   first reported case of a patient with lung cancer who developed autoimmune  diabetes after nivolumab treatment and was found to have three diabetes related  (islet) autoantibodies present before ICI treatment and seroconversion of another  after ICI treatment and onset of autoimmune DM. CASE PRESENTATION: A 34 year old   African American woman with metastatic non-small cell lung cancer (NSCLC) was  treated with nivolumab in the second line setting after disease progression  following standard chemoradiation therapy. After receiving two doses of  nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic  ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable  C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies  and absolute insulin dependence. The patient eventually required use of  continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic  excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA)  genoyping revealed none of the high risk haplotypes associated with the  development of type 1 diabetes. Interestingly, a frozen blood sample obtained  prior to treatment with nivolumab tested positive for three of the four diabetes   related (islet) autoantibodies despite no prior history of diabetes and no family  history of diabetes. Notably, at the time of manuscript preparation, the patient   is without evidence of NSCLC recurrence with no further treatment since the  nivolumab therapy. CONCLUSION: New onset autoimmune diabetes mellitus associated   with nivolumab has been described only in case reports and occurs at rates of <  1% in the large clinical trials which garnered FDA approval in the second line  setting for NSCLC. As ICI use continues to expand across a wide variety of  malignancies, clinicians must maintain a high index of suspicion for irAE,  including autoimmune DM and other endocrinopathies. A multidisciplinary team and   thorough education of the patient are recommended to optimize management of new  onset adult autoimmune DM. Our patient may have been at greater risk for the  development of ICI related autoimmune diabetes due to the presence of three  diabetes related autoantibodies prior to therapy; however, about half of the  reported cases of autoimmune DM after anti-PD-1 therapy occurred in patients with  no detectable diabetes related autoantibodies. Further studies are needed to  delineate genetic and immunologic biomarkers that may be useful in identifying  patients at risk of developing ICI related autoimmune DM.
CANIT0001056	28515943	Clinical research	1611 Melanoma, 1358non-small cell lung carcinoma, 573 urothelial carcinoma, 47 head and neck squamous cell carcinoma etc.	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3647	N/A	N/A	Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no advantage to either dosing approach with respect to controlling PK variability. These findings suggest that weight-based and fixed-dose regimens are appropriate for pembrolizumab.	N/A	N/A	N/A	N/A	N/A	N/A	2017	 Evaluation of dosing strategy for pembrolizumab for oncology indications.	 J Immunother Cancer	 BACKGROUND: Traditionally, most monoclonal antibodies (mAbs) have been dosed  based on body weight because of perceived contribution of body size in  pharmacokinetic variability. The same approach was used in the initial  pembrolizumab studies; however, following availability of PK data, the need for  weight-based dosing for pembrolizumab was reassessed. METHODS: A previously  established population PK (popPK) model as well as exposure-response results from  patients with advanced melanoma or non-small cell lung cancer (NSCLC) were used  to evaluate the potential application of a fixed dosing regimen with the aim of  maintaining pembrolizumab exposures within the range demonstrated to provide near  maximal efficacy and acceptable safety. Individual PK exposures for the selected   fixed dosing regimen from recently completed trials with head and neck cancer,  NSCLC, microsatellite instability high (MSI-H) in colorectal cancer (CRC) and  urothelial cancer were used to confirm acceptability. To determine whether fixed   dosing would maintain exposures within the range of clinical experience, the  individual AUC distributions with fixed dosing were compared with the range of  exposures from the pembrolizumab doses that were evaluated in early studies (2  mg/kg Q3W, 10 mg/kg Q3W/Q2W). RESULTS: Body-weight dependence of clearance was  characterized by a power relationship with an exponent of 0.578, a value  consistent with fixed- and weight-based dosing providing similar control of PK  variability. A fixed dose of 200 mg Q3W was investigated in trials based on  predicted exposures maintained within the established exposure range in all  patients. Mean (% CV, n) AUCss, 6-weeks was 1.87 (37%, 830), 1.38 (38%, 760) and   7.63 (35%, 1405) mg*day/mL in patients receiving 200 mg, 2 mg/kg and 10 mg/kg Q3W  pembrolizumab. High-weight patients had the lowest exposures with 200 mg Q3W;  however, exposures in this group (>90 kg) were within the range of prior clinical  experience at 2 mg/kg Q3W associated with near maximal efficacy. CONCLUSIONS:  Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no  advantage to either dosing approach with respect to controlling PK variability.  These findings suggest that weight-based and fixed-dose regimens are appropriate   for pembrolizumab.
CANIT0001057	28515943	Clinical research	1611 Melanoma, 1358non-small cell lung carcinoma, 573 urothelial carcinoma, 47 head and neck squamous cell carcinoma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3647	N/A	N/A	Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no advantage to either dosing approach with respect to controlling PK variability. These findings suggest that weight-based and fixed-dose regimens are appropriate for pembrolizumab.	N/A	N/A	N/A	N/A	N/A	N/A	2017	 Evaluation of dosing strategy for pembrolizumab for oncology indications.	 J Immunother Cancer	 BACKGROUND: Traditionally, most monoclonal antibodies (mAbs) have been dosed  based on body weight because of perceived contribution of body size in  pharmacokinetic variability. The same approach was used in the initial  pembrolizumab studies; however, following availability of PK data, the need for  weight-based dosing for pembrolizumab was reassessed. METHODS: A previously  established population PK (popPK) model as well as exposure-response results from  patients with advanced melanoma or non-small cell lung cancer (NSCLC) were used  to evaluate the potential application of a fixed dosing regimen with the aim of  maintaining pembrolizumab exposures within the range demonstrated to provide near  maximal efficacy and acceptable safety. Individual PK exposures for the selected   fixed dosing regimen from recently completed trials with head and neck cancer,  NSCLC, microsatellite instability high (MSI-H) in colorectal cancer (CRC) and  urothelial cancer were used to confirm acceptability. To determine whether fixed   dosing would maintain exposures within the range of clinical experience, the  individual AUC distributions with fixed dosing were compared with the range of  exposures from the pembrolizumab doses that were evaluated in early studies (2  mg/kg Q3W, 10 mg/kg Q3W/Q2W). RESULTS: Body-weight dependence of clearance was  characterized by a power relationship with an exponent of 0.578, a value  consistent with fixed- and weight-based dosing providing similar control of PK  variability. A fixed dose of 200 mg Q3W was investigated in trials based on  predicted exposures maintained within the established exposure range in all  patients. Mean (% CV, n) AUCss, 6-weeks was 1.87 (37%, 830), 1.38 (38%, 760) and   7.63 (35%, 1405) mg*day/mL in patients receiving 200 mg, 2 mg/kg and 10 mg/kg Q3W  pembrolizumab. High-weight patients had the lowest exposures with 200 mg Q3W;  however, exposures in this group (>90 kg) were within the range of prior clinical  experience at 2 mg/kg Q3W associated with near maximal efficacy. CONCLUSIONS:  Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no  advantage to either dosing approach with respect to controlling PK variability.  These findings suggest that weight-based and fixed-dose regimens are appropriate   for pembrolizumab.
CANIT0001058	28515943	Clinical research	1611 Melanoma, 1358non-small cell lung carcinoma, 573 urothelial carcinoma, 47 head and neck squamous cell carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3647	N/A	N/A	Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no advantage to either dosing approach with respect to controlling PK variability. These findings suggest that weight-based and fixed-dose regimens are appropriate for pembrolizumab.	N/A	N/A	N/A	N/A	N/A	N/A	2017	 Evaluation of dosing strategy for pembrolizumab for oncology indications.	 J Immunother Cancer	 BACKGROUND: Traditionally, most monoclonal antibodies (mAbs) have been dosed  based on body weight because of perceived contribution of body size in  pharmacokinetic variability. The same approach was used in the initial  pembrolizumab studies; however, following availability of PK data, the need for  weight-based dosing for pembrolizumab was reassessed. METHODS: A previously  established population PK (popPK) model as well as exposure-response results from  patients with advanced melanoma or non-small cell lung cancer (NSCLC) were used  to evaluate the potential application of a fixed dosing regimen with the aim of  maintaining pembrolizumab exposures within the range demonstrated to provide near  maximal efficacy and acceptable safety. Individual PK exposures for the selected   fixed dosing regimen from recently completed trials with head and neck cancer,  NSCLC, microsatellite instability high (MSI-H) in colorectal cancer (CRC) and  urothelial cancer were used to confirm acceptability. To determine whether fixed   dosing would maintain exposures within the range of clinical experience, the  individual AUC distributions with fixed dosing were compared with the range of  exposures from the pembrolizumab doses that were evaluated in early studies (2  mg/kg Q3W, 10 mg/kg Q3W/Q2W). RESULTS: Body-weight dependence of clearance was  characterized by a power relationship with an exponent of 0.578, a value  consistent with fixed- and weight-based dosing providing similar control of PK  variability. A fixed dose of 200 mg Q3W was investigated in trials based on  predicted exposures maintained within the established exposure range in all  patients. Mean (% CV, n) AUCss, 6-weeks was 1.87 (37%, 830), 1.38 (38%, 760) and   7.63 (35%, 1405) mg*day/mL in patients receiving 200 mg, 2 mg/kg and 10 mg/kg Q3W  pembrolizumab. High-weight patients had the lowest exposures with 200 mg Q3W;  however, exposures in this group (>90 kg) were within the range of prior clinical  experience at 2 mg/kg Q3W associated with near maximal efficacy. CONCLUSIONS:  Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no  advantage to either dosing approach with respect to controlling PK variability.  These findings suggest that weight-based and fixed-dose regimens are appropriate   for pembrolizumab.
CANIT0001059	28515943	Clinical research	1611 Melanoma, 1358non-small cell lung carcinoma, 573 urothelial carcinoma, 47 head and neck squamous cell carcinoma etc.	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3647	N/A	N/A	Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no advantage to either dosing approach with respect to controlling PK variability. These findings suggest that weight-based and fixed-dose regimens are appropriate for pembrolizumab.	N/A	N/A	N/A	N/A	N/A	N/A	2017	 Evaluation of dosing strategy for pembrolizumab for oncology indications.	 J Immunother Cancer	 BACKGROUND: Traditionally, most monoclonal antibodies (mAbs) have been dosed  based on body weight because of perceived contribution of body size in  pharmacokinetic variability. The same approach was used in the initial  pembrolizumab studies; however, following availability of PK data, the need for  weight-based dosing for pembrolizumab was reassessed. METHODS: A previously  established population PK (popPK) model as well as exposure-response results from  patients with advanced melanoma or non-small cell lung cancer (NSCLC) were used  to evaluate the potential application of a fixed dosing regimen with the aim of  maintaining pembrolizumab exposures within the range demonstrated to provide near  maximal efficacy and acceptable safety. Individual PK exposures for the selected   fixed dosing regimen from recently completed trials with head and neck cancer,  NSCLC, microsatellite instability high (MSI-H) in colorectal cancer (CRC) and  urothelial cancer were used to confirm acceptability. To determine whether fixed   dosing would maintain exposures within the range of clinical experience, the  individual AUC distributions with fixed dosing were compared with the range of  exposures from the pembrolizumab doses that were evaluated in early studies (2  mg/kg Q3W, 10 mg/kg Q3W/Q2W). RESULTS: Body-weight dependence of clearance was  characterized by a power relationship with an exponent of 0.578, a value  consistent with fixed- and weight-based dosing providing similar control of PK  variability. A fixed dose of 200 mg Q3W was investigated in trials based on  predicted exposures maintained within the established exposure range in all  patients. Mean (% CV, n) AUCss, 6-weeks was 1.87 (37%, 830), 1.38 (38%, 760) and   7.63 (35%, 1405) mg*day/mL in patients receiving 200 mg, 2 mg/kg and 10 mg/kg Q3W  pembrolizumab. High-weight patients had the lowest exposures with 200 mg Q3W;  however, exposures in this group (>90 kg) were within the range of prior clinical  experience at 2 mg/kg Q3W associated with near maximal efficacy. CONCLUSIONS:  Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no  advantage to either dosing approach with respect to controlling PK variability.  These findings suggest that weight-based and fixed-dose regimens are appropriate   for pembrolizumab.
CANIT0001060	28520840	Clinical research	Melanoma, NSCLC, RCC, cHL, SCCHN, UC, gastric cancer (GC), and small cell lung cancer (SCLC)	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3458	N/A	N/A	Based on population  pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a   3-mg/kg dosing regimen in patients with advanced tumors.	 Ann Oncol	 Background: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the  standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell   carcinoma (RCC). However, flat dosing is expected to shorten preparation time and  improve ease of administration. With knowledge of nivolumab safety, efficacy, and  pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment   of the benefit-risk profile of a 240-mg flat dose relative to the approved  3-mg/kg dose was approached by quantitative clinical pharmacology. Patients and  methods: A flat dose of 240 mg was selected based on its equivalence to the  3-mg/kg dose at the median BW of approximately 80 kg in patients in the nivolumab  program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing   exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical  safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC;  and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC,  and RCC. Results: The median nivolumab exposure and its distribution at 240 mg  Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did   not demonstrate a clinically meaningful relationship between BW or nivolumab  exposure quartiles and frequency or severity of adverse events. The predicted  safety and efficacy were similar across nivolumab exposure ranges achieved with 3  mg/kg Q2W or 240 mg Q2W flat dose. Conclusion: Based on population  pharmacokinetic modeling, established flat exposure-response relationships for  efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab  240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology   approach provided evidence for regulatory decision-making on dose modification,  obviating the need for an independent clinical study.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology.
CANIT0001061	28520840	Clinical research	Melanoma, NSCLC, RCC, cHL, SCCHN, UC, gastric cancer (GC), and small cell lung cancer (SCLC)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3458	N/A	N/A	Based on population  pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a   3-mg/kg dosing regimen in patients with advanced tumors.	 Ann Oncol	 Background: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the  standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell   carcinoma (RCC). However, flat dosing is expected to shorten preparation time and  improve ease of administration. With knowledge of nivolumab safety, efficacy, and  pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment   of the benefit-risk profile of a 240-mg flat dose relative to the approved  3-mg/kg dose was approached by quantitative clinical pharmacology. Patients and  methods: A flat dose of 240 mg was selected based on its equivalence to the  3-mg/kg dose at the median BW of approximately 80 kg in patients in the nivolumab  program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing   exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical  safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC;  and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC,  and RCC. Results: The median nivolumab exposure and its distribution at 240 mg  Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did   not demonstrate a clinically meaningful relationship between BW or nivolumab  exposure quartiles and frequency or severity of adverse events. The predicted  safety and efficacy were similar across nivolumab exposure ranges achieved with 3  mg/kg Q2W or 240 mg Q2W flat dose. Conclusion: Based on population  pharmacokinetic modeling, established flat exposure-response relationships for  efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab  240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology   approach provided evidence for regulatory decision-making on dose modification,  obviating the need for an independent clinical study.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology.
CANIT0001062	28520840	Clinical research	Melanoma, NSCLC, RCC, cHL, SCCHN, UC, gastric cancer (GC), and small cell lung cancer (SCLC)	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3458	N/A	N/A	Based on population  pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a   3-mg/kg dosing regimen in patients with advanced tumors.	 Ann Oncol	 Background: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the  standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell   carcinoma (RCC). However, flat dosing is expected to shorten preparation time and  improve ease of administration. With knowledge of nivolumab safety, efficacy, and  pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment   of the benefit-risk profile of a 240-mg flat dose relative to the approved  3-mg/kg dose was approached by quantitative clinical pharmacology. Patients and  methods: A flat dose of 240 mg was selected based on its equivalence to the  3-mg/kg dose at the median BW of approximately 80 kg in patients in the nivolumab  program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing   exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical  safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC;  and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC,  and RCC. Results: The median nivolumab exposure and its distribution at 240 mg  Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did   not demonstrate a clinically meaningful relationship between BW or nivolumab  exposure quartiles and frequency or severity of adverse events. The predicted  safety and efficacy were similar across nivolumab exposure ranges achieved with 3  mg/kg Q2W or 240 mg Q2W flat dose. Conclusion: Based on population  pharmacokinetic modeling, established flat exposure-response relationships for  efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab  240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology   approach provided evidence for regulatory decision-making on dose modification,  obviating the need for an independent clinical study.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology.
CANIT0001063	28520840	Clinical research	Melanoma, NSCLC, RCC, cHL, SCCHN, UC, gastric cancer (GC), and small cell lung cancer (SCLC)	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3458	N/A	N/A	Based on population  pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a   3-mg/kg dosing regimen in patients with advanced tumors.	 Ann Oncol	 Background: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the  standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell   carcinoma (RCC). However, flat dosing is expected to shorten preparation time and  improve ease of administration. With knowledge of nivolumab safety, efficacy, and  pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment   of the benefit-risk profile of a 240-mg flat dose relative to the approved  3-mg/kg dose was approached by quantitative clinical pharmacology. Patients and  methods: A flat dose of 240 mg was selected based on its equivalence to the  3-mg/kg dose at the median BW of approximately 80 kg in patients in the nivolumab  program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing   exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical  safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC;  and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC,  and RCC. Results: The median nivolumab exposure and its distribution at 240 mg  Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did   not demonstrate a clinically meaningful relationship between BW or nivolumab  exposure quartiles and frequency or severity of adverse events. The predicted  safety and efficacy were similar across nivolumab exposure ranges achieved with 3  mg/kg Q2W or 240 mg Q2W flat dose. Conclusion: Based on population  pharmacokinetic modeling, established flat exposure-response relationships for  efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab  240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology   approach provided evidence for regulatory decision-making on dose modification,  obviating the need for an independent clinical study.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology.
CANIT0001064	28520840	Clinical research	Melanoma, NSCLC, RCC, cHL, SCCHN, UC, gastric cancer (GC), and small cell lung cancer (SCLC)	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3458	N/A	N/A	Based on population  pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a   3-mg/kg dosing regimen in patients with advanced tumors.	 Ann Oncol	 Background: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the  standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell   carcinoma (RCC). However, flat dosing is expected to shorten preparation time and  improve ease of administration. With knowledge of nivolumab safety, efficacy, and  pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment   of the benefit-risk profile of a 240-mg flat dose relative to the approved  3-mg/kg dose was approached by quantitative clinical pharmacology. Patients and  methods: A flat dose of 240 mg was selected based on its equivalence to the  3-mg/kg dose at the median BW of approximately 80 kg in patients in the nivolumab  program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing   exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical  safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC;  and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC,  and RCC. Results: The median nivolumab exposure and its distribution at 240 mg  Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did   not demonstrate a clinically meaningful relationship between BW or nivolumab  exposure quartiles and frequency or severity of adverse events. The predicted  safety and efficacy were similar across nivolumab exposure ranges achieved with 3  mg/kg Q2W or 240 mg Q2W flat dose. Conclusion: Based on population  pharmacokinetic modeling, established flat exposure-response relationships for  efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab  240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology   approach provided evidence for regulatory decision-making on dose modification,  obviating the need for an independent clinical study.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology.
CANIT0001065	28520840	Clinical research	Melanoma, NSCLC, RCC, cHL, SCCHN, UC, gastric cancer (GC), and small cell lung cancer (SCLC)	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3458	N/A	N/A	Based on population  pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a   3-mg/kg dosing regimen in patients with advanced tumors.	 Ann Oncol	 Background: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the  standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell   carcinoma (RCC). However, flat dosing is expected to shorten preparation time and  improve ease of administration. With knowledge of nivolumab safety, efficacy, and  pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment   of the benefit-risk profile of a 240-mg flat dose relative to the approved  3-mg/kg dose was approached by quantitative clinical pharmacology. Patients and  methods: A flat dose of 240 mg was selected based on its equivalence to the  3-mg/kg dose at the median BW of approximately 80 kg in patients in the nivolumab  program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing   exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical  safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC;  and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC,  and RCC. Results: The median nivolumab exposure and its distribution at 240 mg  Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did   not demonstrate a clinically meaningful relationship between BW or nivolumab  exposure quartiles and frequency or severity of adverse events. The predicted  safety and efficacy were similar across nivolumab exposure ranges achieved with 3  mg/kg Q2W or 240 mg Q2W flat dose. Conclusion: Based on population  pharmacokinetic modeling, established flat exposure-response relationships for  efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab  240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology   approach provided evidence for regulatory decision-making on dose modification,  obviating the need for an independent clinical study.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology.
CANIT0001066	28524161	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	66	N/A	A retrospective cohort study	IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jun 6	 Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases.	 Br J Cancer	 BACKGROUND: There is limited data on the efficacy of anti-programmed death 1  (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM),  particularly those which are symptomatic. METHOD: We retrospectively assessed pts  with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab.  Clinicopathologic and treatment parameters were collected and outcomes determined  for intracranial (IC) response rate (RR) using a modified RECIST criteria, with  up to five IC target lesions used to determine IC response, disease control rate   (DCR) and progression-free survival (PFS). RESULTS: A total of 66 pts were  identified with a median follow up of 7.0 months (range 0.8-24.5 months). A total  of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody  commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to  commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic  radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and  radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic  therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR  56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9   months (95% CI 6.93-17.74). Pts with symptomatic BM had shorter PFS than those  without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs   13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically  shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039).  CONCLUSIONS: IC responses to anti-PD-1 antibodies occur in pts with BM, including  those with symptomatic BM requiring corticosteroids. Prospective trials  evaluating anti-PD-1 therapy in pts with BM are underway.
CANIT0001067	28524161	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	66	N/A	A retrospective cohort study	IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jun 6	 Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases.	 Br J Cancer	 BACKGROUND: There is limited data on the efficacy of anti-programmed death 1  (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM),  particularly those which are symptomatic. METHOD: We retrospectively assessed pts  with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab.  Clinicopathologic and treatment parameters were collected and outcomes determined  for intracranial (IC) response rate (RR) using a modified RECIST criteria, with  up to five IC target lesions used to determine IC response, disease control rate   (DCR) and progression-free survival (PFS). RESULTS: A total of 66 pts were  identified with a median follow up of 7.0 months (range 0.8-24.5 months). A total  of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody  commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to  commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic  radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and  radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic  therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR  56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9   months (95% CI 6.93-17.74). Pts with symptomatic BM had shorter PFS than those  without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs   13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically  shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039).  CONCLUSIONS: IC responses to anti-PD-1 antibodies occur in pts with BM, including  those with symptomatic BM requiring corticosteroids. Prospective trials  evaluating anti-PD-1 therapy in pts with BM are underway.
CANIT0001068	28532567	Case report	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Chemotherapy followed by pembrolizumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	1	N/A	Case	Histologic transformation	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Histologic Transformation in a Patient with Lung Cancer Treated with Chemotherapy  and Pembrolizumab.	 J Thorac Oncol	Unable to provide
CANIT0001069	28537531	Case report	Malignant melanoma, advanced nonCsmall cell lung cancer, and advanced renal cell carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	N/A	All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed within four weeks from the first administration of nivolumab and normalized within four weeks of onset in three of the five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients, and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism, and the other developed mild, transient hypothyroidism.	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study.	 Thyroid	 BACKGROUND: The programmed cell death-1 (PD-1) pathway is a novel therapeutic  target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor   and its two ligands, programmed death-ligand 1 (PD-L1) and programmed  death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved  for malignant melanoma, advanced non-small cell lung cancer, and advanced renal  cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been  reported in international Phase 3 studies and national post-marketing  surveillance of nivolumab in Japan. METHODS: This study analyzed five consecutive  cases with thyroid dysfunction associated with nivolumab therapy. Second, it  examined the mRNA and protein expressions of PD-L1 and PD-L2 by reverse  transcription polymerase chain reaction and Western blotting. RESULTS: All  patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed  within four weeks from the first administration of nivolumab and normalized  within four weeks of onset in three of the five patients. Hypothyroidism after  transient thyrotoxicosis developed in two patients, and preexisting  hypothyroidism persisted in one patient. The other two patients were treated with  glucocorticoids and discontinued nivolumab therapy for comorbid adverse events.  One did not develop hypothyroidism, and the other developed mild, transient  hypothyroidism. In addition, it was verified that normal thyroid tissue expresses  PD-L1 and PD-L2 mRNA and those proteins. CONCLUSIONS: In the present cases,  nivolumab-induced thyrotoxicosis seemed to be associated with painless  thyroiditis, while no patient with Graves' disease was observed. A transient and   rapid course with subsequent hypothyroidism was observed in nivolumab-induced  thyroiditis. In addition, it was verified that PD-L1 and PD-L2 are expressed in  normal thyroid tissue. This suggests that nivolumab therapy reduces immune  tolerance, even in normal thyroid tissue, and leads to the development of  thyroiditis. Treating thyrotoxicosis with only supportive care and considering  levothyroxine replacement therapy once subsequent hypothyroidism occurs is  proposed. Further investigations are required to confirm whether glucocorticoid  therapy and discontinuation of nivolumab therapy prevent subsequent  hypothyroidism.
CANIT0001070	28537531	Case report	Malignant melanoma, advanced nonCsmall cell lung cancer, and advanced renal cell carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	N/A	All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed within four weeks from the first administration of nivolumab and normalized within four weeks of onset in three of the five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients, and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism, and the other developed mild, transient hypothyroidism.	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study.	 Thyroid	 BACKGROUND: The programmed cell death-1 (PD-1) pathway is a novel therapeutic  target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor   and its two ligands, programmed death-ligand 1 (PD-L1) and programmed  death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved  for malignant melanoma, advanced non-small cell lung cancer, and advanced renal  cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been  reported in international Phase 3 studies and national post-marketing  surveillance of nivolumab in Japan. METHODS: This study analyzed five consecutive  cases with thyroid dysfunction associated with nivolumab therapy. Second, it  examined the mRNA and protein expressions of PD-L1 and PD-L2 by reverse  transcription polymerase chain reaction and Western blotting. RESULTS: All  patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed  within four weeks from the first administration of nivolumab and normalized  within four weeks of onset in three of the five patients. Hypothyroidism after  transient thyrotoxicosis developed in two patients, and preexisting  hypothyroidism persisted in one patient. The other two patients were treated with  glucocorticoids and discontinued nivolumab therapy for comorbid adverse events.  One did not develop hypothyroidism, and the other developed mild, transient  hypothyroidism. In addition, it was verified that normal thyroid tissue expresses  PD-L1 and PD-L2 mRNA and those proteins. CONCLUSIONS: In the present cases,  nivolumab-induced thyrotoxicosis seemed to be associated with painless  thyroiditis, while no patient with Graves' disease was observed. A transient and   rapid course with subsequent hypothyroidism was observed in nivolumab-induced  thyroiditis. In addition, it was verified that PD-L1 and PD-L2 are expressed in  normal thyroid tissue. This suggests that nivolumab therapy reduces immune  tolerance, even in normal thyroid tissue, and leads to the development of  thyroiditis. Treating thyrotoxicosis with only supportive care and considering  levothyroxine replacement therapy once subsequent hypothyroidism occurs is  proposed. Further investigations are required to confirm whether glucocorticoid  therapy and discontinuation of nivolumab therapy prevent subsequent  hypothyroidism.
CANIT0001071	28537531	Case report	Malignant melanoma, advanced nonCsmall cell lung cancer, and advanced renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	N/A	All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed within four weeks from the first administration of nivolumab and normalized within four weeks of onset in three of the five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients, and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism, and the other developed mild, transient hypothyroidism.	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study.	 Thyroid	 BACKGROUND: The programmed cell death-1 (PD-1) pathway is a novel therapeutic  target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor   and its two ligands, programmed death-ligand 1 (PD-L1) and programmed  death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved  for malignant melanoma, advanced non-small cell lung cancer, and advanced renal  cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been  reported in international Phase 3 studies and national post-marketing  surveillance of nivolumab in Japan. METHODS: This study analyzed five consecutive  cases with thyroid dysfunction associated with nivolumab therapy. Second, it  examined the mRNA and protein expressions of PD-L1 and PD-L2 by reverse  transcription polymerase chain reaction and Western blotting. RESULTS: All  patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed  within four weeks from the first administration of nivolumab and normalized  within four weeks of onset in three of the five patients. Hypothyroidism after  transient thyrotoxicosis developed in two patients, and preexisting  hypothyroidism persisted in one patient. The other two patients were treated with  glucocorticoids and discontinued nivolumab therapy for comorbid adverse events.  One did not develop hypothyroidism, and the other developed mild, transient  hypothyroidism. In addition, it was verified that normal thyroid tissue expresses  PD-L1 and PD-L2 mRNA and those proteins. CONCLUSIONS: In the present cases,  nivolumab-induced thyrotoxicosis seemed to be associated with painless  thyroiditis, while no patient with Graves' disease was observed. A transient and   rapid course with subsequent hypothyroidism was observed in nivolumab-induced  thyroiditis. In addition, it was verified that PD-L1 and PD-L2 are expressed in  normal thyroid tissue. This suggests that nivolumab therapy reduces immune  tolerance, even in normal thyroid tissue, and leads to the development of  thyroiditis. Treating thyrotoxicosis with only supportive care and considering  levothyroxine replacement therapy once subsequent hypothyroidism occurs is  proposed. Further investigations are required to confirm whether glucocorticoid  therapy and discontinuation of nivolumab therapy prevent subsequent  hypothyroidism.
CANIT0001072	28537896	Basic research	Mouse prostate cancer model	Prostate cancer	MONDO:0008315	Prostate	5T4 (Q13641); 	5T4; 	MVA-5T4 vaccine	N/A	Tumor vaccine	MVA-5T4 vaccine (NCIT:C49087); 	Cell lines/ animal models	N/A	Basic research	Our findings support a translation of the combinatorial approach based on the heterologous ChAdOx1-MVA vaccination platform with immune checkpoint blockade into the clinic for the treatment of 5T4-positive tumours such as prostate, renal, colorectal, gastric, ovarian, lung cancer and mesothelioma.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2017 Jul 18	 5T4 oncofoetal glycoprotein: an old target for a novel prostate cancer  immunotherapy.	 Oncotarget	 The tumour-associated antigen 5T4 is an attractive target for cancer  immunotherapy. However to date, reported 5T4-specific cellular immune responses  induced by various immunisation platforms have been largely weak or non-existent.  In the present study, we have evaluated a heterologous prime boost regime based  on the simian adenovirus ChAdOx1 and modified vaccinia virus Ankara (MVA)  expressing 5T4 for immunogenicity and tumour protective efficacy in a mouse  cancer model. Vaccination-induced immune responses were strong, durable and  attributable primarily to CD8+ T cells. By comparison, homologous MVA vaccination  regimen did not induce detectable 5T4-specific T cell responses. ChAdOx1-MVA  vaccinated mice were completely protected against subsequent B16 melanoma  challenge, but in therapeutic settings this regime was only modestly effective in  delaying tumour outgrowth. Concomitant delivery of the vaccine with monoclonal  antibodies (mAbs) targeting immune checkpoint regulators LAG-3, PD-1 or PD-L1  demonstrated that the combination of vaccine with anti PD-1 mAb could  significantly delay tumour growth and increase overall survival of tumour-bearing  mice. Our findings support a translation of the combinatorial approach based on  the heterologous ChAdOx1-MVA vaccination platform with immune checkpoint blockade  into the clinic for the treatment of 5T4-positive tumours such as prostate,  renal, colorectal, gastric, ovarian, lung cancer and mesothelioma.
CANIT0001073	28548891	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	N/A	Ipilimumab administration results in elevations of effector lymphocytes and pro-inflammatory mediators in the gut lamina propria.	Colitis	N/A	N/A	FOXP3 (Q9BZS1); IL17A (Q16552); IFNG (P01579); Immune response (NCIT:C17930); 	Effector lymphocytes	Gene expression signature on/in immune cell	 2017 Aug 9	 Immunological Characteristics of Colitis Associated with Anti-CTLA-4 Antibody  Therapy.	 Cancer Invest	 Anti-CTL4-A therapy is associated with development of colitis. We characterized  ipilimumab-associated colitis in nine melanoma patients (6 male, mean age:  55.3-yrs). Median value for diarrhea grade was 2, number of ipilimumab doses 2,  and interval since last administration 3-wks. Endoscopic characteristics  resembled inflammatory bowel disease and histology revealed predominance of  plasmacytes or CD4+ T-cells. We observed significant upregulation of Th1 and Th17  effector pathways (>10-fold increase for IFN-gammamRNA, >5-fold for IL-17A, p <  0.01 vs. controls). Significant elevation of FoxP3 was also detected. In  conclusion, ipilimumab administration results in elevations of effector  lymphocytes and pro-inflammatory mediators in the gut lamina propria.
CANIT0001074	28548891	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	N/A	Ipilimumab administration results in elevations of effector lymphocytes and pro-inflammatory mediators in the gut lamina propria.	Colitis	N/A	N/A	FOXP3 (Q9BZS1); IL17A (Q16552); IFNG (P01579); Immune response (NCIT:C17930); 	Serum FoxP3 expression levels	Gene expression signature on/in immune cell	 2017 Aug 9	 Immunological Characteristics of Colitis Associated with Anti-CTLA-4 Antibody  Therapy.	 Cancer Invest	 Anti-CTL4-A therapy is associated with development of colitis. We characterized  ipilimumab-associated colitis in nine melanoma patients (6 male, mean age:  55.3-yrs). Median value for diarrhea grade was 2, number of ipilimumab doses 2,  and interval since last administration 3-wks. Endoscopic characteristics  resembled inflammatory bowel disease and histology revealed predominance of  plasmacytes or CD4+ T-cells. We observed significant upregulation of Th1 and Th17  effector pathways (>10-fold increase for IFN-gammamRNA, >5-fold for IL-17A, p <  0.01 vs. controls). Significant elevation of FoxP3 was also detected. In  conclusion, ipilimumab administration results in elevations of effector  lymphocytes and pro-inflammatory mediators in the gut lamina propria.
CANIT0001075	28548891	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	N/A	Ipilimumab administration results in elevations of effector lymphocytes and pro-inflammatory mediators in the gut lamina propria.	Colitis	N/A	N/A	FOXP3 (Q9BZS1); IL17A (Q16552); IFNG (P01579); Immune response (NCIT:C17930); 	Serum IFNG expression levels	Gene expression signature on/in immune cell	 2017 Aug 9	 Immunological Characteristics of Colitis Associated with Anti-CTLA-4 Antibody  Therapy.	 Cancer Invest	 Anti-CTL4-A therapy is associated with development of colitis. We characterized  ipilimumab-associated colitis in nine melanoma patients (6 male, mean age:  55.3-yrs). Median value for diarrhea grade was 2, number of ipilimumab doses 2,  and interval since last administration 3-wks. Endoscopic characteristics  resembled inflammatory bowel disease and histology revealed predominance of  plasmacytes or CD4+ T-cells. We observed significant upregulation of Th1 and Th17  effector pathways (>10-fold increase for IFN-gammamRNA, >5-fold for IL-17A, p <  0.01 vs. controls). Significant elevation of FoxP3 was also detected. In  conclusion, ipilimumab administration results in elevations of effector  lymphocytes and pro-inflammatory mediators in the gut lamina propria.
CANIT0001076	28548891	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	N/A	Ipilimumab administration results in elevations of effector lymphocytes and pro-inflammatory mediators in the gut lamina propria.	Colitis	N/A	N/A	FOXP3 (Q9BZS1); IL17A (Q16552); IFNG (P01579); Immune response (NCIT:C17930); 	Serum IL17A expression levels	Gene expression signature on/in immune cell	 2017 Aug 9	 Immunological Characteristics of Colitis Associated with Anti-CTLA-4 Antibody  Therapy.	 Cancer Invest	 Anti-CTL4-A therapy is associated with development of colitis. We characterized  ipilimumab-associated colitis in nine melanoma patients (6 male, mean age:  55.3-yrs). Median value for diarrhea grade was 2, number of ipilimumab doses 2,  and interval since last administration 3-wks. Endoscopic characteristics  resembled inflammatory bowel disease and histology revealed predominance of  plasmacytes or CD4+ T-cells. We observed significant upregulation of Th1 and Th17  effector pathways (>10-fold increase for IFN-gammamRNA, >5-fold for IL-17A, p <  0.01 vs. controls). Significant elevation of FoxP3 was also detected. In  conclusion, ipilimumab administration results in elevations of effector  lymphocytes and pro-inflammatory mediators in the gut lamina propria.
CANIT0001077	28551359	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Radiotherapy followed by pembrolizumab	Pembrolizumab	Radiotherapy followed by Immune checkpoint therapy	Radiotherapy (NCIT:C15313); pembrolizumab (DB09037); 	55	42	A phase I clinical trial 	Our data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile.	15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group).	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in   the treatment of non-small-cell lung cancer: a secondary analysis of the  KEYNOTE-001 phase 1 trial.	 Lancet Oncol	 BACKGROUND: Preclinical studies have found radiotherapy enhances antitumour  immune responses. We aimed to assess disease control and pulmonary toxicity in  patients who previously received radiotherapy for non-small-cell lung cancer  (NSCLC) before receiving pembrolizumab. METHODS: We assessed patients with  advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution  (University of California, Los Angeles, CA, USA). Patients were aged 18 years or   older, had an Eastern Cooperative Oncology Group performance status of 1 or less,  had adequate organ function, and no history of pneumonitis. Patients received  pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3  weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable  toxicity, or other protocol-defined reasons for discontinuation. Disease response  and pulmonary toxicity were prospectively assessed by Immune-related Response  Criteria and Common Terminology Criteria for Adverse Events version 4.0. The  primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect   profile, and antitumour activity of pembrolizumab. For our secondary analysis,  patients were divided into subgroups to compare patients who previously received   radiotherapy with patients who had not. Our primary objective was to determine  whether previous radiotherapy affected progression-free survival, overall  survival, and pulmonary toxicity in the intention-to-treat population. The  KEYNOTE-001 trial was registered with ClinicalTrials.gov, number NCT01295827.  FINDINGS: Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and   received their first cycle of pembrolizumab. One patient was lost to follow-up.  42 (43%) of 97 patients had previously received any radiotherapy for the  treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97  patients received extracranial radiotherapy and 24 (25%) of 97 patients received   thoracic radiotherapy. Median follow-up for surviving patients was 32.5 months  (IQR 29.8-34.1). Progression-free survival with pembrolizumab was significantly  longer in patients who previously received any radiotherapy than in patients  without previous radiotherapy (hazard ratio [HR] 0.56 [95% CI 0.34-0.91],  p=0.019; median progression-free survival 4.4 months [95% CI 2.1-8.6] vs 2.1  months [1.6-2.3]) and for patients who previously received extracranial  radiotherapy compared with those without previous extracranial radiotherapy (HR  0.50 [0.30-0.84], p=0.0084; median progression-free survival 6.3 months [95% CI  2.1-10.4] vs 2.0 months [1.8-2.1]). Overall survival with pembrolizumab was  significantly longer in patients who previously received any radiotherapy than in  patients without previous radiotherapy (HR 0.58 [95% CI 0.36-0.94], p=0.026;  median overall survival 10.7 months [95% CI 6.5-18.9] vs 5.3 months [2.7-7.7])  and for patients who previously received extracranial radiotherapy compared with   those without previous extracranial radiotherapy (0.59 [95% CI 0.36-0.96],  p=0.034; median overall survival 11.6 months [95% CI 6.5-20.5] vs 5.3 months  [3.0-8.5]). 15 (63%) of 24 patients who had previously received thoracic  radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients  with no previous thoracic radiotherapy. Three (13%) patients with previous  thoracic radiotherapy had treatment-related pulmonary toxicity compared with one   (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary   toxicities was similar (one patient in each group). INTERPRETATION: Our data  suggest that previous treatment with radiotherapy in patients with advanced NSCLC  results in longer progression-free survival and overall survival with  pembrolizumab treatment than that seen in patients who did not have previous  radiotherapy, with an acceptable safety profile. Further clinical trials  investigating this combination are needed to determine the optimal treatment  strategy for patients with advanced NSCLC. FUNDING: US National Institutes of  Health.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001078	28551664	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	74	N/A	A retrospective cohort study	Microbiota modification induced by antibiotics does not appear to affect the efficacy of nivolumab in patients with non-small-cell lung cancer (NSCLC).	N/A	N/A	N/A	Microbiota modification (NCIT:C128320); 	Microbiota modification	Microbiota	 2017 Jun	 Antibiotic Use Does Not Appear to Influence Response to Nivolumab.	 Anticancer Res	 BACKGROUND: Microbiota is known to influence response to anticancer  immunotherapy. We examined whether antibiotic usage could impact nivolumab  efficacy in patients treated for non-small-cell lung cancer (NSCLC). PATIENTS AND  METHODS: Seventy-four patients with NSCLC were included in this retrospective  study. They received nivolumab between 2015 and 2016 (3 mg/kg i.v. q2w). The  association between RECIST response and antibiotic usage was determined using  Chi-square and Cox proportional hazard model. RESULTS: A total of 17, 21 and 36  patients experienced response, stable disease and progression disease under  nivolumab. Only 15 (20.3%) patients were exposed to antibiotic medication in the   3 months before the first nivolumab injection or during treatment. We found a  similar response rate for the two populations, without impact of antibiotic  exposure (Chi-square test p=0.75). Moreover, we observed no impact of antibiotic   medication on progression-free survival under nivolumab (log-rank test, p=0.72).   CONCLUSION: Microbiota modification induced by antibiotics does not appear to  affect the efficacy of nivolumab in patients with NSCLC.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001079	28552987	Clinical research	Metastatic urothelial cancers	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	29	N/A	N/A	Better outcome and no significance with expressed neoantigen load	N/A	N/A	N/A	Neoantigen load (NCIT:C154155); 	Expressed neoantigen load	Gene expression signature on/in tumor cell	 2017 May	 Contribution of systemic and somatic factors to clinical response and resistance   to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.	 PLoS Med	 BACKGROUND: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can  induce durable clinical benefit (DCB) in patients with metastatic urothelial  cancers, including complete remissions in patients with chemotherapy refractory  disease. Although mutation load and PD-L1 immune cell (IC) staining have been  associated with response, they lack sufficient sensitivity and specificity for  clinical use. Thus, there is a need to evaluate the peripheral blood immune  environment and to conduct detailed analyses of mutation load, predicted  neoantigens, and immune cellular infiltration in tumors to enhance our  understanding of the biologic underpinnings of response and resistance. METHODS  AND FINDINGS: The goals of this study were to (1) evaluate the association of  mutation load and predicted neoantigen load with therapeutic benefit and (2)  determine whether intratumoral and peripheral blood T cell receptor (TCR)  clonality inform clinical outcomes in urothelial carcinoma treated with  atezolizumab. We hypothesized that an elevated mutation load in combination with   T cell clonal dominance among intratumoral lymphocytes prior to treatment or  among peripheral T cells after treatment would be associated with effective tumor  control upon treatment with anti-PD-L1 therapy. We performed whole exome  sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing  (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially  collected peripheral blood, collected before and after treatment with  atezolizumab. These parameters were assessed for correlation with DCB (defined as  progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both   alone and in the context of clinical and intratumoral parameters known to be  predictive of survival in this disease state. Patients with DCB displayed a  higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney  p = 0.047). Pretreatment peripheral blood TCR clonality below the median was  associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29,  log-rank p = 0.011). Patients with DCB also demonstrated more substantial  expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after  starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high  pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in  tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard   ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1)   = 0.0014). Marked variations in mutation loads were seen with different somatic  variant calling methodologies, which, in turn, impacted associations with  clinical outcomes. Missense mutation load, predicted neoantigen load, and  expressed neoantigen load did not demonstrate significant association with DCB (n  = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25,  Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying   effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A  limitation of our study is its small sample size (n = 29), a subset of the  patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory  analyses performed, we intend for these results to be hypothesis-generating.  CONCLUSIONS: These results demonstrate the complex nature of immune response to  checkpoint blockade and the compelling need for greater interrogation and data  integration of both host and tumor factors. Incorporating these variables in  prospective studies will facilitate identification and treatment of resistant  patients.
CANIT0001080	28552987	Clinical research	Metastatic urothelial cancers	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	29	N/A	N/A	Better outcome and no significance with missense mutation load	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor missense mutational burden	Mutational status	 2017 May	 Contribution of systemic and somatic factors to clinical response and resistance   to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.	 PLoS Med	 BACKGROUND: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can  induce durable clinical benefit (DCB) in patients with metastatic urothelial  cancers, including complete remissions in patients with chemotherapy refractory  disease. Although mutation load and PD-L1 immune cell (IC) staining have been  associated with response, they lack sufficient sensitivity and specificity for  clinical use. Thus, there is a need to evaluate the peripheral blood immune  environment and to conduct detailed analyses of mutation load, predicted  neoantigens, and immune cellular infiltration in tumors to enhance our  understanding of the biologic underpinnings of response and resistance. METHODS  AND FINDINGS: The goals of this study were to (1) evaluate the association of  mutation load and predicted neoantigen load with therapeutic benefit and (2)  determine whether intratumoral and peripheral blood T cell receptor (TCR)  clonality inform clinical outcomes in urothelial carcinoma treated with  atezolizumab. We hypothesized that an elevated mutation load in combination with   T cell clonal dominance among intratumoral lymphocytes prior to treatment or  among peripheral T cells after treatment would be associated with effective tumor  control upon treatment with anti-PD-L1 therapy. We performed whole exome  sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing  (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially  collected peripheral blood, collected before and after treatment with  atezolizumab. These parameters were assessed for correlation with DCB (defined as  progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both   alone and in the context of clinical and intratumoral parameters known to be  predictive of survival in this disease state. Patients with DCB displayed a  higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney  p = 0.047). Pretreatment peripheral blood TCR clonality below the median was  associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29,  log-rank p = 0.011). Patients with DCB also demonstrated more substantial  expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after  starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high  pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in  tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard   ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1)   = 0.0014). Marked variations in mutation loads were seen with different somatic  variant calling methodologies, which, in turn, impacted associations with  clinical outcomes. Missense mutation load, predicted neoantigen load, and  expressed neoantigen load did not demonstrate significant association with DCB (n  = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25,  Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying   effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A  limitation of our study is its small sample size (n = 29), a subset of the  patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory  analyses performed, we intend for these results to be hypothesis-generating.  CONCLUSIONS: These results demonstrate the complex nature of immune response to  checkpoint blockade and the compelling need for greater interrogation and data  integration of both host and tumor factors. Incorporating these variables in  prospective studies will facilitate identification and treatment of resistant  patients.
CANIT0001081	28552987	Clinical research	Metastatic urothelial cancers	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	29	N/A	N/A	Better outcome and no significance with predicted neoantigen load	N/A	N/A	N/A	Neoantigen load (NCIT:C154155); 	Predicted neoantigen load	Gene expression signature on/in tumor cell	 2017 May	 Contribution of systemic and somatic factors to clinical response and resistance   to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.	 PLoS Med	 BACKGROUND: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can  induce durable clinical benefit (DCB) in patients with metastatic urothelial  cancers, including complete remissions in patients with chemotherapy refractory  disease. Although mutation load and PD-L1 immune cell (IC) staining have been  associated with response, they lack sufficient sensitivity and specificity for  clinical use. Thus, there is a need to evaluate the peripheral blood immune  environment and to conduct detailed analyses of mutation load, predicted  neoantigens, and immune cellular infiltration in tumors to enhance our  understanding of the biologic underpinnings of response and resistance. METHODS  AND FINDINGS: The goals of this study were to (1) evaluate the association of  mutation load and predicted neoantigen load with therapeutic benefit and (2)  determine whether intratumoral and peripheral blood T cell receptor (TCR)  clonality inform clinical outcomes in urothelial carcinoma treated with  atezolizumab. We hypothesized that an elevated mutation load in combination with   T cell clonal dominance among intratumoral lymphocytes prior to treatment or  among peripheral T cells after treatment would be associated with effective tumor  control upon treatment with anti-PD-L1 therapy. We performed whole exome  sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing  (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially  collected peripheral blood, collected before and after treatment with  atezolizumab. These parameters were assessed for correlation with DCB (defined as  progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both   alone and in the context of clinical and intratumoral parameters known to be  predictive of survival in this disease state. Patients with DCB displayed a  higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney  p = 0.047). Pretreatment peripheral blood TCR clonality below the median was  associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29,  log-rank p = 0.011). Patients with DCB also demonstrated more substantial  expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after  starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high  pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in  tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard   ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1)   = 0.0014). Marked variations in mutation loads were seen with different somatic  variant calling methodologies, which, in turn, impacted associations with  clinical outcomes. Missense mutation load, predicted neoantigen load, and  expressed neoantigen load did not demonstrate significant association with DCB (n  = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25,  Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying   effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A  limitation of our study is its small sample size (n = 29), a subset of the  patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory  analyses performed, we intend for these results to be hypothesis-generating.  CONCLUSIONS: These results demonstrate the complex nature of immune response to  checkpoint blockade and the compelling need for greater interrogation and data  integration of both host and tumor factors. Incorporating these variables in  prospective studies will facilitate identification and treatment of resistant  patients.
CANIT0001082	28552987	Clinical research	Metastatic urothelial cancers	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	29	N/A	N/A	Better outcome with a higher proportion of tumor-infiltrating T lymphocytes (TIL)	N/A	N/A	N/A	T-cell receptor (NCIT:C12476); T-Lymphocyte (NCIT:C12476); 	Tumor-infiltrating T-cell 	Tumor-infiltrating immune cell	 2017 May	 Contribution of systemic and somatic factors to clinical response and resistance   to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.	 PLoS Med	 BACKGROUND: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can  induce durable clinical benefit (DCB) in patients with metastatic urothelial  cancers, including complete remissions in patients with chemotherapy refractory  disease. Although mutation load and PD-L1 immune cell (IC) staining have been  associated with response, they lack sufficient sensitivity and specificity for  clinical use. Thus, there is a need to evaluate the peripheral blood immune  environment and to conduct detailed analyses of mutation load, predicted  neoantigens, and immune cellular infiltration in tumors to enhance our  understanding of the biologic underpinnings of response and resistance. METHODS  AND FINDINGS: The goals of this study were to (1) evaluate the association of  mutation load and predicted neoantigen load with therapeutic benefit and (2)  determine whether intratumoral and peripheral blood T cell receptor (TCR)  clonality inform clinical outcomes in urothelial carcinoma treated with  atezolizumab. We hypothesized that an elevated mutation load in combination with   T cell clonal dominance among intratumoral lymphocytes prior to treatment or  among peripheral T cells after treatment would be associated with effective tumor  control upon treatment with anti-PD-L1 therapy. We performed whole exome  sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing  (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially  collected peripheral blood, collected before and after treatment with  atezolizumab. These parameters were assessed for correlation with DCB (defined as  progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both   alone and in the context of clinical and intratumoral parameters known to be  predictive of survival in this disease state. Patients with DCB displayed a  higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney  p = 0.047). Pretreatment peripheral blood TCR clonality below the median was  associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29,  log-rank p = 0.011). Patients with DCB also demonstrated more substantial  expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after  starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high  pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in  tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard   ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1)   = 0.0014). Marked variations in mutation loads were seen with different somatic  variant calling methodologies, which, in turn, impacted associations with  clinical outcomes. Missense mutation load, predicted neoantigen load, and  expressed neoantigen load did not demonstrate significant association with DCB (n  = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25,  Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying   effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A  limitation of our study is its small sample size (n = 29), a subset of the  patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory  analyses performed, we intend for these results to be hypothesis-generating.  CONCLUSIONS: These results demonstrate the complex nature of immune response to  checkpoint blockade and the compelling need for greater interrogation and data  integration of both host and tumor factors. Incorporating these variables in  prospective studies will facilitate identification and treatment of resistant  patients.
CANIT0001083	28552987	Clinical research	Metastatic urothelial cancers	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	29	N/A	N/A	Better outcome with more substantial expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after starting treatment	N/A	N/A	N/A	T-cell receptor (NCIT:C12476); T-Lymphocyte (NCIT:C12476); 	More substantial expansion of tumor-associated T-cell receptor clonality in the peripheral blood 3 weeks after starting treatment	Cell percentage/counts in blood	 2017 May	 Contribution of systemic and somatic factors to clinical response and resistance   to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.	 PLoS Med	 BACKGROUND: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can  induce durable clinical benefit (DCB) in patients with metastatic urothelial  cancers, including complete remissions in patients with chemotherapy refractory  disease. Although mutation load and PD-L1 immune cell (IC) staining have been  associated with response, they lack sufficient sensitivity and specificity for  clinical use. Thus, there is a need to evaluate the peripheral blood immune  environment and to conduct detailed analyses of mutation load, predicted  neoantigens, and immune cellular infiltration in tumors to enhance our  understanding of the biologic underpinnings of response and resistance. METHODS  AND FINDINGS: The goals of this study were to (1) evaluate the association of  mutation load and predicted neoantigen load with therapeutic benefit and (2)  determine whether intratumoral and peripheral blood T cell receptor (TCR)  clonality inform clinical outcomes in urothelial carcinoma treated with  atezolizumab. We hypothesized that an elevated mutation load in combination with   T cell clonal dominance among intratumoral lymphocytes prior to treatment or  among peripheral T cells after treatment would be associated with effective tumor  control upon treatment with anti-PD-L1 therapy. We performed whole exome  sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing  (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially  collected peripheral blood, collected before and after treatment with  atezolizumab. These parameters were assessed for correlation with DCB (defined as  progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both   alone and in the context of clinical and intratumoral parameters known to be  predictive of survival in this disease state. Patients with DCB displayed a  higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney  p = 0.047). Pretreatment peripheral blood TCR clonality below the median was  associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29,  log-rank p = 0.011). Patients with DCB also demonstrated more substantial  expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after  starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high  pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in  tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard   ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1)   = 0.0014). Marked variations in mutation loads were seen with different somatic  variant calling methodologies, which, in turn, impacted associations with  clinical outcomes. Missense mutation load, predicted neoantigen load, and  expressed neoantigen load did not demonstrate significant association with DCB (n  = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25,  Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying   effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A  limitation of our study is its small sample size (n = 29), a subset of the  patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory  analyses performed, we intend for these results to be hypothesis-generating.  CONCLUSIONS: These results demonstrate the complex nature of immune response to  checkpoint blockade and the compelling need for greater interrogation and data  integration of both host and tumor factors. Incorporating these variables in  prospective studies will facilitate identification and treatment of resistant  patients.
CANIT0001084	28552987	Clinical research	Metastatic urothelial cancers	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	29	N/A	N/A	Better outcome with pretreatment peripheral blood TCR clonality below the median	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	Pretreatment peripheral blood T-cell receptor clonality below the median.	Cell percentage/counts in blood	 2017 May	 Contribution of systemic and somatic factors to clinical response and resistance   to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.	 PLoS Med	 BACKGROUND: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can  induce durable clinical benefit (DCB) in patients with metastatic urothelial  cancers, including complete remissions in patients with chemotherapy refractory  disease. Although mutation load and PD-L1 immune cell (IC) staining have been  associated with response, they lack sufficient sensitivity and specificity for  clinical use. Thus, there is a need to evaluate the peripheral blood immune  environment and to conduct detailed analyses of mutation load, predicted  neoantigens, and immune cellular infiltration in tumors to enhance our  understanding of the biologic underpinnings of response and resistance. METHODS  AND FINDINGS: The goals of this study were to (1) evaluate the association of  mutation load and predicted neoantigen load with therapeutic benefit and (2)  determine whether intratumoral and peripheral blood T cell receptor (TCR)  clonality inform clinical outcomes in urothelial carcinoma treated with  atezolizumab. We hypothesized that an elevated mutation load in combination with   T cell clonal dominance among intratumoral lymphocytes prior to treatment or  among peripheral T cells after treatment would be associated with effective tumor  control upon treatment with anti-PD-L1 therapy. We performed whole exome  sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing  (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially  collected peripheral blood, collected before and after treatment with  atezolizumab. These parameters were assessed for correlation with DCB (defined as  progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both   alone and in the context of clinical and intratumoral parameters known to be  predictive of survival in this disease state. Patients with DCB displayed a  higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney  p = 0.047). Pretreatment peripheral blood TCR clonality below the median was  associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29,  log-rank p = 0.011). Patients with DCB also demonstrated more substantial  expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after  starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high  pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in  tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard   ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1)   = 0.0014). Marked variations in mutation loads were seen with different somatic  variant calling methodologies, which, in turn, impacted associations with  clinical outcomes. Missense mutation load, predicted neoantigen load, and  expressed neoantigen load did not demonstrate significant association with DCB (n  = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25,  Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying   effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A  limitation of our study is its small sample size (n = 29), a subset of the  patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory  analyses performed, we intend for these results to be hypothesis-generating.  CONCLUSIONS: These results demonstrate the complex nature of immune response to  checkpoint blockade and the compelling need for greater interrogation and data  integration of both host and tumor factors. Incorporating these variables in  prospective studies will facilitate identification and treatment of resistant  patients.
CANIT0001085	28552987	Clinical research	Metastatic urothelial cancers	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	29	N/A	N/A	Poor outcome with the combination of high pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in tumor tissue	N/A	N/A	N/A	PD-L1 (Q9NZQ7); T-cell receptor (NCIT:C12476); T-Lymphocyte (NCIT:C12476); 	High pretreatment peripheral blood T-cell receptor clonality with elevated PD-L1 expression levels on tumor cells.	Gene expression signature on/in tumor cell	 2017 May	 Contribution of systemic and somatic factors to clinical response and resistance   to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis.	 PLoS Med	 BACKGROUND: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can  induce durable clinical benefit (DCB) in patients with metastatic urothelial  cancers, including complete remissions in patients with chemotherapy refractory  disease. Although mutation load and PD-L1 immune cell (IC) staining have been  associated with response, they lack sufficient sensitivity and specificity for  clinical use. Thus, there is a need to evaluate the peripheral blood immune  environment and to conduct detailed analyses of mutation load, predicted  neoantigens, and immune cellular infiltration in tumors to enhance our  understanding of the biologic underpinnings of response and resistance. METHODS  AND FINDINGS: The goals of this study were to (1) evaluate the association of  mutation load and predicted neoantigen load with therapeutic benefit and (2)  determine whether intratumoral and peripheral blood T cell receptor (TCR)  clonality inform clinical outcomes in urothelial carcinoma treated with  atezolizumab. We hypothesized that an elevated mutation load in combination with   T cell clonal dominance among intratumoral lymphocytes prior to treatment or  among peripheral T cells after treatment would be associated with effective tumor  control upon treatment with anti-PD-L1 therapy. We performed whole exome  sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing  (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially  collected peripheral blood, collected before and after treatment with  atezolizumab. These parameters were assessed for correlation with DCB (defined as  progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both   alone and in the context of clinical and intratumoral parameters known to be  predictive of survival in this disease state. Patients with DCB displayed a  higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney  p = 0.047). Pretreatment peripheral blood TCR clonality below the median was  associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29,  log-rank p = 0.011). Patients with DCB also demonstrated more substantial  expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after  starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high  pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in  tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard   ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1)   = 0.0014). Marked variations in mutation loads were seen with different somatic  variant calling methodologies, which, in turn, impacted associations with  clinical outcomes. Missense mutation load, predicted neoantigen load, and  expressed neoantigen load did not demonstrate significant association with DCB (n  = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25,  Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying   effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A  limitation of our study is its small sample size (n = 29), a subset of the  patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory  analyses performed, we intend for these results to be hypothesis-generating.  CONCLUSIONS: These results demonstrate the complex nature of immune response to  checkpoint blockade and the compelling need for greater interrogation and data  integration of both host and tumor factors. Incorporating these variables in  prospective studies will facilitate identification and treatment of resistant  patients.
CANIT0001086	28557813	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Diabetic ketoacidosis	N/A	N/A	N/A	N/A	N/A	 2017 Jul/Aug	 Diabetic Ketoacidosis as an Immune-related Adverse Event from Pembrolizumab in  Non-Small Cell Lung Cancer.	 J Immunother	 Programmed cell death protein 1 pathway inhibitors are now routinely administered  to patients with non-small cell lung cancer, and prompt recognition of  immune-related adverse events is critical to managing serious drug toxicities.  Here, we describe a 66-year-old man with no known history of diabetes who  presented with diabetic ketoacidosis after receiving 3 doses of pembrolizumab for  lung adenocarcinoma. Autoimmune diabetes is a rare but potentially  life-threatening complication of programmed cell death protein 1 inhibitors.
CANIT0001087	28559410	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab followed by pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); ipilimumab (DB06186); 	1	N/A	Case	N/A	Encephalitis, with brainstem involvement	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Case Report: Encephalitis, with Brainstem Involvement, Following Checkpoint  Inhibitor Therapy in Metastatic Melanoma.	 Oncologist	 Checkpoint inhibitors are increasingly being used in the treatment of malignant  melanoma and other cancers. With the use of such therapies, autoimmune-mediated  adverse events in the central and peripheral nervous system are likely to occur  more frequently. We report a unique case of brainstem encephalitis with a sudden   lethal outcome following ipilimumab and pembrolizumab therapy in a patient with  malignant melanoma. The autopsy showed a diffuse nodular activation of microglia   in the whole encephalon with prominent intraparenchymal and perivascular  lymphocytic infiltration of the brainstem. Non-infectious brainstem encephalitis   is a well-recognized subset of paraneoplastic encephalitis. Brainstem involvement  is usually accompanied by a wide spectrum of signs and symptoms, which were not  observed in this case. The timing of the clinical symptoms as well as the  histopathological findings suggest an autoimmune-adverse event of ipilimumab and   pembrolizumab administration rather than a paraneoplastic disorder. In the  presence of neurological symptoms, immediate cessation of the immunotherapy and  immunosuppressive therapy may lead to successful therapeutic intervention, as  described in previous reports. Therefore, it is crucial that physicians are aware  of the possible side effects of immunotherapies on the nervous system.  IMPLICATIONS FOR PRACTICE: Metastatic melanoma patients treated with the  anti-CTLA-4 inhibitor ipilimumab have a high utilization of various types of  health care services, such as inpatient hospital stays or doctor visits. There  are differences across countries regarding patterns of health care utilization  and economic burden of the disease. Health care services are used more frequently  after patients experience progression of their disease. The study highlights that  better therapies leading to durable response in patients with metastatic melanoma  have the potential to decrease health care costs and patient burden in terms of  hospitalizations and other health care services.CI  - (c) AlphaMed Press 2017.
CANIT0001088	28564739	Case report	Lynch-Syndrome and primarily unresectable relapse of rectum carcinoma	Rectum cancer	EFO:1000657	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Histologic remission	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 [Histologic Remission following Neoadjuvant Immunotherapy in a Patient with  Lynch-Syndrome and Primarily Unresectable Relapse of Rectum Carcinoma].	 Dtsch Med Wochenschr	 Clinical History A 43-year-old male patient was diagnosed to have rectum  carcinoma cT4N2M0 with underlying Lynch-Syndrome. After initializing neoadjuvant   radio-chemotherapy followed by operation, the patient presents with an extensive   locoregional relapse within a short time. In order to achieve resectability, a  second line treatment with FOLFOXIRI protocol in addition to Bevacizumab was  conducted. However, after completing six cycles of this intensiv treatment  protocol, the tumour showed further progression. Clinical Course Having no  evidence of distance metastasis, we decided to initiate off-label use of  Pembrolizumab, a PD-1-receptor inhibitor. Clinical symptoms decreased rapidly and  after receiving six cycles, PET/CT imaging showed regression. The side effects  were limited to subclinical autoimmune thyroiditis. After re-operation no  evidence of malignancy were found in the resectates of exenteration of the  pelvis. Currently the patient is capable of working with only limited symptoms.  Conclusion Pembrolizumab offers new treatment options for patients with  DNA-repair-deficiency mismatch, e. g. Lynch-Syndrome. A phase II study already  showed effectiveness in this particular group of patients. The striking and  unexpected histo-pathologic results showing full remission should draw attention   to the use of Pembrolizumab in neoadjuvant settings.CI  - (c) Georg Thieme Verlag KG Stuttgart . New York.
CANIT0001089	28569347	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	63	N/A	N/A	Better outcome with lower lactate dehydrogenase	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2017 Dec	 Clinical parameters associated with anti-programmed death-1 (PD-1)  inhibitors-induced tumor response in melanoma patients.	 Invest New Drugs	 Background The identification of the melanoma patients sensitive to anti-PD-1  inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an  urgent need. We hypothesized that the natural history of the disease might partly  reflect the immune state of the patients. Methods We analyzed our cohort of  melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our   institution. Objective response was defined as a complete or partial response  according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients,  the overall response rate was 43%. Median time from diagnosis to anti-PD-1  initiation was longer among responders than non-responders (64 months vs. 35  months, p = 0.02). The response rate was 10% in patients starting anti-PD-1  within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status  (PS) 0 was also associated with enhanced tumor response: 70% of responders were  PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type   BRAF status were significant predictors of progression free survival. Conclusion   A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated   with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical  features might reflect a potentially intact immune system of the host.
CANIT0001090	28569347	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	63	N/A	N/A	Better outcome with lower lactate dehydrogenase	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2017 Dec	 Clinical parameters associated with anti-programmed death-1 (PD-1)  inhibitors-induced tumor response in melanoma patients.	 Invest New Drugs	 Background The identification of the melanoma patients sensitive to anti-PD-1  inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an  urgent need. We hypothesized that the natural history of the disease might partly  reflect the immune state of the patients. Methods We analyzed our cohort of  melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our   institution. Objective response was defined as a complete or partial response  according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients,  the overall response rate was 43%. Median time from diagnosis to anti-PD-1  initiation was longer among responders than non-responders (64 months vs. 35  months, p = 0.02). The response rate was 10% in patients starting anti-PD-1  within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status  (PS) 0 was also associated with enhanced tumor response: 70% of responders were  PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type   BRAF status were significant predictors of progression free survival. Conclusion   A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated   with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical  features might reflect a potentially intact immune system of the host.
CANIT0001091	28569347	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	63	N/A	N/A	Better outcome without BRAF V600 mutation	N/A	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2017 Dec	 Clinical parameters associated with anti-programmed death-1 (PD-1)  inhibitors-induced tumor response in melanoma patients.	 Invest New Drugs	 Background The identification of the melanoma patients sensitive to anti-PD-1  inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an  urgent need. We hypothesized that the natural history of the disease might partly  reflect the immune state of the patients. Methods We analyzed our cohort of  melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our   institution. Objective response was defined as a complete or partial response  according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients,  the overall response rate was 43%. Median time from diagnosis to anti-PD-1  initiation was longer among responders than non-responders (64 months vs. 35  months, p = 0.02). The response rate was 10% in patients starting anti-PD-1  within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status  (PS) 0 was also associated with enhanced tumor response: 70% of responders were  PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type   BRAF status were significant predictors of progression free survival. Conclusion   A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated   with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical  features might reflect a potentially intact immune system of the host.
CANIT0001092	28569347	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	63	N/A	N/A	Better outcome without BRAF V600 mutation	N/A	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2017 Dec	 Clinical parameters associated with anti-programmed death-1 (PD-1)  inhibitors-induced tumor response in melanoma patients.	 Invest New Drugs	 Background The identification of the melanoma patients sensitive to anti-PD-1  inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an  urgent need. We hypothesized that the natural history of the disease might partly  reflect the immune state of the patients. Methods We analyzed our cohort of  melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our   institution. Objective response was defined as a complete or partial response  according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients,  the overall response rate was 43%. Median time from diagnosis to anti-PD-1  initiation was longer among responders than non-responders (64 months vs. 35  months, p = 0.02). The response rate was 10% in patients starting anti-PD-1  within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status  (PS) 0 was also associated with enhanced tumor response: 70% of responders were  PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type   BRAF status were significant predictors of progression free survival. Conclusion   A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated   with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical  features might reflect a potentially intact immune system of the host.
CANIT0001093	28569347	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	63	N/A	N/A	Better outcome with performance status 0	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2017 Dec	 Clinical parameters associated with anti-programmed death-1 (PD-1)  inhibitors-induced tumor response in melanoma patients.	 Invest New Drugs	 Background The identification of the melanoma patients sensitive to anti-PD-1  inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an  urgent need. We hypothesized that the natural history of the disease might partly  reflect the immune state of the patients. Methods We analyzed our cohort of  melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our   institution. Objective response was defined as a complete or partial response  according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients,  the overall response rate was 43%. Median time from diagnosis to anti-PD-1  initiation was longer among responders than non-responders (64 months vs. 35  months, p = 0.02). The response rate was 10% in patients starting anti-PD-1  within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status  (PS) 0 was also associated with enhanced tumor response: 70% of responders were  PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type   BRAF status were significant predictors of progression free survival. Conclusion   A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated   with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical  features might reflect a potentially intact immune system of the host.
CANIT0001094	28569347	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	63	N/A	N/A	Better outcome with performance status 0	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2017 Dec	 Clinical parameters associated with anti-programmed death-1 (PD-1)  inhibitors-induced tumor response in melanoma patients.	 Invest New Drugs	 Background The identification of the melanoma patients sensitive to anti-PD-1  inhibitors, nivolumab or pembrolizumab, is a major therapeutic challenge and an  urgent need. We hypothesized that the natural history of the disease might partly  reflect the immune state of the patients. Methods We analyzed our cohort of  melanoma patients treated with anti-PD-1 from August 2014 to January 2016 in our   institution. Objective response was defined as a complete or partial response  according to v1.1 RECIST criteria. Results Among 63 metastatic melanoma patients,  the overall response rate was 43%. Median time from diagnosis to anti-PD-1  initiation was longer among responders than non-responders (64 months vs. 35  months, p = 0.02). The response rate was 10% in patients starting anti-PD-1  within 1 year, 35% after 1 to 5 years and 63% after 5 years. Performance status  (PS) 0 was also associated with enhanced tumor response: 70% of responders were  PS 0 vs. 36% of non-responders (p = 0.04). PS 0, normal LDH levels and wild-type   BRAF status were significant predictors of progression free survival. Conclusion   A long time lapse from diagnosis to anti-PD-1 initiation and PS 0 are associated   with higher sensitivity to anti-PD-1 in melanoma patients. These two clinical  features might reflect a potentially intact immune system of the host.
CANIT0001095	28574922	Case report	Metastatic non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Severe complicated neutropenia	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Severe complicated neutropenia in two patients with metastatic non-small-cell  lung cancer treated with nivolumab.	 Anticancer Drugs	 Checkpoint inhibitors effectively enhance the natural immune response against  cancer, but they are also known to induce a unique spectrum of immune-related  adverse events. Here, we report the first case of isolated neutropenia subsequent  to nivolumab therapy. Prominent activated T-cells were found in the patient's  serum and bone marrow alongside evidence of maturational defects in neutrophil  precursors. Antineutrophil antibodies were not detected despite reliable testing   techniques. A T-cell-mediated response is probable, consistent with the  established mechanism for the development of other immune-related toxicities.  Awareness of this rare and severe side effect reinforces the importance of early   diagnosis and prompt initiation of proper treatment.
CANIT0001096	28574977	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Biclonal cutaneous T-cell lymphoproliferative disorder	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Development of a biclonal cutaneous T-cell lymphoproliferative process during  treatment with immune checkpoint inhibitors for metastatic melanoma.	 Melanoma Res	 The immune checkpoint inhibitors targeting cytotoxic T-lymphocyte associated  antigen 4 (CTLA-4) and the programmed death protein 1 (PD-1)/PD-L1 pathway have  recently shown promising therapeutic results in patients with metastatic  melanoma. Dermatologic side effects of these agents occur in approximately 30-40%  of cases. Here, we report the development of a biclonal cutaneous T-cell  lymphoproliferative disorder in a patient being treated with ipilimumab (a CTLA-4  inhibitor) for metastatic melanoma. Nivolumab (a PD-1 inhibitor) had also been  administered to him previously. An 8 mm reddish papule appeared on the skin of  the left forearm. A biopsy of that lesion showed an atypical population of  predominantly CD4-positive, CD30-positive T-cells that also expressed PD-1 and  PD-L1 immunohistochemically. PCR studies for T-cell receptor rearrangements  showed the presence of two distinct clonal T-cell populations. The lesion was  completely excised and the patient had no local recurrences. There was also no  subsequent evidence of a systemic lymphoproliferative process. Although the  development of a lymphoid skin lesion in our patient may have only been  coincidentally related to his treatment, immunostimulatory drugs could  theoretically cause clonal expansion of a population of lymphocytes that leads to  a lymphoproliferative disorder.
CANIT0001097	28577948	Case report	Lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Vitiligo	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Vitiligo in a patient with lung adenocarcinoma treated with nivolumab: A case  report.	 Lung Cancer	 Nivolumab, an anti-programmed cell death-1 protein monoclonal antibody, is  effective for treating patients with late-stage non-small-cell lung cancer.  Immune checkpoint inhibitors such as nivolumab induce various kinds of  immune-related adverse events, including vitiligo. Vitiligo has been reported in   patients with melanoma but not lung cancer. We describe a 75-year-old man with  lung adenocarcinoma, stage 4 with pleural and pericardial effusion, that  progressed after first-line chemotherapy. Subsequently, he was treated with  nivolumab as second-line therapy. After 6days of administering nivolumab, he  developed vitiligo suddenly on the trunk of his body. Except for vitiligo, his  physical examination was normal, and treatment with nivolumab was well tolerated.  Therefore, this treatment was continued without further development or expansion   of vitiligo. A computed tomography scan showed a reduction in the size of the  lung nodule and stabilization of the pleural and pericardial effusion. This is  the first case of vitiligo associated with the use of nivolumab in a patient with  lung adenocarcinoma.CI  - Copyright (c) 2017. Published by Elsevier B.V.
CANIT0001098	28577951	Case report	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Severe refractory pruritus can arise from ICIs, and aprepitant may be a useful treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Aprepitant for refractory nivolumab-induced pruritus.	 Lung Cancer	 Although substantial progress has been made in the treatment of non-small-cell  lung cancer (NSCLC) patients with immune checkpoint inhibitors (ICIs), severe  immune-related adverse events (irAEs) sometimes occur. Here, we report a case of   severe refractory pruritus after Stevens-Johnson syndrome (SJS) in a patient with  NSCLC treated with nivolumab. The patient was a 76-year-old Japanese woman with  advanced NSCLC treated with nivolumab. After the second dose, she experienced  severe rash with mucous involvement. We diagnosed SJS and started 50mg of oral  prednisolone (1mg/kg). The rash completely resolved after prednisolone was  started, but we could not manage the severe pruritus with emollients,  antihistamines, and steroids. Finally, we administered aprepitant, an oral  neurokinin-1 receptor antagonist, for her refractory pruritus. Her symptoms  improved within 5days. Severe refractory pruritus can arise from ICIs, and  aprepitant may be a useful treatment.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001099	28577954	Case report	Squamous non-small-cell lung cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Recurrent dysphasia due to nivolumab-induced encephalopathy with presence of Hu autoantibody.	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Recurrent dysphasia due to nivolumab-induced encephalopathy with presence of Hu  autoantibody.	 Lung Cancer	 A 58-year-old man was being treated for squamous non-small-cell lung cancer with   nivolumab. At the 17th of biweekly administrations he presented with global  dysphasia, dysarthria and myoclonus in the right upper extremity. MRI showed  multiple T2/FLAIR hyperintense lesions in the left hemisphere; lumbar puncture  showed lymphocytic pleiocytosis in the CSF without identifiable pathogens. Hu  antibodies were present in serum and CSF. Nivolumab was discontinued and  corticosteroids were administered. The neurological symptoms gradually improved;   MRI showed complete remission of cerebral lesions. After rechallenge with  nivolumab his symptoms and cerebral lesions recurred, proving the causal  relationship with nivolumab. After tapering of corticosteroids, a second relapse   occurred.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001100	28588322	Clinical research	12 Breast cancer, 11 Pancreatic cancer, 8 NSCLC, 7Sarcoma, 5 SCLC, 2 Ovarian cancer and 3 others	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Chemotherapy (NCIT:C15632); pembrolizumab (DB09037); 	49	N/A	A phase Ib clinical trial	Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.	The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 27	 A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced  cancer (PembroPlus).	 Br J Cancer	 BACKGROUND: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the  interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1  and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken  to evaluate the safety and efficacy. METHODS: Patients with advanced, metastatic   solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was  given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP),  G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with  liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety  monitoring and response assessments were conducted. RESULTS: Forty-nine patients   were enrolled and treated. The most common adverse events were transaminitis,  cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due  to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1,   3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.   CONCLUSIONS: Standard dose P can be safely combined with G, G+NP, G+V, I and LD.   Efficacy was observed in multiple tumour types and evaluation to determine if  response and duration of response are more robust than what would be expected for  chemotherapy or immunotherapy alone requires further validation.
CANIT0001101	28588322	Clinical research	12 Breast cancer, 11 Pancreatic cancer, 8 NSCLC, 7Sarcoma, 5 SCLC, 2 Ovarian cancer and 3 others	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Chemotherapy (NCIT:C15632); pembrolizumab (DB09037); 	49	N/A	A phase Ib clinical trial	Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.	The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 27	 A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced  cancer (PembroPlus).	 Br J Cancer	 BACKGROUND: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the  interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1  and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken  to evaluate the safety and efficacy. METHODS: Patients with advanced, metastatic   solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was  given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP),  G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with  liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety  monitoring and response assessments were conducted. RESULTS: Forty-nine patients   were enrolled and treated. The most common adverse events were transaminitis,  cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due  to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1,   3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.   CONCLUSIONS: Standard dose P can be safely combined with G, G+NP, G+V, I and LD.   Efficacy was observed in multiple tumour types and evaluation to determine if  response and duration of response are more robust than what would be expected for  chemotherapy or immunotherapy alone requires further validation.
CANIT0001102	28588322	Clinical research	12 Breast cancer, 11 Pancreatic cancer, 8 NSCLC, 7Sarcoma, 5 SCLC, 2 Ovarian cancer and 3 others	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Chemotherapy (NCIT:C15632); pembrolizumab (DB09037); 	49	N/A	A phase Ib clinical trial	Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.	The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 27	 A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced  cancer (PembroPlus).	 Br J Cancer	 BACKGROUND: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the  interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1  and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken  to evaluate the safety and efficacy. METHODS: Patients with advanced, metastatic   solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was  given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP),  G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with  liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety  monitoring and response assessments were conducted. RESULTS: Forty-nine patients   were enrolled and treated. The most common adverse events were transaminitis,  cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due  to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1,   3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.   CONCLUSIONS: Standard dose P can be safely combined with G, G+NP, G+V, I and LD.   Efficacy was observed in multiple tumour types and evaluation to determine if  response and duration of response are more robust than what would be expected for  chemotherapy or immunotherapy alone requires further validation.
CANIT0001103	28588322	Clinical research	12 Breast cancer, 11 Pancreatic cancer, 8 NSCLC, 7Sarcoma, 5 SCLC, 2 Ovarian cancer and 3 others	Pancreatic carcinoma	EFO:0002618	Pancreas	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Chemotherapy (NCIT:C15632); pembrolizumab (DB09037); 	49	N/A	A phase Ib clinical trial	Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.	The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 27	 A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced  cancer (PembroPlus).	 Br J Cancer	 BACKGROUND: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the  interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1  and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken  to evaluate the safety and efficacy. METHODS: Patients with advanced, metastatic   solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was  given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP),  G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with  liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety  monitoring and response assessments were conducted. RESULTS: Forty-nine patients   were enrolled and treated. The most common adverse events were transaminitis,  cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due  to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1,   3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.   CONCLUSIONS: Standard dose P can be safely combined with G, G+NP, G+V, I and LD.   Efficacy was observed in multiple tumour types and evaluation to determine if  response and duration of response are more robust than what would be expected for  chemotherapy or immunotherapy alone requires further validation.
CANIT0001104	28588322	Clinical research	12 Breast cancer, 11 Pancreatic cancer, 8 NSCLC, 7Sarcoma, 5 SCLC, 2 Ovarian cancer and 3 others	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Chemotherapy (NCIT:C15632); pembrolizumab (DB09037); 	49	N/A	A phase Ib clinical trial	Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.	The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 27	 A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced  cancer (PembroPlus).	 Br J Cancer	 BACKGROUND: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the  interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1  and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken  to evaluate the safety and efficacy. METHODS: Patients with advanced, metastatic   solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was  given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP),  G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with  liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety  monitoring and response assessments were conducted. RESULTS: Forty-nine patients   were enrolled and treated. The most common adverse events were transaminitis,  cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due  to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1,   3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.   CONCLUSIONS: Standard dose P can be safely combined with G, G+NP, G+V, I and LD.   Efficacy was observed in multiple tumour types and evaluation to determine if  response and duration of response are more robust than what would be expected for  chemotherapy or immunotherapy alone requires further validation.
CANIT0001105	28588322	Clinical research	12 Breast cancer, 11 Pancreatic cancer, 8 NSCLC, 7Sarcoma, 5 SCLC, 2 Ovarian cancer and 3 others	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Chemotherapy (NCIT:C15632); pembrolizumab (DB09037); 	49	N/A	A phase Ib clinical trial	Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation.	The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting.	N/A	N/A	N/A	N/A	N/A	 2017 Jun 27	 A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced  cancer (PembroPlus).	 Br J Cancer	 BACKGROUND: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the  interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1  and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken  to evaluate the safety and efficacy. METHODS: Patients with advanced, metastatic   solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was  given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP),  G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with  liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety  monitoring and response assessments were conducted. RESULTS: Forty-nine patients   were enrolled and treated. The most common adverse events were transaminitis,  cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due  to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1,   3a, 4, 5 and 6. There were eight partial responses across multiple tumour types.   CONCLUSIONS: Standard dose P can be safely combined with G, G+NP, G+V, I and LD.   Efficacy was observed in multiple tumour types and evaluation to determine if  response and duration of response are more robust than what would be expected for  chemotherapy or immunotherapy alone requires further validation.
CANIT0001106	28595336	Clinical research	Melanoma or non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	15	N/A	N/A	Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.	N/A	N/A	N/A	IL8 (P10145); 	Serum IL8 expression levels	Gene expression signature in serum	 2017 Aug 1	 Changes in serum interleukin-8 (IL-8) levels reflect and predict response to  anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients.	 Ann Oncol	 Background: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1  therapy, given the existence of delayed responses and pseudo-progressions. We  evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1  blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. Patients  and methods: Metastatic melanoma and NSCLC patients treated with nivolumab or  pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was  collected at baseline; at 2-4 weeks after the first dose; and at the time-points   of response evaluation. Serum IL-8 levels were determined by sandwich ELISA.  Changes in serum IL-8 levels were compared with the Wilcoxon test and their  strength of association with response was assessed with the Mann-Whitney test.  Accuracy of changes in IL-8 levels to predict response was estimated using  receiver operation characteristics curves. Results: Twenty-nine melanoma patients  treated with nivolumab or pembrolizumab were studied. In responding patients,  serum IL-8 levels significantly decreased between baseline and best response (P  <0.001), and significantly increased upon progression (P = 0.004). In  non-responders, IL-8 levels significantly increased between baseline and  progression (P = 0.013). Early changes in serum IL-8 levels (2-4 weeks after  treatment initiation) were strongly associated with response (P <0.001). These  observations were validated in 19 NSCLC patients treated with nivolumab or  pembrolizumab (P = 0.001), and in 15 melanoma patients treated with nivolumab  plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated   with longer overall survival in melanoma (P = 0.001) and NSCLC (P = 0.015)  patients. Serum IL-8 levels also correctly reflected true response in three  cancer patients presenting pseudoprogression. Conclusions: Changes in serum IL-8   levels could be used to monitor and predict clinical benefit from immune  checkpoint blockade in melanoma and NSCLC patients.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For Permissions,  please email: journals.permissions@oup.com.
CANIT0001107	28595336	Clinical research	Melanoma or non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	19	N/A	N/A	Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.	N/A	N/A	N/A	IL8 (P10145); 	Serum IL8 expression levels	Gene expression signature in serum	 2017 Aug 1	 Changes in serum interleukin-8 (IL-8) levels reflect and predict response to  anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients.	 Ann Oncol	 Background: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1  therapy, given the existence of delayed responses and pseudo-progressions. We  evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1  blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. Patients  and methods: Metastatic melanoma and NSCLC patients treated with nivolumab or  pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was  collected at baseline; at 2-4 weeks after the first dose; and at the time-points   of response evaluation. Serum IL-8 levels were determined by sandwich ELISA.  Changes in serum IL-8 levels were compared with the Wilcoxon test and their  strength of association with response was assessed with the Mann-Whitney test.  Accuracy of changes in IL-8 levels to predict response was estimated using  receiver operation characteristics curves. Results: Twenty-nine melanoma patients  treated with nivolumab or pembrolizumab were studied. In responding patients,  serum IL-8 levels significantly decreased between baseline and best response (P  <0.001), and significantly increased upon progression (P = 0.004). In  non-responders, IL-8 levels significantly increased between baseline and  progression (P = 0.013). Early changes in serum IL-8 levels (2-4 weeks after  treatment initiation) were strongly associated with response (P <0.001). These  observations were validated in 19 NSCLC patients treated with nivolumab or  pembrolizumab (P = 0.001), and in 15 melanoma patients treated with nivolumab  plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated   with longer overall survival in melanoma (P = 0.001) and NSCLC (P = 0.015)  patients. Serum IL-8 levels also correctly reflected true response in three  cancer patients presenting pseudoprogression. Conclusions: Changes in serum IL-8   levels could be used to monitor and predict clinical benefit from immune  checkpoint blockade in melanoma and NSCLC patients.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For Permissions,  please email: journals.permissions@oup.com.
CANIT0001108	28595336	Clinical research	Melanoma or non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	19	N/A	N/A	Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.	N/A	N/A	N/A	IL8 (P10145); 	Serum IL8 expression levels	Gene expression signature in serum	 2017 Aug 1	 Changes in serum interleukin-8 (IL-8) levels reflect and predict response to  anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients.	 Ann Oncol	 Background: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1  therapy, given the existence of delayed responses and pseudo-progressions. We  evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1  blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. Patients  and methods: Metastatic melanoma and NSCLC patients treated with nivolumab or  pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was  collected at baseline; at 2-4 weeks after the first dose; and at the time-points   of response evaluation. Serum IL-8 levels were determined by sandwich ELISA.  Changes in serum IL-8 levels were compared with the Wilcoxon test and their  strength of association with response was assessed with the Mann-Whitney test.  Accuracy of changes in IL-8 levels to predict response was estimated using  receiver operation characteristics curves. Results: Twenty-nine melanoma patients  treated with nivolumab or pembrolizumab were studied. In responding patients,  serum IL-8 levels significantly decreased between baseline and best response (P  <0.001), and significantly increased upon progression (P = 0.004). In  non-responders, IL-8 levels significantly increased between baseline and  progression (P = 0.013). Early changes in serum IL-8 levels (2-4 weeks after  treatment initiation) were strongly associated with response (P <0.001). These  observations were validated in 19 NSCLC patients treated with nivolumab or  pembrolizumab (P = 0.001), and in 15 melanoma patients treated with nivolumab  plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated   with longer overall survival in melanoma (P = 0.001) and NSCLC (P = 0.015)  patients. Serum IL-8 levels also correctly reflected true response in three  cancer patients presenting pseudoprogression. Conclusions: Changes in serum IL-8   levels could be used to monitor and predict clinical benefit from immune  checkpoint blockade in melanoma and NSCLC patients.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For Permissions,  please email: journals.permissions@oup.com.
CANIT0001109	28597713	Case report	Stage IVB Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	He reached a major response after four cycles of nivolumab and got married.  Nivolumab induces clinically meaningful responses with excellent tolerance.	Nivolumab induces clinically meaningful responses with excellent tolerance.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Back to life with checkpoint inhibitors in Hodgkin lymphoma.	 J Oncol Pharm Pract	 Cancer can escape the immune system through different mechanisms. One of which is  the expression of program death ligand-1 (PD-L1). This ligand binds to programmed  cell death 1 receptor on activated T cells, subsequently leading to inhibition of  the immune response. Nivolumab is a novel antibody that binds to programmed cell   death 1 and prevents such immune tolerance. Several recently published clinical  trials confirmed the clinical efficacy of single agent nivolumab in pretreated  patients with different cancer types. Publications on nivolumab in Hodgkin  lymphoma are very scarce. We report on a 30-year-old man with stage IVB Hodgkin  lymphoma, who failed nine lines of treatments including high-dose chemotherapy  and autologous stem cell transplantation and brentuximab vedotin. He reached a  major response after four cycles of nivolumab and got married. The available  literature is being reviewed. Pre-treated Hodgkin lymphoma is amenable to novel  immunotherapy. Nivolumab induces clinically meaningful responses with excellent  tolerance. The drug enriches our treatment options by reviving the immune system   response against cancer. Further clinical studies are needed to determine the  effectiveness on a large patients' cohort.
CANIT0001110	28599746	Case report	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Case	Scleroderma	We describe cases of 2 patients with scleroderma (patient 1 had diffuse scleroderma, and patient 2 had limited scleroderma) that developed while they were receiving pembrolizumab therapy for metastatic melanoma.	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Scleroderma Induced by Pembrolizumab: A Case Series.	 Mayo Clin Proc	 Immune checkpoint inhibitors are approved for select cancer treatment and have  shown survival benefit in patients with advanced melanoma. Adverse events,  including immune-related adverse events, are common and potentially  life-threatening. We describe cases of 2 patients with scleroderma (patient 1 had  diffuse scleroderma, and patient 2 had limited scleroderma) that developed while   they were receiving pembrolizumab therapy for metastatic melanoma. Prompt  recognition and treatment of immune-related adverse events may improve tolerance   to immune checkpoint inhibitors and contribute to an understanding of the  manifesting autoimmune disease.CI  - Copyright (c) 2017 Mayo Foundation for Medical Education and Research. Published   by Elsevier Inc. All rights reserved.
CANIT0001111	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Endometrium adenocarcinoma	EFO:0005232	Uterus	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001112	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Endometrium adenocarcinoma	EFO:0005232	Uterus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001113	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Endometrium adenocarcinoma	EFO:0005232	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001114	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001115	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001116	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001117	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001118	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001119	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001120	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Vaginal squamous cell carcinoma	EFO:1000620	Vaginal	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001121	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Vaginal squamous cell carcinoma	EFO:1000620	Vaginal	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001122	28600350	Clinical research	2 Lung adenocarcinoma,  2 Metastatic melanoma, 1 Squamous cell carcinoma of the vagina, Endometrial adenocarcinoma	Vaginal squamous cell carcinoma	EFO:1000620	Vaginal	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	A retrospective cohort study	This is the first description of rheumatoid arthritis occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.	In 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint  inhibitor treatment.	 Ann Rheum Dis	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting cytotoxic  T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have  demonstrated improved survival for multiple cancers. However, these new drug  classes have led to increased immune-related adverse events (IrAE). Rheumatic  IrAEs have not been well described in clinical trials. We report here cases of  rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI  treatment. METHODS: This was a retrospective study of patients receiving an ICI  in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of  RA or PMR. RESULTS: In 10 patients who received ICI therapy (all anti-PD-1 or  anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after   exposure. No patient had pre-existing rheumatic or autoimmune disease. RA  developed in six patients; all six were positive for anti-cyclic citrullinated  peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies  were detected in two out of three patients tested before immunotherapy.  Disease-modifying antirheumatic drugs were needed for three patients; the three  others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was  diagnosed in four patients, all responded to corticosteroids. Despite these  IrAEs, immunotherapy was pursued for all but one patient until cancer  progression. CONCLUSIONS: This is the first description of RA occurring after ICI  therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1  therapy. All cases responded to corticosteroids or with immunosuppressive  therapy. Collaboration between rheumatologists and oncologists is crucial and  could lead to better recognition and care of these patients.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001123	28601918	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Osimertinib reactivated immune-related colitis	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Osimertinib reactivated immune-related colitis after treatment with anti-PD1  antibody for non-small cell lung cancer.	 Invest New Drugs	 We reported a case of relapsing immune-related colitis (initially caused by  nivolumab) following osimertinib therapy for lung adenocarcinoma. A 45-year-old  female who had never smoked was diagnosed with adenocarcinoma of the lung and  underwent surgical resection. Four years after surgical resection, she was  diagnosed with recurrent disease and was eventually treated with nivolumab as  third-line therapy. One month after the completion of nivolumab therapy, the  patient reported abdominal pain and frequent diarrhea. We diagnosed  immune-related colitis and started oral prednisolone. However, the steroid  therapy was ineffective, so the patient was administered infliximab and an  increased dose of prednisolone. Her symptoms subsequently resolved, and her  mucosal lesions improved. Six months after the last administration of nivolumab,   osimertinib was initiated as fourth-line therapy, but 3 days later, the patient  developed blood in the stool and frequent diarrhea. Osimertinib treatment was  discontinued, given the possibility that it had reactivated the patient's  immune-related colitis. We subsequently re-administered oral prednisolone (2  mg/kg/day), and the colitis resolved within a few weeks.
CANIT0001124	28604555	Case report	Adolescent with refractory Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Immune-related neurological symptoms	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Immune-related Neurological Symptoms in an Adolescent Patient Receiving the  Checkpoint Inhibitor Nivolumab.	 J Immunother	 Immune checkpoint inhibitors are a novel group of immunotherapeutic agents for  the treatment of cancer. Immune-related adverse events, including neurological  symptoms, have been associated with these agents. We present the case of an  adolescent with refractory Hodgkin lymphoma treated with nivolumab, a PD1  inhibitor, who developed Hashimoto thyroiditis, posterior reversible  encephalopathy syndrome causing seizures, as well as urinary retention,  truncal/appendicular spasticity, dysphagia, and a progressive encephalopathy that  was clinically consistent with a diagnosis of progressive encephalopathy with  rigidity and myoclonus, a stiff-person-syndrome spectrum disorder. He showed  response and ultimately full recovery to a combination of intravenous steroids,  intravenous immunoglobulin, and plasma exchange. To our knowledge, this is the  first documented report of an immune-related neurological reaction to nivolumab  in an adolescent patient and expands the spectrum of known nivolumab-associated  toxicities.
CANIT0001125	28608115	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	ANTIGEN PRESENTING CELL (N/A); 	ANTIGEN PRESENTING CELL; 	BPX101	N/A	Tumor vaccine	783. BPX-101 Vaccine (NCIT:C82361); 	18	N/A	A phase I clinical trial 	This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.	There were no dose-limiting toxicities.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in  vivo activation of inducible CD40 for advanced prostate cancer.	 Cancer Immunol Immunother	 This phase I trial reports the safety and activity of BPX101, a second-generation  antigen-targeted autologous antigen presenting cell (APC) vaccine in men with  metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101,  APCs collected in a single leukapheresis were transduced with adenoviral vector  Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein  PA001, which contains the extracellular domain of human prostate-specific  membrane antigen. The ih-CD40 represents a modified chimeric version of the  dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert  membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting  temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men  with progressive mCRPC following </=1 prior chemotherapy regimen were enrolled to  evaluate three doses of BPX101 (4 x 10(6), 12.5 x 10(6) and 25 x 10(6) cells)  administered intradermally every 2-4 weeks followed by rimiducid (0.4 mg/kg)  intravenous (IV) infusion 24 h after each BPX101 dose. There were no  dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was   observed with PSA declines, objective tumor regressions and robust efficacy of  post-trial therapy. This novel antigen-targeted and in vivo activated  immunotherapy platform may warrant further development as monotherapy and as a  component of rational combinations.
CANIT0001126	28608286	Clinical research	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Chemotherapy (NCIT:C15632); dabrafenib (DB08912); vemurafenib (DB08881); ipilimumab (DB06186); 	3397	N/A	A retrospective cohort study	Novel drugs for melanoma provide a significant advantage in survival over classic chemotherapy. Comparative assessment of IPI and VEM indicated no difference, but only immunotherapy-treated patients achieved long-lasting results.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Survival of melanoma patients treated with novel drugs: retrospective analysis of  real-world data.	 J Cancer Res Clin Oncol	 PURPOSE: Recently, several new drugs have been licensed for advanced melanoma  therapy, significantly changing the therapeutic landscape. Ipilimumab and  vemurafenib were the first drugs that demonstrated a survival benefit over the  long-standing standard therapy with dacarbazine. However, the comparative  efficacy of these novel drugs has not been properly assessed yet. PATIENTS AND  METHODS: We conducted a retrospective analysis of all the Polish population  treated between January 2012 and October 2016 with one of the following agents:  ipilimumab (IPI), vemurafenib (VEM), dabrafenib (DAB), and classic chemotherapy  (CTH). The main objective was to assess the overall survival of melanoma patients  treated in real-world conditions, taking into account sequences of treatment.  RESULTS: We identified 3397 patients with malignant melanoma treated for the  first line and the second line. Patients receiving CTH were significantly older  than those treated with the novel drugs. At the same time, the population treated  with immunotherapy and targeted therapy was well balanced. Overall survival was  significantly better for the novel drugs compared to classic chemotherapy in both  lines (for the first line, VEM vs CTH HR = 0.72, 95% CI 0.65-0.81; p < .01, and  for the second line, VEM vs CTH HR = 0.78, 95% CI 0.62-0.98; p = .03; IPI vs CTH   HR = 0.72, 95% CI 0.62-0.86; p < .01). There was no statistically significant  difference for IPI vs VEM; however, subgroup analysis revealed superior results  in the case of the CTH-IPI over BRAFi-IPI sequence. CONCLUSION: Novel drugs for  melanoma provide a significant advantage in survival over classic chemotherapy.  Comparative assessment of IPI and VEM indicated no difference, but only  immunotherapy-treated patients achieved long-lasting results. Our data on  sequential treatment indicate that immunotherapy might be a better option for the  first line rather than targeted therapy, but that conclusion requires further  studies of the best way to manage the treatment of melanoma patients.
CANIT0001127	28609226	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	659	N/A	A phase II clinical trial 	BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab. Responses occurred regardless of EGFR or KRAS mutation status.	The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials.	N/A	N/A	EGFR (P00533); 	EGFR exon 19 deletion	Mutational status	 2017 Aug 20	 Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients  With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer  (BIRCH).	 J Clin Oncol	 Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized  anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced  non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were  selected on the basis of PD-L1 expression on tumor cells (TC) or  tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had   advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior  chemotherapy. Patients whose tumors expressed PD-L1 using the SP142  immunohistochemistry assay on >/= 5% of TC or IC (TC2/3 or IC2/3 [TC or IC >/= 5%  PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was  administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659)  comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n  = 268); and third line or higher (cohort 3; n = 252). The primary end point was  independent review facility-assessed objective response rate (ORR; Response  Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points  included median duration of response, progression-free survival, and overall  survival (OS). Results BIRCH met its primary objective of demonstrating a  significant ORR versus historical controls. With a minimum of 12 months of  follow-up, the independent review facility-assessed ORR was 18% to 22% for the  three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are  ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The  median OS from an updated survival analysis (minimum of 20 month follow up) for  cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in   cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was  similar across cohorts and consistent with previous atezolizumab monotherapy  trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab.
CANIT0001128	28609226	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	659	N/A	A phase II clinical trial 	BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab. Responses occurred regardless of EGFR or KRAS mutation status.	The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials.	N/A	N/A	EGFR (P00533); 	EGFR exon 19 insertion	Mutational status	 2017 Aug 20	 Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients  With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer  (BIRCH).	 J Clin Oncol	 Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized  anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced  non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were  selected on the basis of PD-L1 expression on tumor cells (TC) or  tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had   advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior  chemotherapy. Patients whose tumors expressed PD-L1 using the SP142  immunohistochemistry assay on >/= 5% of TC or IC (TC2/3 or IC2/3 [TC or IC >/= 5%  PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was  administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659)  comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n  = 268); and third line or higher (cohort 3; n = 252). The primary end point was  independent review facility-assessed objective response rate (ORR; Response  Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points  included median duration of response, progression-free survival, and overall  survival (OS). Results BIRCH met its primary objective of demonstrating a  significant ORR versus historical controls. With a minimum of 12 months of  follow-up, the independent review facility-assessed ORR was 18% to 22% for the  three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are  ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The  median OS from an updated survival analysis (minimum of 20 month follow up) for  cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in   cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was  similar across cohorts and consistent with previous atezolizumab monotherapy  trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab.
CANIT0001129	28609226	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	659	N/A	A phase II clinical trial 	BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab. Responses occurred regardless of EGFR or KRAS mutation status.	The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials.	N/A	N/A	EGFR (P00533); 	EGFR exon 20 insertion	Mutational status	 2017 Aug 20	 Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients  With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer  (BIRCH).	 J Clin Oncol	 Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized  anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced  non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were  selected on the basis of PD-L1 expression on tumor cells (TC) or  tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had   advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior  chemotherapy. Patients whose tumors expressed PD-L1 using the SP142  immunohistochemistry assay on >/= 5% of TC or IC (TC2/3 or IC2/3 [TC or IC >/= 5%  PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was  administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659)  comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n  = 268); and third line or higher (cohort 3; n = 252). The primary end point was  independent review facility-assessed objective response rate (ORR; Response  Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points  included median duration of response, progression-free survival, and overall  survival (OS). Results BIRCH met its primary objective of demonstrating a  significant ORR versus historical controls. With a minimum of 12 months of  follow-up, the independent review facility-assessed ORR was 18% to 22% for the  three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are  ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The  median OS from an updated survival analysis (minimum of 20 month follow up) for  cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in   cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was  similar across cohorts and consistent with previous atezolizumab monotherapy  trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab.
CANIT0001130	28609226	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	659	N/A	A phase II clinical trial 	BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab. Responses occurred regardless of EGFR or KRAS mutation status.	The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials.	N/A	N/A	EGFR (P00533); 	EGFR G719X mutation	Mutational status	 2017 Aug 20	 Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients  With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer  (BIRCH).	 J Clin Oncol	 Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized  anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced  non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were  selected on the basis of PD-L1 expression on tumor cells (TC) or  tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had   advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior  chemotherapy. Patients whose tumors expressed PD-L1 using the SP142  immunohistochemistry assay on >/= 5% of TC or IC (TC2/3 or IC2/3 [TC or IC >/= 5%  PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was  administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659)  comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n  = 268); and third line or higher (cohort 3; n = 252). The primary end point was  independent review facility-assessed objective response rate (ORR; Response  Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points  included median duration of response, progression-free survival, and overall  survival (OS). Results BIRCH met its primary objective of demonstrating a  significant ORR versus historical controls. With a minimum of 12 months of  follow-up, the independent review facility-assessed ORR was 18% to 22% for the  three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are  ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The  median OS from an updated survival analysis (minimum of 20 month follow up) for  cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in   cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was  similar across cohorts and consistent with previous atezolizumab monotherapy  trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab.
CANIT0001131	28609226	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	659	N/A	A phase II clinical trial 	BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab. Responses occurred regardless of EGFR or KRAS mutation status.	The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials.	N/A	N/A	EGFR (P00533); 	EGFR L858R mutation	Mutational status	 2017 Aug 20	 Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients  With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer  (BIRCH).	 J Clin Oncol	 Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized  anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced  non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were  selected on the basis of PD-L1 expression on tumor cells (TC) or  tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had   advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior  chemotherapy. Patients whose tumors expressed PD-L1 using the SP142  immunohistochemistry assay on >/= 5% of TC or IC (TC2/3 or IC2/3 [TC or IC >/= 5%  PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was  administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659)  comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n  = 268); and third line or higher (cohort 3; n = 252). The primary end point was  independent review facility-assessed objective response rate (ORR; Response  Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points  included median duration of response, progression-free survival, and overall  survival (OS). Results BIRCH met its primary objective of demonstrating a  significant ORR versus historical controls. With a minimum of 12 months of  follow-up, the independent review facility-assessed ORR was 18% to 22% for the  three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are  ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The  median OS from an updated survival analysis (minimum of 20 month follow up) for  cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in   cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was  similar across cohorts and consistent with previous atezolizumab monotherapy  trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab.
CANIT0001132	28609226	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	659	N/A	A phase II clinical trial 	BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab. Responses occurred regardless of EGFR or KRAS mutation status.	The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials.	N/A	N/A	EGFR (P00533); 	EGFR L861Q mutation	Mutational status	 2017 Aug 20	 Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients  With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer  (BIRCH).	 J Clin Oncol	 Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized  anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced  non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were  selected on the basis of PD-L1 expression on tumor cells (TC) or  tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had   advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior  chemotherapy. Patients whose tumors expressed PD-L1 using the SP142  immunohistochemistry assay on >/= 5% of TC or IC (TC2/3 or IC2/3 [TC or IC >/= 5%  PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was  administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659)  comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n  = 268); and third line or higher (cohort 3; n = 252). The primary end point was  independent review facility-assessed objective response rate (ORR; Response  Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points  included median duration of response, progression-free survival, and overall  survival (OS). Results BIRCH met its primary objective of demonstrating a  significant ORR versus historical controls. With a minimum of 12 months of  follow-up, the independent review facility-assessed ORR was 18% to 22% for the  three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are  ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The  median OS from an updated survival analysis (minimum of 20 month follow up) for  cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in   cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was  similar across cohorts and consistent with previous atezolizumab monotherapy  trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab.
CANIT0001133	28609226	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	659	N/A	A phase II clinical trial 	BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab. Responses occurred regardless of EGFR or KRAS mutation status.	The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials.	N/A	N/A	EGFR (P00533); 	EGFR S768I mutation	Mutational status	 2017 Aug 20	 Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients  With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer  (BIRCH).	 J Clin Oncol	 Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized  anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced  non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were  selected on the basis of PD-L1 expression on tumor cells (TC) or  tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had   advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior  chemotherapy. Patients whose tumors expressed PD-L1 using the SP142  immunohistochemistry assay on >/= 5% of TC or IC (TC2/3 or IC2/3 [TC or IC >/= 5%  PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was  administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659)  comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n  = 268); and third line or higher (cohort 3; n = 252). The primary end point was  independent review facility-assessed objective response rate (ORR; Response  Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points  included median duration of response, progression-free survival, and overall  survival (OS). Results BIRCH met its primary objective of demonstrating a  significant ORR versus historical controls. With a minimum of 12 months of  follow-up, the independent review facility-assessed ORR was 18% to 22% for the  three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are  ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The  median OS from an updated survival analysis (minimum of 20 month follow up) for  cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in   cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was  similar across cohorts and consistent with previous atezolizumab monotherapy  trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab.
CANIT0001134	28609226	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	659	N/A	A phase II clinical trial 	BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab. Responses occurred regardless of EGFR or KRAS mutation status.	The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials.	N/A	N/A	KRAS (P01116); 	KRAS expression levels	Gene expression signature on/in tumor cell	 2017 Aug 20	 Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients  With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer  (BIRCH).	 J Clin Oncol	 Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized  anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced  non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were  selected on the basis of PD-L1 expression on tumor cells (TC) or  tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had   advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior  chemotherapy. Patients whose tumors expressed PD-L1 using the SP142  immunohistochemistry assay on >/= 5% of TC or IC (TC2/3 or IC2/3 [TC or IC >/= 5%  PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was  administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659)  comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n  = 268); and third line or higher (cohort 3; n = 252). The primary end point was  independent review facility-assessed objective response rate (ORR; Response  Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points  included median duration of response, progression-free survival, and overall  survival (OS). Results BIRCH met its primary objective of demonstrating a  significant ORR versus historical controls. With a minimum of 12 months of  follow-up, the independent review facility-assessed ORR was 18% to 22% for the  three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are  ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The  median OS from an updated survival analysis (minimum of 20 month follow up) for  cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in   cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was  similar across cohorts and consistent with previous atezolizumab monotherapy  trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in   patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status  may serve as a predictive biomarker for identifying patients most likely to  benefit from atezolizumab.
CANIT0001135	28609832	Clinical research	12 metastatic malignant melanoma, 1 nonCsmall cell lung carcinoma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	93	N/A	A retrospective cohort study	Thyroid dysfunction is common in cancer patients treated with pembrolizumab. Reversible destructive thyroiditis and overt hypothyroidism are the most common clinical presentations. The mechanism of thyroid destruction appears independent of thyroid autoantibodies and may include T cell, NK cell, and/or monocyte-mediated pathways. Because the thyroid is a frequent target of anti-PD-1 therapies, patients with therapeutically refractory thyroid cancer may be ideal candidates for this treatment.	Thirteen (14%) thyroid irAEs were observed. Thyroiditis occurred in seven patients (54%), from which four recovered. New onset of hypothyroidism overt/subclinical developed in three patients. Levothyroxine dosing required doubling in three patients with a known history of hypothyroidism. Thyroperoxidase antibodies were positive in the minority of the patients [4/13 (31%)] and diffuse increased 18fludeoxyglucose uptake of the thyroid gland was observed in the majority [7/11 (64%)] of patients. We observed more circulating CD56+CD16+ natural killer (NK) cells and an elevated HLA-DR surface expression in the inflammatory intermediate CD14+CD16+ monocytes in anti-PD-1-treated patients.	N/A	N/A	Monocyte counts (NCIT:C12547); CD14 (P08571); HLA (P04439); CD16 (P08637); CD56 (P13591); Natural killer-cell immune responses (NCIT:C12536); 	Circulating CD56(+)CD16(+) natural killer (NK) cells	Gene expression signature on/in immune cell	 2017 Aug 1	 Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights  Into Underlying Involved Mechanisms.	 J Clin Endocrinol Metab	 Context: Thyroid immune-related adverse events (irAEs) in patients treated with  programmed death receptor-1 (PD-1) blockade are increasingly recognized as one of  the most common adverse effects. Our aim was to determine the incidence and  examine the potential mechanisms of anti-PD-1-induced thyroid irAEs. Design:  Single-center, retrospective cohort study. Patients and Measurements: We studied   93 patients with advanced cancer (ages 24 to 82 years; 60% males) who received at  least one infusion of pembrolizumab. Thyroid test results and thyroid imaging  modalities were reviewed. Comprehensive 10-color flow cytometry of peripheral  blood was performed. Results: Thirteen (14%) thyroid irAEs were observed.  Thyroiditis occurred in seven patients (54%), from which four recovered. New  onset of hypothyroidism overt/subclinical developed in three patients.  Levothyroxine dosing required doubling in three patients with a known history of   hypothyroidism. Thyroperoxidase antibodies were positive in the minority of the  patients [4/13 (31%)] and diffuse increased 18fludeoxyglucose uptake of the  thyroid gland was observed in the majority [7/11 (64%)] of patients. We observed   more circulating CD56+CD16+ natural killer (NK) cells and an elevated HLA-DR  surface expression in the inflammatory intermediate CD14+CD16+ monocytes in  anti-PD-1-treated patients. Conclusions: Thyroid dysfunction is common in cancer   patients treated with pembrolizumab. Reversible destructive thyroiditis and overt  hypothyroidism are the most common clinical presentations. The mechanism of  thyroid destruction appears independent of thyroid autoantibodies and may include  T cell, NK cell, and/or monocyte-mediated pathways. Because the thyroid is a  frequent target of anti-PD-1 therapies, patients with therapeutically refractory   thyroid cancer may be ideal candidates for this treatment.CI  - Copyright (c) 2017 Endocrine Society
CANIT0001136	28609832	Clinical research	12 metastatic malignant melanoma, 1 nonCsmall cell lung carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	93	N/A	A retrospective cohort study	Thyroid dysfunction is common in cancer patients treated with pembrolizumab. Reversible destructive thyroiditis and overt hypothyroidism are the most common clinical presentations. The mechanism of thyroid destruction appears independent of thyroid autoantibodies and may include T cell, NK cell, and/or monocyte-mediated pathways. Because the thyroid is a frequent target of anti-PD-1 therapies, patients with therapeutically refractory thyroid cancer may be ideal candidates for this treatment.	Thirteen (14%) thyroid irAEs were observed. Thyroiditis occurred in seven patients (54%), from which four recovered. New onset of hypothyroidism overt/subclinical developed in three patients. Levothyroxine dosing required doubling in three patients with a known history of hypothyroidism. Thyroperoxidase antibodies were positive in the minority of the patients [4/13 (31%)] and diffuse increased 18fludeoxyglucose uptake of the thyroid gland was observed in the majority [7/11 (64%)] of patients. We observed more circulating CD56+CD16+ natural killer (NK) cells and an elevated HLA-DR surface expression in the inflammatory intermediate CD14+CD16+ monocytes in anti-PD-1-treated patients.	N/A	N/A	Monocyte counts (NCIT:C12547); CD14 (P08571); HLA (P04439); CD16 (P08637); CD56 (P13591); Natural killer-cell immune responses (NCIT:C12536); 	An elevated HLA-DR surface expression in the inflammatory intermediate CD14(+)CD16(+) monocytes	Gene expression signature on/in immune cell	 2017 Aug 1	 Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights  Into Underlying Involved Mechanisms.	 J Clin Endocrinol Metab	 Context: Thyroid immune-related adverse events (irAEs) in patients treated with  programmed death receptor-1 (PD-1) blockade are increasingly recognized as one of  the most common adverse effects. Our aim was to determine the incidence and  examine the potential mechanisms of anti-PD-1-induced thyroid irAEs. Design:  Single-center, retrospective cohort study. Patients and Measurements: We studied   93 patients with advanced cancer (ages 24 to 82 years; 60% males) who received at  least one infusion of pembrolizumab. Thyroid test results and thyroid imaging  modalities were reviewed. Comprehensive 10-color flow cytometry of peripheral  blood was performed. Results: Thirteen (14%) thyroid irAEs were observed.  Thyroiditis occurred in seven patients (54%), from which four recovered. New  onset of hypothyroidism overt/subclinical developed in three patients.  Levothyroxine dosing required doubling in three patients with a known history of   hypothyroidism. Thyroperoxidase antibodies were positive in the minority of the  patients [4/13 (31%)] and diffuse increased 18fludeoxyglucose uptake of the  thyroid gland was observed in the majority [7/11 (64%)] of patients. We observed   more circulating CD56+CD16+ natural killer (NK) cells and an elevated HLA-DR  surface expression in the inflammatory intermediate CD14+CD16+ monocytes in  anti-PD-1-treated patients. Conclusions: Thyroid dysfunction is common in cancer   patients treated with pembrolizumab. Reversible destructive thyroiditis and overt  hypothyroidism are the most common clinical presentations. The mechanism of  thyroid destruction appears independent of thyroid autoantibodies and may include  T cell, NK cell, and/or monocyte-mediated pathways. Because the thyroid is a  frequent target of anti-PD-1 therapies, patients with therapeutically refractory   thyroid cancer may be ideal candidates for this treatment.CI  - Copyright (c) 2017 Endocrine Society
CANIT0001137	28614096	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	2	N/A	Case	N/A	Aseptic sinusitis	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Two Cases of Sinusitis Induced by Immune Checkpoint Inhibition.	 J Immunother	 We report the acute onset of aseptic sinusitis in 2 patients receiving the immune  checkpoint inhibitors, ipilimumab and nivolumab, for treatment of metastatic  melanoma. Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte  antigen-4, and nivolumab, targeting programmed cell death-1, have been associated  with numerous immune-related adverse events. To the authors' knowledge, this is  the first report of aseptic sinusitis as a consequence of immune checkpoint  inhibition therapy.
CANIT0001138	28619747	Case report	Advanced stage microsatellite-unstable biliary tract cancer	Biliary tract cancer	MONDO:0003060	Bilie duct	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Strong and durable response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Successful immune checkpoint blockade in a patient with advanced stage  microsatellite-unstable biliary tract cancer.	 Cold Spring Harb Mol Case Stud	 Cancers acquire multiple somatic mutations that can lead to the generation of  immunogenic mutation-induced neoantigens. These neoantigens can be recognized by   the host's immune system. However, continuous stimulation of immune cells against  tumor antigens can lead to immune cell exhaustion, which allows uncontrolled  outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as   a novel approach to overcome immune cell exhaustion and reactivate antitumor  immune responses. In particular, antibodies blocking the exhaustion-mediating  programmed death receptor (PD-1)/programmed death receptor ligand (PD-L1) pathway  have shown clinical efficacy. The effects were particularly pronounced in tumors   with DNA mismatch repair (MMR) deficiency and a high mutational load, which  typically occur in the colon and endometrium. Here, we report on a 24-yr-old  woman diagnosed with extrahepatic cholangiocarcinoma who showed strong and  durable response to the immune checkpoint inhibitor pembrolizumab, although  treatment was initiated at an advanced stage of disease. The patient's tumor  displayed DNA MMR deficiency and microsatellite instability (MSI) but lacked  other features commonly discussed as predictors of response toward checkpoint  blockade, such as PD-L1 expression or dense infiltration with cytotoxic T cells.   Notably, high levels of HLA class I and II antigen expression were detected in  the tumor, suggesting a potential causal relation between functionality of the  tumor's antigen presentation machinery and the success of immune checkpoint  blockade. We suggest determining MSI status in combination with HLA class I and  II antigen expression in tumors potentially eligible for immune checkpoint  blockade even in the absence of conventional markers predictive for  anti-PD-1/PD-L1 therapy and in entities not commonly linked to the MSI phenotype.  Further studies are required to determine the value of these markers for  predicting the success of immune checkpoint blockade.CI  - (c) 2017 Czink et al.; Published by Cold Spring Harbor Laboratory Press.
CANIT0001139	28619999	Clinical research	Head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	172	N/A	N/A	Clinical response to pembrolizumab in  patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L2 (Q9BQ51); 	PD-L2 expression levels	Gene expression signature on/in tumor cell	 2017 Jun 15	 PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer.	 Clin Cancer Res	 Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to   PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to  PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to  the clinical activity of these therapies. The prevalence of PD-L2, the other  known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were   evaluated.Experimental Design: PD-L2 expression was assessed in archival tumor  tissue from seven indications using a novel immunohistochemical assay. In  addition, relationships between clinical response and PD-L2 status were evaluated  in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC)  with recurrent or metastatic disease, treated with pembrolizumab.Results: PD-L2  expression was observed in all tumor types and present in stromal, tumor, and  endothelial cells. The prevalence and distribution of PD-L2 correlated  significantly with PD-L1 (P = 0.0012-<0.0001); however, PD-L2 was detected in the  absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity  significantly predicted clinical response to pembrolizumab on combined tumor,  stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response  was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those  positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of  progression-free survival (PFS) with pembrolizumab independent of PD-L1 status.  Longer median times for PFS and overall survival were observed for PD-L2-positive  than PD-L2-negative patients.Conclusions: Clinical response to pembrolizumab in  patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions.  Therapy targeting both PD-1 ligands may provide clinical benefit in these  patients. Clin Cancer Res; 23(12); 3158-67. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001140	28625652	Case report	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Symptomatic leptomeningeal metastasis improvement	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jun	 Symptomatic leptomeningeal metastasis improvement with nivolumab in advanced  non-small cell lung cancer patient.	 Lung Cancer	 Leptomeningeal metastasis (LM) is reported in 3.8% of non-small-cell lung cancer   (NSCLC) patients, more frequently in adenocarcinoma, and it correlates with poor   prognosis. Data regarding the activity of immune checkpoint inhibitors in LM is  lacking. We present a case report about the efficacy of nivolumab in a patient  with advanced NSCLC and symptomatic LM.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001141	28625691	Case report	Locally advanced castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Remarkable response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 A Case of Locally Advanced Castration-resistant Prostate Cancer With Remarkable  Response to Nivolumab.	 Clin Genitourin Cancer	Unable to provide
CANIT0001142	28628690	Case report	Multiple keratoacanthomas and squamous cell carcinomas	Multiple keratoacanthoma, ferguson-smith type	Orphanet:65748	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We describe a case of an 84 year old female with stage 4 metastatic melanoma in a trial of the PD-1 inhibitor pembrolizumab who developed multiple keratoacanthomas after several months of treatment. While keratoacanthomas have been reported in patients taking BRAF inhibitors, no such reports exist for those on pembrolizumab, making this the first case report to point out this association for further investigative studies.	Developed multiple keratoacanthomas after several months of treatment	N/A	N/A	N/A	N/A	N/A	 2017 May 1	 Case Report of Multiple Keratoacanthomas and Squamous Cell Carcinomas in a  Patient Receiving Pembrolizumab.	 J Drugs Dermatol	Unable to provide
CANIT0001143	28628690	Case report	Multiple keratoacanthomas and squamous cell carcinomas	Multiple keratoacanthoma, ferguson-smith type	Orphanet:65748	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We describe a case of an 84 year old female with stage 4 metastatic melanoma in a trial of the PD-1 inhibitor pembrolizumab who developed multiple keratoacanthomas after several months of treatment. While keratoacanthomas have been reported in patients taking BRAF inhibitors, no such reports exist for those on pembrolizumab, making this the first case report to point out this association for further investigative studies.	Developed multiple keratoacanthomas after several months of treatment	N/A	N/A	N/A	N/A	N/A	 2017 May 1	 Case Report of Multiple Keratoacanthomas and Squamous Cell Carcinomas in a  Patient Receiving Pembrolizumab.	 J Drugs Dermatol	Unable to provide
CANIT0001144	28629548	Case report	Lung squamous cell carcinoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Idiopathic pulmonary fibrosis	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 A Case of a Patient with Idiopathic Pulmonary Fibrosis with Lung Squamous Cell  Carcinoma Treated with Nivolumab.	 J Thorac Oncol	Unable to provide
CANIT0001145	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001146	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Head and neck carcinoma	MONDO:0002038	Head and neck	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001147	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001148	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001149	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Pancreatic carcinoma	EFO:0002618	Pancreas	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001150	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001151	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001152	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001153	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Thymic cancer	MONDO:0002586	Thymus	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001154	28634283	Clinical research	Non-small cell lung carcinoma, Head and neck cancer, renal cell carcinoma, Pancreatic cancer, Thyroid cancer, small cell lung carcinoma, colorectal cancer, Sarcoma, Thymic cancer, Melanoma	Thyroid cancer	MONDO:0002108	Thyroid	PD-1 (Q15116); CD137 (Q07011); 	PD-1; CD137	Pembrolizumab plus utomilumab	N/A	Immune checkpoint therapy plus Target therapy	Utomilumab (DB15113); pembrolizumab (DB09037); 	23	N/A	A phase Ib clinical trial	The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors.	Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination  with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors.	 Clin Cancer Res	 Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor  activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human  IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination   with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with  advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and  pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab  dose escalation was conducted using the time-to-event continual reassessment  method.Results: Twenty-three patients received combination treatment with no  dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1   to 2, without any treatment-related discontinuations. Six patients (26.1%) had  confirmed complete or partial responses. Pharmacokinetics and immunogenicity of  utomilumab and pembrolizumab were similar when administered alone or in  combination. A trend toward higher levels of activated memory/effector peripheral  blood CD8(+) T cells was observed in responders versus nonresponders.Conclusions:  The safety, tolerability, and clinical activity demonstrated by utomilumab in  combination with pembrolizumab support further investigation in patients with  advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related   commentary by Perez-Ruiz et al., p. 5326.CI  - (c)2017 American Association for Cancer Research.
CANIT0001155	28639409	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	4	N/A	A retrospective cohort study	Patients with multiple organ metastases and elevated serum lactate dehydrogenase   did not respond well to treatment. 	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2017 Jul	 Anti-PD-1 antibodies in metastatic uveal melanoma: a treatment option 	 Cancer Med	 Uveal melanomas (UMs) are a rare form of cancer with clinical and pathological  characteristics distinct from cutaneous melanomas. Ipilimumab has shown efficacy   and safety in the treatment of metastatic UM. This provides a rationale for  treatment with other immune checkpoint inhibitors. This is a retrospective review  of 15 patients with metastatic UM treated between June 2014 and February 2016,  who received treatment with the anti-PD-1 Abs pembrolizumab or nivolumab.  Patients were treated at two German university hospitals. Therapy was  administered at the approved dosing schedules of 2 mg/kg q3w for pembrolizumab  and 3 mg/kg q2w for nivolumab. Treatment was given until first tumor assessment  and continued if tumor assessment showed disease control. Tumor assessments were   performed at baseline and following scans every 12 weeks. Patients were monitored  throughout for adverse events. Best response to treatment was stable disease in  four patients. Eight out of 15 (53%) patients received treatment until first  tumor assessment. As of February 2016, median progression-free survival (PFS) is   3 months (range 0.75-6.75 months) and overall survival (OS) is 5 months (range  1-16 months). Eight out of 15 (53%) patients are still alive (two patients lost  to follow-up) with one out of four patients is in ongoing disease control.  Patients with multiple organ metastases and elevated serum lactate dehydrogenase   did not respond well to treatment. No objective response to PD-1 Ab therapy was  seen. Best response to treatment was stable disease in four patients. Treatment  was well tolerated with manageable toxicity.CI  - (c) 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0001156	28639409	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	11	N/A	A retrospective cohort study	Patients with multiple organ metastases and elevated serum lactate dehydrogenase   did not respond well to treatment. 	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Organ metastasis	Disease status	 2017 Jul	 Anti-PD-1 antibodies in metastatic uveal melanoma: a treatment option 	 Cancer Med	 Uveal melanomas (UMs) are a rare form of cancer with clinical and pathological  characteristics distinct from cutaneous melanomas. Ipilimumab has shown efficacy   and safety in the treatment of metastatic UM. This provides a rationale for  treatment with other immune checkpoint inhibitors. This is a retrospective review  of 15 patients with metastatic UM treated between June 2014 and February 2016,  who received treatment with the anti-PD-1 Abs pembrolizumab or nivolumab.  Patients were treated at two German university hospitals. Therapy was  administered at the approved dosing schedules of 2 mg/kg q3w for pembrolizumab  and 3 mg/kg q2w for nivolumab. Treatment was given until first tumor assessment  and continued if tumor assessment showed disease control. Tumor assessments were   performed at baseline and following scans every 12 weeks. Patients were monitored  throughout for adverse events. Best response to treatment was stable disease in  four patients. Eight out of 15 (53%) patients received treatment until first  tumor assessment. As of February 2016, median progression-free survival (PFS) is   3 months (range 0.75-6.75 months) and overall survival (OS) is 5 months (range  1-16 months). Eight out of 15 (53%) patients are still alive (two patients lost  to follow-up) with one out of four patients is in ongoing disease control.  Patients with multiple organ metastases and elevated serum lactate dehydrogenase   did not respond well to treatment. No objective response to PD-1 Ab therapy was  seen. Best response to treatment was stable disease in four patients. Treatment  was well tolerated with manageable toxicity.CI  - (c) 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
CANIT0001157	28642818	Case report	HIV-related relapsed/refractory Hodgkin lymphoma and liver failure with encephalopathy	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Successfully treated with nivolumab without major side effects and encouraging prolonged disease control.	N/A	N/A	N/A	N/A	N/A	N/A	2017	 Nivolumab as salvage treatment in a patient with HIV-related relapsed/refractory   Hodgkin lymphoma and liver failure with encephalopathy.	 J Immunother Cancer	 BACKGROUND: We report the first case to our knowledge of a patient with  relapsed/refractory classical hodgkin lymphoma and liver failure with  encephalopathy along with human immunodeficiency virus/acquired immunodeficiency   syndrome infection, successfully treated with nivolumab without major side  effects and encouraging prolonged disease control. CASE PRESENTATION: In December  2015, at the time of the patient's progression from his Hodgkin lymphoma after  fourth line treatment, he developed persistent fevers, abdominal distension,  jaundice and worsening of his liver function tests. Magnetic resonance imaging of  abdomen/pelvis demonstrated hepatomegaly with innumerable new liver lesions,  splenomegaly with multiple splenic nodules and several new mediastinal,  intraperitoneal and retroperitoneal lymphadenopathy. In accordance with the  patient's wishes before admission, and after agreement with the family, nivolumab  (3 mg/kg every 2 weeks) was given. Of note, antiretroviral therapy was on hold  due to liver function tests, his viral load was undectable and cluster of  differentiation 4 counts were 103/uL at the time of nivolumab administration. One  week after the first dose of nivolumab both his hepatic encephalopathy and  constitutional symptoms started to improve, and after 2 doses, (January 2016) his  LFTs were almost back to normal. After 5 months of nivolumab treatment (10  doses), restaging (computerized tomography scans of neck, chest, abdomen, pelvis)  done on May 2016 showed resolution of hepatosplenomegaly with two residual small   hepatic lesions, heterogeneous spleen with no splenic lesions, and stable  non-enlarged retroperitoneal lymph nodes without intraabdominal lymphadenopathy;   consistent with partial response. CONCLUSIONS: We report a case of a patient with  human immunodeficiency virus/acquired immunodeficiency syndrome -related  relapsed/refractory classical Hodgkin lymphoma and acute liver failure with  encephalopathy successfully treated with nivolumab after failing all standard  therapeutic options. Unlike classic cytotoxic chemotherapy, which relies on  preserved organ function to ameliorate potential severe side effects (i.e.  myelosuppression), elimination of monoclonal antibodies is fairly independent of   baseline renal and hepatic function since they are usually metabolized by  circulating phagocytes and/or by their target antigen-expressing cell.
CANIT0001158	28643391	Case report	Refractory, metastatic hepatocellular carcinoma	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Fatal orthotopic liver transplant organ rejection	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Fatal orthotopic liver transplant organ rejection induced by a checkpoint  inhibitor in two patients with refractory, metastatic hepatocellular carcinoma.	 Pediatr Blood Cancer	 Although checkpoint inhibitor therapies have demonstrated significant efficacy in  many malignancies, they have not been well studied in patients with a history of   solid organ transplant. We describe two patients with recurrent, refractory, and   progressive advanced fibrolamellar hepatocellular carcinoma (HCC) following  orthotopic liver transplantation who received programmed cell death protein 1  (PD-1) inhibitor, nivolumab, on a patient access, off-label basis. Both rapidly  developed irreversible acute liver rejection shortly after starting therapy, and   ultimately died. While checkpoint inhibitors clearly have tremendous potential as  a targeted therapy, they should be avoided or used with extreme caution in the  context of an organ transplant.CI  - (c) 2017 Wiley Periodicals, Inc.
CANIT0001159	28648302	Case report	Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Following his second dose, he developed nephrotic syndrome and acute kidney injury. Biopsy showed diffuse foot-process effacement consistent with minimal change disease and findings of acute tubular injury. Pembrolizumab therapy cessation and corticosteroid treatment yielded improvement in proteinuria and acute kidney injury.	Nephrotic Syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Nephrotic Syndrome With Cancer Immunotherapies: A Report of 2 Cases.	 Am J Kidney Dis	 Oncologic immunotherapies use a patient's immune response to eliminate tumor  cells by modulation of immune checkpoints, including programmed cell death 1  (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) proteins.  Immune-mediated sequelae, including interstitial nephritis, have been reported;  however, glomerular disease appears rare. We describe 2 cases of nephrotic  syndrome in patients treated with these agents. Patient 1 received the anti-PD-1   antibody pembrolizumab for Hodgkin lymphoma. Following his second dose, he  developed nephrotic syndrome and acute kidney injury. Biopsy showed diffuse  foot-process effacement consistent with minimal change disease and findings of  acute tubular injury. Pembrolizumab therapy cessation and corticosteroid  treatment yielded improvement in proteinuria and acute kidney injury. Patient 2  received the CTLA-4 antibody ipilimumab for melanoma. He developed nephrotic  syndrome with biopsy changes consistent with minimal change disease. Ipilimumab  therapy was stopped and proteinuria resolved following corticosteroid treatment.   Ipilimumab rechallenge caused relapse of nephrotic-range proteinuria. These cases  suggest an association between therapeutic immune activation and the development   of nephrotic syndrome. Given the increasing prevalence of oncologic  immunotherapies, monitoring patients for renal sequelae is warranted.CI  - Copyright (c) 2017 National Kidney Foundation, Inc. Published by Elsevier Inc.  All rights reserved.
CANIT0001160	28648302	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	He developed nephrotic syndrome with biopsy changes consistent with minimal change disease. Ipilimumab therapy was stopped and proteinuria resolved following corticosteroid treatment. Ipilimumab rechallenge caused relapse of nephrotic-range proteinuria.	Nephrotic Syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Nephrotic Syndrome With Cancer Immunotherapies: A Report of 2 Cases.	 Am J Kidney Dis	 Oncologic immunotherapies use a patient's immune response to eliminate tumor  cells by modulation of immune checkpoints, including programmed cell death 1  (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) proteins.  Immune-mediated sequelae, including interstitial nephritis, have been reported;  however, glomerular disease appears rare. We describe 2 cases of nephrotic  syndrome in patients treated with these agents. Patient 1 received the anti-PD-1   antibody pembrolizumab for Hodgkin lymphoma. Following his second dose, he  developed nephrotic syndrome and acute kidney injury. Biopsy showed diffuse  foot-process effacement consistent with minimal change disease and findings of  acute tubular injury. Pembrolizumab therapy cessation and corticosteroid  treatment yielded improvement in proteinuria and acute kidney injury. Patient 2  received the CTLA-4 antibody ipilimumab for melanoma. He developed nephrotic  syndrome with biopsy changes consistent with minimal change disease. Ipilimumab  therapy was stopped and proteinuria resolved following corticosteroid treatment.   Ipilimumab rechallenge caused relapse of nephrotic-range proteinuria. These cases  suggest an association between therapeutic immune activation and the development   of nephrotic syndrome. Given the increasing prevalence of oncologic  immunotherapies, monitoring patients for renal sequelae is warranted.CI  - Copyright (c) 2017 National Kidney Foundation, Inc. Published by Elsevier Inc.  All rights reserved.
CANIT0001161	28648699	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Ivolumab (DB09035); 	86	N/A	N/A	Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2017 Sep	 Prognostic factors and outcomes in metastatic uveal melanoma treated with  programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4  inhibition.	 Eur J Cancer	 BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for  metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet  shown convincing efficacy in patients with UM. Combined immune checkpoint  blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic   T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed  for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with  either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an  anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer  centres. Records from 96 cases were analysed for treatment outcomes. Clinical and  blood parameters associated with overall survival (OS) or treatment response were  identified with multivariate Cox regression and binary logistic regression.  RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for  pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of   4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for  nivolumab-treated patients (p = 0.765). Fifteen patients were treated with  combined immune checkpoint blockade with partial response observed in two cases.   Median OS was not reached in this group. Multivariate Cox regression identified  Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002),  elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive  protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p =  0.002) as independent risk factors for poor survival. Patients with elevated CRP   and LDH and a REC <1.5% were at highest risk for disease progression and death (p  = 0.001). CONCLUSIONS: Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001162	28648699	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	86	N/A	N/A	Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2017 Sep	 Prognostic factors and outcomes in metastatic uveal melanoma treated with  programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4  inhibition.	 Eur J Cancer	 BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for  metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet  shown convincing efficacy in patients with UM. Combined immune checkpoint  blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic   T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed  for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with  either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an  anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer  centres. Records from 96 cases were analysed for treatment outcomes. Clinical and  blood parameters associated with overall survival (OS) or treatment response were  identified with multivariate Cox regression and binary logistic regression.  RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for  pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of   4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for  nivolumab-treated patients (p = 0.765). Fifteen patients were treated with  combined immune checkpoint blockade with partial response observed in two cases.   Median OS was not reached in this group. Multivariate Cox regression identified  Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002),  elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive  protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p =  0.002) as independent risk factors for poor survival. Patients with elevated CRP   and LDH and a REC <1.5% were at highest risk for disease progression and death (p  = 0.001). CONCLUSIONS: Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001163	28648699	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Ivolumab (DB09035); 	86	N/A	N/A	Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.	N/A	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Relative eosinophil counts	Cell percentage/counts in blood	 2017 Sep	 Prognostic factors and outcomes in metastatic uveal melanoma treated with  programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4  inhibition.	 Eur J Cancer	 BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for  metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet  shown convincing efficacy in patients with UM. Combined immune checkpoint  blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic   T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed  for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with  either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an  anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer  centres. Records from 96 cases were analysed for treatment outcomes. Clinical and  blood parameters associated with overall survival (OS) or treatment response were  identified with multivariate Cox regression and binary logistic regression.  RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for  pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of   4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for  nivolumab-treated patients (p = 0.765). Fifteen patients were treated with  combined immune checkpoint blockade with partial response observed in two cases.   Median OS was not reached in this group. Multivariate Cox regression identified  Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002),  elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive  protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p =  0.002) as independent risk factors for poor survival. Patients with elevated CRP   and LDH and a REC <1.5% were at highest risk for disease progression and death (p  = 0.001). CONCLUSIONS: Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001164	28648699	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	86	N/A	N/A	Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.	N/A	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Relative eosinophil counts	Cell percentage/counts in blood	 2017 Sep	 Prognostic factors and outcomes in metastatic uveal melanoma treated with  programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4  inhibition.	 Eur J Cancer	 BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for  metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet  shown convincing efficacy in patients with UM. Combined immune checkpoint  blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic   T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed  for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with  either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an  anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer  centres. Records from 96 cases were analysed for treatment outcomes. Clinical and  blood parameters associated with overall survival (OS) or treatment response were  identified with multivariate Cox regression and binary logistic regression.  RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for  pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of   4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for  nivolumab-treated patients (p = 0.765). Fifteen patients were treated with  combined immune checkpoint blockade with partial response observed in two cases.   Median OS was not reached in this group. Multivariate Cox regression identified  Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002),  elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive  protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p =  0.002) as independent risk factors for poor survival. Patients with elevated CRP   and LDH and a REC <1.5% were at highest risk for disease progression and death (p  = 0.001). CONCLUSIONS: Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001165	28648699	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Ivolumab (DB09035); 	86	N/A	N/A	Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2017 Sep	 Prognostic factors and outcomes in metastatic uveal melanoma treated with  programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4  inhibition.	 Eur J Cancer	 BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for  metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet  shown convincing efficacy in patients with UM. Combined immune checkpoint  blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic   T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed  for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with  either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an  anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer  centres. Records from 96 cases were analysed for treatment outcomes. Clinical and  blood parameters associated with overall survival (OS) or treatment response were  identified with multivariate Cox regression and binary logistic regression.  RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for  pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of   4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for  nivolumab-treated patients (p = 0.765). Fifteen patients were treated with  combined immune checkpoint blockade with partial response observed in two cases.   Median OS was not reached in this group. Multivariate Cox regression identified  Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002),  elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive  protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p =  0.002) as independent risk factors for poor survival. Patients with elevated CRP   and LDH and a REC <1.5% were at highest risk for disease progression and death (p  = 0.001). CONCLUSIONS: Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001166	28648699	Clinical research	Metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	86	N/A	N/A	Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2017 Sep	 Prognostic factors and outcomes in metastatic uveal melanoma treated with  programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4  inhibition.	 Eur J Cancer	 BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for  metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet  shown convincing efficacy in patients with UM. Combined immune checkpoint  blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic   T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed  for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with  either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an  anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer  centres. Records from 96 cases were analysed for treatment outcomes. Clinical and  blood parameters associated with overall survival (OS) or treatment response were  identified with multivariate Cox regression and binary logistic regression.  RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for  pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of   4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for  nivolumab-treated patients (p = 0.765). Fifteen patients were treated with  combined immune checkpoint blockade with partial response observed in two cases.   Median OS was not reached in this group. Multivariate Cox regression identified  Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002),  elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive  protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p =  0.002) as independent risk factors for poor survival. Patients with elevated CRP   and LDH and a REC <1.5% were at highest risk for disease progression and death (p  = 0.001). CONCLUSIONS: Blood markers predict survival in metastatic UM treated  with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high  REC may help identify patients with better prognosis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001167	28649876	Case report	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Myasthenia gravis	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Myasthenia gravis induced by nivolumab in patients with non-small-cell lung  cancer: a case report and literature review.	 Immunotherapy	 A 76-year-old woman who was diagnosed with non-small-cell lung cancer presented  with left eyelid ptosis and grade 4 creatine phosphokinase elevation after the  second cycle of nivolumab monotherapy. Nivolumab has demonstrated promising  efficacy in patients with non-small-cell lung cancer in several trials. Dyspnea  and muscle weakness developed rapidly with an acute exacerbation. She underwent  plasmapheresis and intravenous immune globulin followed by treatment with  low-dose prednisolone. She had gradual symptoms improvement. We diagnosed her  with myasthenia gravis (MG) based on her symptoms and the detection of  anti-acetylcholine receptor antibody. According to postmarketing surveillance in   15,740 Japanese patients, the total incidence rate of MG is 0.1%. We report a  rare case of drug-induced MG in a patient receiving nivolumab.
CANIT0001168	28650338	Clinical research	62 melanoma, 43 HNSCC, 34 gastric cancer etc.	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	220	N/A	N/A	We identified  immune-related signatures correlating with clinical benefit using a  learn-and-confirm paradigm based on data from different clinical studies of  pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually  defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers.  Predictive value was independently confirmed and compared with that of PD-L1  immunohistochemistry in 96 patients with head and neck squamous cell carcinoma.  The T cell-inflamed GEP contained IFNG-responsive genes related to antigen  presentation, chemokine expression, cytotoxic activity, and adaptive immune  resistance, and these features were necessary, but not always sufficient, for  clinical benefit. 	N/A	N/A	N/A	IFNG (P01579); 	IFNG-response gene expression signatures	Gene expression signature on/in tumor cell	 2017 Aug 1	 IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade.	 J Clin Invest	 Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in  durable antitumor activity in many advanced malignancies. Recent studies suggest   that IFNG is a critical driver of programmed death ligand-1 (PD-L1)  expression in cancer and host cells, and baseline intratumoral T cell  infiltration may improve response likelihood to anti-PD-1 therapies, including  pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a  useful pan-tumor determinant of PD-1-directed therapy response has not been  rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA  from baseline tumor samples of pembrolizumab-treated patients. We identified  immune-related signatures correlating with clinical benefit using a  learn-and-confirm paradigm based on data from different clinical studies of  pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually  defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers.  Predictive value was independently confirmed and compared with that of PD-L1  immunohistochemistry in 96 patients with head and neck squamous cell carcinoma.  The T cell-inflamed GEP contained IFN-gamma-responsive genes related to antigen  presentation, chemokine expression, cytotoxic activity, and adaptive immune  resistance, and these features were necessary, but not always sufficient, for  clinical benefit. The T cell-inflamed GEP has been developed into a  clinical-grade assay that is currently being evaluated in ongoing pembrolizumab  trials.
CANIT0001169	28650338	Clinical research	62 melanoma, 43 HNSCC, 34 gastric cancer etc.	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	220	N/A	N/A	We identified  immune-related signatures correlating with clinical benefit using a  learn-and-confirm paradigm based on data from different clinical studies of  pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually  defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers.  Predictive value was independently confirmed and compared with that of PD-L1  immunohistochemistry in 96 patients with head and neck squamous cell carcinoma.  The T cell-inflamed GEP contained IFNG-responsive genes related to antigen  presentation, chemokine expression, cytotoxic activity, and adaptive immune  resistance, and these features were necessary, but not always sufficient, for  clinical benefit. 	N/A	N/A	N/A	IFNG (P01579); 	IFNG-response gene expression signatures	Gene expression signature on/in tumor cell	 2017 Aug 1	 IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade.	 J Clin Invest	 Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in  durable antitumor activity in many advanced malignancies. Recent studies suggest   that IFNG is a critical driver of programmed death ligand-1 (PD-L1)  expression in cancer and host cells, and baseline intratumoral T cell  infiltration may improve response likelihood to anti-PD-1 therapies, including  pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a  useful pan-tumor determinant of PD-1-directed therapy response has not been  rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA  from baseline tumor samples of pembrolizumab-treated patients. We identified  immune-related signatures correlating with clinical benefit using a  learn-and-confirm paradigm based on data from different clinical studies of  pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually  defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers.  Predictive value was independently confirmed and compared with that of PD-L1  immunohistochemistry in 96 patients with head and neck squamous cell carcinoma.  The T cell-inflamed GEP contained IFN-gamma-responsive genes related to antigen  presentation, chemokine expression, cytotoxic activity, and adaptive immune  resistance, and these features were necessary, but not always sufficient, for  clinical benefit. The T cell-inflamed GEP has been developed into a  clinical-grade assay that is currently being evaluated in ongoing pembrolizumab  trials.
CANIT0001170	28650338	Clinical research	62 melanoma, 43 HNSCC, 34 gastric cancer etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	220	N/A	N/A	We identified  immune-related signatures correlating with clinical benefit using a  learn-and-confirm paradigm based on data from different clinical studies of  pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually  defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers.  Predictive value was independently confirmed and compared with that of PD-L1  immunohistochemistry in 96 patients with head and neck squamous cell carcinoma.  The T cell-inflamed GEP contained IFNG-responsive genes related to antigen  presentation, chemokine expression, cytotoxic activity, and adaptive immune  resistance, and these features were necessary, but not always sufficient, for  clinical benefit. 	N/A	N/A	N/A	IFNG (P01579); 	IFNG-response gene expression signatures	Gene expression signature on/in tumor cell	 2017 Aug 1	 IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade.	 J Clin Invest	 Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in  durable antitumor activity in many advanced malignancies. Recent studies suggest   that IFNG is a critical driver of programmed death ligand-1 (PD-L1)  expression in cancer and host cells, and baseline intratumoral T cell  infiltration may improve response likelihood to anti-PD-1 therapies, including  pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a  useful pan-tumor determinant of PD-1-directed therapy response has not been  rigorously evaluated. Here, we analyzed gene expression profiles (GEPs) using RNA  from baseline tumor samples of pembrolizumab-treated patients. We identified  immune-related signatures correlating with clinical benefit using a  learn-and-confirm paradigm based on data from different clinical studies of  pembrolizumab, starting with a small pilot of 19 melanoma patients and eventually  defining a pan-tumor T cell-inflamed GEP in 220 patients with 9 cancers.  Predictive value was independently confirmed and compared with that of PD-L1  immunohistochemistry in 96 patients with head and neck squamous cell carcinoma.  The T cell-inflamed GEP contained IFN-gamma-responsive genes related to antigen  presentation, chemokine expression, cytotoxic activity, and adaptive immune  resistance, and these features were necessary, but not always sufficient, for  clinical benefit. The T cell-inflamed GEP has been developed into a  clinical-grade assay that is currently being evaluated in ongoing pembrolizumab  trials.
CANIT0001171	28651929	Clinical research	Platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	Chemotherapy	Immune checkpoint therapy	Chemotherapy (NCIT:C15632); nivolumab (DB09035); 	240	121	A international, phase III, randomised, open-label study	In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug	 Nivolumab versus standard, single-agent therapy of investigator's choice in  recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate  141): health-related quality-of-life results from a randomised, phase 3 trial.	 Lancet Oncol	 BACKGROUND: Patients with platinum-refractory recurrent or metastatic squamous  cell carcinoma of the head and neck have few treatment options and poor  prognosis. Nivolumab significantly improved survival of this patient population  when compared with standard single-agent therapy of investigator's choice in  Checkmate 141; here we report the effect of nivolumab on patient-reported  outcomes (PROs). METHODS: CheckMate 141 was a randomised, open-label, phase 3  trial in patients with recurrent or metastatic squamous cell carcinoma of the  head and neck who progressed within 6 months after platinum-based chemotherapy.  Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240)   or investigator's choice (n=121) of methotrexate (40-60 mg/m(2) of body surface  area), docetaxel (30-40 mg/m(2)), or cetuximab (250 mg/m(2) after a loading dose   of 400 mg/m(2)) until disease progression, intolerable toxicity, or withdrawal of  consent. On Jan 26, 2016, the independent data monitoring committee reviewed the   data at the planned interim analysis and declared overall survival superiority  for nivolumab over investigator's choice therapy (primary endpoint; described  previously). The protocol was amended to allow patients in the investigator's  choice group to cross over to nivolumab. All patients not on active therapy are  being followed for survival. As an exploratory endpoint, PROs were assessed at  baseline, week 9, and every 6 weeks thereafter using the European Organisation  for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core  30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35),  and the three-level European Quality of Life-5 Dimensions (EQ-5D) questionnaire.   Differences within and between treatment groups in PROs were analysed by ANCOVA  among patients with baseline and at least one other assessment. All randomised  patients were included in the time to clinically meaningful deterioration  analyses. Median time to clinically meaningful deterioration was analysed by  Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org,  number NCT02105636. FINDINGS: Patients were enrolled between May 29, 2014, and  July 31, 2015, and subsequently 361 patients were randomly assigned to receive  nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93   in the nivolumab group and 36 in the investigator's choice group) completed any  of the PRO questionnaires at baseline and at least one other assessment.  Treatment with nivolumab resulted in adjusted mean changes from baseline to week   15 ranging from -2.1 to 5.4 across functional and symptom domains measured by the  EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By  contrast, eight (53%) of the 15 domains in the investigator's choice group showed  clinically meaningful deterioration (10 points or more) at week 15 (change from  baseline range, -24.5 to 2.4). Similarly, on the EORTC QLQ-H&N35, clinically  meaningful worsening at week 15 was seen in no domains in the nivolumab group and  eight (44%) of 18 domains in the investigator's choice group. Patients in the  nivolumab group had a clinically meaningful improvement (according to a  difference of 7 points or greater) in adjusted mean change from baseline to week   15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful  deterioration in the investigator's choice group (7.3 vs -7.8). Differences  between groups were significant and clinically meaningful at weeks 9 and 15 in  favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea,   and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC  QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab  versus investigator's choice for 13 (37%) of 35 domains assessed across the three  questionnaires. INTERPRETATION: In this exploratory analysis of CheckMate 141,  nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15,  whereas investigator's choice led to clinically meaningful deterioration.  Nivolumab delayed time to deterioration of patient-reported quality-of-life  outcomes compared with single-agent therapy of investigator's choice in patients   with platinum-refractory recurrent or metastatic squamous cell carcinoma of the  head and neck. In view of the major unmet need in this population and the  importance of maintaining or improving quality of life for patients with  recurrent or metastatic squamous cell carcinoma of the head and neck, these data   support nivolumab as a new standard-of-care option in this setting. FUNDING:  Bristol-Myers Squibb.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001172	28652280	Clinical research	Head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma.	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	160	N/A	A retrospective cohort study	We demonstrate several positive associations between the development of immune-related adverse events and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Oct	 Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated  with Programmed Cell Death 1 Inhibitors.	 Oncologist	 BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead  to immune-related adverse events (irAEs). We sought to evaluate whether the  development of irAEs correlates with treatment response in non-melanoma  malignancies. MATERIALS AND METHODS: We conducted a retrospective study of  patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center.  Endpoints included overall response rate (ORR), time to next therapy or death  (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression   models were used to determine the association between irAE incidence and ORR, and  Kaplan-Meier curves with log-rank tests and Cox regression models were used for  the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016,  160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%)  were treated on a clinical trial. Immune-related adverse events were noted in 64   patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable  for clinical response, 28 patients (20%) achieved a partial response at first  scan. An association between irAEs and ORR was seen in clinical trial patients (p  = .007), but not in non-trial patients (p = .13). When controlling for clinical  trial participation and cancer type using multivariate analysis, low-grade irAEs   had higher ORR (p = .017) and longer TTNTD (p = .008). No association between  irAE incidence and OS was seen (p = .827). Immune-related adverse events that  required steroid treatment were marginally associated with increased TTNTD (p =  .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We  demonstrate several positive associations between the development of irAEs and  clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which  further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated  whether the development of immune-related adverse events in non-melanoma patients  treated with programmed cell death 1 checkpoint inhibitors correlates with  improved clinical outcomes. The results indicate that for a subset of patients,  in particular those with low-grade immune-related adverse events, immune-related   adverse events predicted for an improved response rate and longer time to next  therapy or death.CI  - (c) AlphaMed Press 2017.
CANIT0001173	28652280	Clinical research	Head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma.	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	160	N/A	A retrospective cohort study	We demonstrate several positive associations between the development of immune-related adverse events and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Oct	 Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated  with Programmed Cell Death 1 Inhibitors.	 Oncologist	 BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead  to immune-related adverse events (irAEs). We sought to evaluate whether the  development of irAEs correlates with treatment response in non-melanoma  malignancies. MATERIALS AND METHODS: We conducted a retrospective study of  patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center.  Endpoints included overall response rate (ORR), time to next therapy or death  (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression   models were used to determine the association between irAE incidence and ORR, and  Kaplan-Meier curves with log-rank tests and Cox regression models were used for  the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016,  160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%)  were treated on a clinical trial. Immune-related adverse events were noted in 64   patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable  for clinical response, 28 patients (20%) achieved a partial response at first  scan. An association between irAEs and ORR was seen in clinical trial patients (p  = .007), but not in non-trial patients (p = .13). When controlling for clinical  trial participation and cancer type using multivariate analysis, low-grade irAEs   had higher ORR (p = .017) and longer TTNTD (p = .008). No association between  irAE incidence and OS was seen (p = .827). Immune-related adverse events that  required steroid treatment were marginally associated with increased TTNTD (p =  .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We  demonstrate several positive associations between the development of irAEs and  clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which  further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated  whether the development of immune-related adverse events in non-melanoma patients  treated with programmed cell death 1 checkpoint inhibitors correlates with  improved clinical outcomes. The results indicate that for a subset of patients,  in particular those with low-grade immune-related adverse events, immune-related   adverse events predicted for an improved response rate and longer time to next  therapy or death.CI  - (c) AlphaMed Press 2017.
CANIT0001174	28652280	Clinical research	Head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	160	N/A	A retrospective cohort study	We demonstrate several positive associations between the development of immune-related adverse events and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Oct	 Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated  with Programmed Cell Death 1 Inhibitors.	 Oncologist	 BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead  to immune-related adverse events (irAEs). We sought to evaluate whether the  development of irAEs correlates with treatment response in non-melanoma  malignancies. MATERIALS AND METHODS: We conducted a retrospective study of  patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center.  Endpoints included overall response rate (ORR), time to next therapy or death  (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression   models were used to determine the association between irAE incidence and ORR, and  Kaplan-Meier curves with log-rank tests and Cox regression models were used for  the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016,  160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%)  were treated on a clinical trial. Immune-related adverse events were noted in 64   patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable  for clinical response, 28 patients (20%) achieved a partial response at first  scan. An association between irAEs and ORR was seen in clinical trial patients (p  = .007), but not in non-trial patients (p = .13). When controlling for clinical  trial participation and cancer type using multivariate analysis, low-grade irAEs   had higher ORR (p = .017) and longer TTNTD (p = .008). No association between  irAE incidence and OS was seen (p = .827). Immune-related adverse events that  required steroid treatment were marginally associated with increased TTNTD (p =  .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We  demonstrate several positive associations between the development of irAEs and  clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which  further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated  whether the development of immune-related adverse events in non-melanoma patients  treated with programmed cell death 1 checkpoint inhibitors correlates with  improved clinical outcomes. The results indicate that for a subset of patients,  in particular those with low-grade immune-related adverse events, immune-related   adverse events predicted for an improved response rate and longer time to next  therapy or death.CI  - (c) AlphaMed Press 2017.
CANIT0001175	28652280	Clinical research	Head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	160	N/A	A retrospective cohort study	We demonstrate several positive associations between the development of immune-related adverse events and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Oct	 Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated  with Programmed Cell Death 1 Inhibitors.	 Oncologist	 BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead  to immune-related adverse events (irAEs). We sought to evaluate whether the  development of irAEs correlates with treatment response in non-melanoma  malignancies. MATERIALS AND METHODS: We conducted a retrospective study of  patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center.  Endpoints included overall response rate (ORR), time to next therapy or death  (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression   models were used to determine the association between irAE incidence and ORR, and  Kaplan-Meier curves with log-rank tests and Cox regression models were used for  the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016,  160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%)  were treated on a clinical trial. Immune-related adverse events were noted in 64   patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable  for clinical response, 28 patients (20%) achieved a partial response at first  scan. An association between irAEs and ORR was seen in clinical trial patients (p  = .007), but not in non-trial patients (p = .13). When controlling for clinical  trial participation and cancer type using multivariate analysis, low-grade irAEs   had higher ORR (p = .017) and longer TTNTD (p = .008). No association between  irAE incidence and OS was seen (p = .827). Immune-related adverse events that  required steroid treatment were marginally associated with increased TTNTD (p =  .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We  demonstrate several positive associations between the development of irAEs and  clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which  further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated  whether the development of immune-related adverse events in non-melanoma patients  treated with programmed cell death 1 checkpoint inhibitors correlates with  improved clinical outcomes. The results indicate that for a subset of patients,  in particular those with low-grade immune-related adverse events, immune-related   adverse events predicted for an improved response rate and longer time to next  therapy or death.CI  - (c) AlphaMed Press 2017.
CANIT0001176	28652280	Clinical research	Head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	160	N/A	A retrospective cohort study	We demonstrate several positive associations between the development of immune-related adverse events and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Oct	 Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated  with Programmed Cell Death 1 Inhibitors.	 Oncologist	 BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead  to immune-related adverse events (irAEs). We sought to evaluate whether the  development of irAEs correlates with treatment response in non-melanoma  malignancies. MATERIALS AND METHODS: We conducted a retrospective study of  patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center.  Endpoints included overall response rate (ORR), time to next therapy or death  (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression   models were used to determine the association between irAE incidence and ORR, and  Kaplan-Meier curves with log-rank tests and Cox regression models were used for  the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016,  160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%)  were treated on a clinical trial. Immune-related adverse events were noted in 64   patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable  for clinical response, 28 patients (20%) achieved a partial response at first  scan. An association between irAEs and ORR was seen in clinical trial patients (p  = .007), but not in non-trial patients (p = .13). When controlling for clinical  trial participation and cancer type using multivariate analysis, low-grade irAEs   had higher ORR (p = .017) and longer TTNTD (p = .008). No association between  irAE incidence and OS was seen (p = .827). Immune-related adverse events that  required steroid treatment were marginally associated with increased TTNTD (p =  .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We  demonstrate several positive associations between the development of irAEs and  clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which  further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated  whether the development of immune-related adverse events in non-melanoma patients  treated with programmed cell death 1 checkpoint inhibitors correlates with  improved clinical outcomes. The results indicate that for a subset of patients,  in particular those with low-grade immune-related adverse events, immune-related   adverse events predicted for an improved response rate and longer time to next  therapy or death.CI  - (c) AlphaMed Press 2017.
CANIT0001177	28652280	Clinical research	Head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	160	N/A	A retrospective cohort study	We demonstrate several positive associations between the development of immune-related adverse events and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Oct	 Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated  with Programmed Cell Death 1 Inhibitors.	 Oncologist	 BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead  to immune-related adverse events (irAEs). We sought to evaluate whether the  development of irAEs correlates with treatment response in non-melanoma  malignancies. MATERIALS AND METHODS: We conducted a retrospective study of  patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center.  Endpoints included overall response rate (ORR), time to next therapy or death  (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression   models were used to determine the association between irAE incidence and ORR, and  Kaplan-Meier curves with log-rank tests and Cox regression models were used for  the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016,  160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%)  were treated on a clinical trial. Immune-related adverse events were noted in 64   patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable  for clinical response, 28 patients (20%) achieved a partial response at first  scan. An association between irAEs and ORR was seen in clinical trial patients (p  = .007), but not in non-trial patients (p = .13). When controlling for clinical  trial participation and cancer type using multivariate analysis, low-grade irAEs   had higher ORR (p = .017) and longer TTNTD (p = .008). No association between  irAE incidence and OS was seen (p = .827). Immune-related adverse events that  required steroid treatment were marginally associated with increased TTNTD (p =  .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We  demonstrate several positive associations between the development of irAEs and  clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which  further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated  whether the development of immune-related adverse events in non-melanoma patients  treated with programmed cell death 1 checkpoint inhibitors correlates with  improved clinical outcomes. The results indicate that for a subset of patients,  in particular those with low-grade immune-related adverse events, immune-related   adverse events predicted for an improved response rate and longer time to next  therapy or death.CI  - (c) AlphaMed Press 2017.
CANIT0001178	28652280	Clinical research	Head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma.	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	160	N/A	A retrospective cohort study	We demonstrate several positive associations between the development of immune-related adverse events and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Oct	 Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated  with Programmed Cell Death 1 Inhibitors.	 Oncologist	 BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead  to immune-related adverse events (irAEs). We sought to evaluate whether the  development of irAEs correlates with treatment response in non-melanoma  malignancies. MATERIALS AND METHODS: We conducted a retrospective study of  patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center.  Endpoints included overall response rate (ORR), time to next therapy or death  (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression   models were used to determine the association between irAE incidence and ORR, and  Kaplan-Meier curves with log-rank tests and Cox regression models were used for  the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016,  160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%)  were treated on a clinical trial. Immune-related adverse events were noted in 64   patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable  for clinical response, 28 patients (20%) achieved a partial response at first  scan. An association between irAEs and ORR was seen in clinical trial patients (p  = .007), but not in non-trial patients (p = .13). When controlling for clinical  trial participation and cancer type using multivariate analysis, low-grade irAEs   had higher ORR (p = .017) and longer TTNTD (p = .008). No association between  irAE incidence and OS was seen (p = .827). Immune-related adverse events that  required steroid treatment were marginally associated with increased TTNTD (p =  .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We  demonstrate several positive associations between the development of irAEs and  clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which  further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated  whether the development of immune-related adverse events in non-melanoma patients  treated with programmed cell death 1 checkpoint inhibitors correlates with  improved clinical outcomes. The results indicate that for a subset of patients,  in particular those with low-grade immune-related adverse events, immune-related   adverse events predicted for an improved response rate and longer time to next  therapy or death.CI  - (c) AlphaMed Press 2017.
CANIT0001179	28652280	Clinical research	Head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma.	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	160	N/A	A retrospective cohort study	We demonstrate several positive associations between the development of immune-related adverse events and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Oct	 Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated  with Programmed Cell Death 1 Inhibitors.	 Oncologist	 BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead  to immune-related adverse events (irAEs). We sought to evaluate whether the  development of irAEs correlates with treatment response in non-melanoma  malignancies. MATERIALS AND METHODS: We conducted a retrospective study of  patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center.  Endpoints included overall response rate (ORR), time to next therapy or death  (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression   models were used to determine the association between irAE incidence and ORR, and  Kaplan-Meier curves with log-rank tests and Cox regression models were used for  the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016,  160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%)  were treated on a clinical trial. Immune-related adverse events were noted in 64   patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable  for clinical response, 28 patients (20%) achieved a partial response at first  scan. An association between irAEs and ORR was seen in clinical trial patients (p  = .007), but not in non-trial patients (p = .13). When controlling for clinical  trial participation and cancer type using multivariate analysis, low-grade irAEs   had higher ORR (p = .017) and longer TTNTD (p = .008). No association between  irAE incidence and OS was seen (p = .827). Immune-related adverse events that  required steroid treatment were marginally associated with increased TTNTD (p =  .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We  demonstrate several positive associations between the development of irAEs and  clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which  further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated  whether the development of immune-related adverse events in non-melanoma patients  treated with programmed cell death 1 checkpoint inhibitors correlates with  improved clinical outcomes. The results indicate that for a subset of patients,  in particular those with low-grade immune-related adverse events, immune-related   adverse events predicted for an improved response rate and longer time to next  therapy or death.CI  - (c) AlphaMed Press 2017.
CANIT0001180	28652455	Case report	Metastatic Renal Cell Carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Case	N/A	The first patient developed severe respiratory failure due to carcinomatous lymphangiosis 14 days after initiation of nivolumab therapy. The second patient developed leg paraplegia due to rapid growth of the metastatic tumour at the sixth thoracic vertebrae 5 days later. The third patient developed grade 4 hypercalcemia due to RPD on day 3.	N/A	N/A	N/A	N/A	N/A	 2017 Jul-Aug	 Rapid Progressive Disease After Nivolumab Therapy in Three Patients with  Metastatic Renal Cell Carcinoma.	 In Vivo	 BACKGROUND/AIM: Rapid progressive disease (RPD), accelerated tumour growth  immediate after the initiation of immune checkpoint inhibitor therapy, has been  reported in melanoma and lung cancer. Herein, we describe 3 cases of RPD during  the initial phase of nivolumab treatment for metastatic renal cell carcinoma.  PATIENTS AND METHODS: The first and second patients received nivolumab in the  fourth-line setting. The third patient received nivolumab therapy as third-line  treatment. RESULTS: The first patient developed severe respiratory failure due to  carcinomatous lymphangiosis 14 days after initiation of nivolumab therapy. The  second patient developed leg paraplegia due to rapid growth of the metastatic  tumour at the sixth thoracic vertebrae 5 days later. The third patient developed   grade 4 hypercalcemia due to RPD on day 3. CONCLUSION: Clinicians should be aware  of RPD during the initial phase of nivolumab therapy, especially in patients with  critical lesions in the late-line setting.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001181	28654547	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	N/A (N/A); 	N/A; 	Autologous dendritic cell vaccine	N/A	Tumor vaccine	Dendritic cell vaccine (NCIT:C28310); 	81	N/A	A retrospective cohort study	Our analysis confirms the excellent tolerability of our vaccine, making it a potential candidate for combination therapies. As efficacy seems largely restricted to immunoresponsive patients, future strategies should aim to increase the number of these patients.	The adverse events observed were generally mild and self-limiting.	N/A	N/A	Immune response (NCIT:C17930); 	Immune responses	Immune response	 2017 Aug	 Dendritic cell vaccination for metastatic melanoma: a 14-year monoinstitutional  experience.	 Melanoma Res	 Although immunomodulating antibodies are highly effective in metastatic melanoma,  their toxicity, related to the activation of T lymphocytes, can be severe.  Anticancer vaccines promote a fairly specific response and are very well  tolerated, but their effectiveness has yet to be demonstrated. We have been  treating patients with advanced melanoma with an autologous dendritic cell  vaccine since 2001; to better characterize the safety and efficacy of our  product, we designed a retrospective study on all of our patients treated with  the vaccine to date. We retrospectively reviewed both case report forms of  patients included in clinical trials and medical records of those treated within   a compassionate use program. Response was assessed according to the Response  Evaluation Criteria In Solid Tumors criteria and toxicity has been graded  according to CTCAE 4.0. Although the response rate has been rather low, the  median overall survival of 11.4 months and the 1-year survival rate of 46.9% are   encouraging, especially considering the fact that data were obtained in a heavily  pretreated population and only about one quarter of the patients had received  ipilimumab and/or BRAF inhibitors. Multivariate analysis confirmed that the  development of an immune response was significantly correlated with a better  prognosis (hazard ratio 0.54; P=0.019). The adverse events observed were  generally mild and self-limiting. Our analysis confirms the excellent  tolerability of our vaccine, making it a potential candidate for combination  therapies. As efficacy seems largely restricted to immunoresponsive patients,  future strategies should aim to increase the number of these patients.
CANIT0001182	28655793	Clinical research	Advanced/metastatic gastric or gastroesophageal junction cancer	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab and chemotherapy	Best supportive care and chemotherapy	Immune checkpoint therapy plus Chemotherapy	Chemotherapy (NCIT:C15632); ipilimumab (DB06186); 	57	57	A randomized, phase II, open-label study	Although ipilimumab at 10 mg/kg was manageable, it did not improve irPFS versus BSC. However, comparable median OS of approximately 1 year and a favorable safety profile support the investigation of ipilimumab in combination with other therapies for advanced gastric cancer.	Grade 3/4 treatment-related adverse events occurred in 23% of ipilimumab-treated patients, in whom diarrhea (9%) and fatigue (5%) were most frequent, and in 9% of active BSC-treated patients.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for  Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction  Cancer.	 Clin Cancer Res	 Purpose: Ipilimumab, a monoclonal antibody that blocks cytotoxic  T-lymphocyte-associated protein-4 interactions, enhances T-cell activation and  promotes tumor immunity. This phase II study evaluated the safety and efficacy of  ipilimumab monotherapy versus best supportive care (BSC) among patients with  advanced/metastatic gastric or gastroesophageal junction cancer who achieved at  least stable disease with first-line chemotherapy.Experimental Design: Eligible  patients were randomized to ipilimumab 10 mg/kg every 3 weeks for four doses,  then 10 mg/kg every 12 weeks for up to 3 years, or BSC, which could include  continuation of fluoropyrimidine until progression or toxicity. The primary  endpoint was immune-related progression-free survival (irPFS); secondary  endpoints included PFS by modified World Health Organization criteria and overall  survival (OS).Results: Of 143 patients screened, 57 were randomized to each arm.   irPFS with ipilimumab versus BSC was not improved [2.92 months, 95% confidence  interval (CI), 1.61-5.16 vs. 4.90 months, 95% CI, 3.45-6.54, HR = 1.44; 80% CI,  1.09-1.91; P = 0.097], resulting in study cessation. At study closeout, which  occurred 8 months after the interim analysis, the median OS durations were 12.7  months (95% CI, 10.5-18.9) and 12.1 months (95% CI, 9.3-not estimable),  respectively. Grade 3/4 treatment-related adverse events occurred in 23% of  ipilimumab-treated patients, in whom diarrhea (9%) and fatigue (5%) were most  frequent, and in 9% of active BSC-treated patients.Conclusions: Although  ipilimumab at 10 mg/kg was manageable, it did not improve irPFS versus BSC.  However, comparable median OS of approximately 1 year and a favorable safety  profile support the investigation of ipilimumab in combination with other  therapies for advanced gastric cancer. Clin Cancer Res; 23(19); 5671-8. (c)2017  AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001183	28662232	Clinical research	Treatment-naive patients with advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	526	N/A	A pooled, retrospective analysis of data from phase III trials (CheckMate 066 or CheckMate 067) 	A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety.	Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively).	N/A	N/A	N/A	N/A	N/A	 2017 Nov 1	 Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression:  Analysis of 2 Phase 3 Clinical Trials.	 JAMA Oncol	 Importance: Immune checkpoint inhibitors have demonstrated atypical response  patterns, which may not be fully captured by conventional response criteria.  There is a need to better understand the potential benefit of continued immune  checkpoint inhibition beyond progression. Objective: To evaluate the safety and  potential benefit of nivolumab (anti-programmed cell death receptor 1)  monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)  v1.1-defined progression. Design, Setting, and Participants: Pooled,  retrospective analysis of data from phase 3 trials of nivolumab in  treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067)   conducted at academic and clinical cancer centers. Participants were patients  treated beyond first disease progression, defined as those who received their  last dose of nivolumab more than 6 weeks after progression (TBP group); and  patients not treated beyond progression, who discontinued nivolumab therapy  before or at progression (non-TBP group). Data analyses were conducted from  November 6, 2015, to January 11, 2017. Interventions: Nivolumab (3 mg/kg every 2   weeks) administered until progression or unacceptable toxic effects. Patients  could be treated beyond progression if deriving apparent clinical benefit and  tolerating study drug, at the investigator's discretion. Main Outcomes and  Measures: Tumor response and safety in TBP and non-TBP patients. Results: Among  526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90  years]), 306 (58%) experienced disease progression, including 85 (28%) TBP  patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients  had a target lesion reduction of greater than 30% after progression compared with  baseline (TBP>30% group). At the time of this analysis, 65 (76%) TBP patients and  21 (87%) TBP>30% patients were still alive; 27 (32%) and 11 (46%), respectively,   continued to receive treatment. Median (range) time from progression to last dose  of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months  for TBP>30% patients. Median (range) time from progression to greater than 30%  tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4  adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%],  respectively). Conclusions and Relevance: A substantial proportion of selected  patients treated with frontline nivolumab who were clinically stable and judged  to be eligible for treatment beyond RECIST v1.1-defined progression by the  treating investigators derived apparent clinical benefit without compromising  safety. Further analysis will help define the potential benefit of continued  nivolumab treatment beyond progression. Trial Registration: clinicaltrials.gov  Identifiers: NCT01721772 (CheckMate 066) and NCT01844505 (CheckMate 067).
CANIT0001184	28662869	Clinical research	NSCLC, melanoma, and RCC	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	137	N/A	A retrospective cohort study	Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation.	 Radiother Oncol	 BACKGROUND AND PURPOSE: Patients with metastatic melanoma, renal cell carcinoma  (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune  checkpoint blockade targeting the programed death (PD)-1 receptor, often with  palliative radiation therapy. Outcome data are limited in this population.  MATERIAL AND METHODS: We retrospectively reviewed consecutive patients with  metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy   at four centers. RESULTS: We identified 137 patients who received radiation and  PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and  121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received  radiation following the start of PD-1 blockade, 25 continued to receive PD-1  inhibition for a median of 179days and survived for a median of 238 additional  days. Median survival following first course of radiation for brain metastases  was 634days. Melanoma patients received brain directed radiation relatively less   frequently following the start of PD-1 inhibitor treatment. CONCLUSIONS:  Incorporation of palliative radiation does not preclude favorable outcomes in  patients treated with PD-1 inhibitors; patients irradiated after the start of  PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of  note, patients irradiated for brain metastases demonstrate favorable outcomes  compared with historical controls.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001185	28662869	Clinical research	NSCLC, melanoma, and RCC	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); radiotherapy (NCIT:C15313); 	137	N/A	A retrospective cohort study	Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation.	 Radiother Oncol	 BACKGROUND AND PURPOSE: Patients with metastatic melanoma, renal cell carcinoma  (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune  checkpoint blockade targeting the programed death (PD)-1 receptor, often with  palliative radiation therapy. Outcome data are limited in this population.  MATERIAL AND METHODS: We retrospectively reviewed consecutive patients with  metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy   at four centers. RESULTS: We identified 137 patients who received radiation and  PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and  121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received  radiation following the start of PD-1 blockade, 25 continued to receive PD-1  inhibition for a median of 179days and survived for a median of 238 additional  days. Median survival following first course of radiation for brain metastases  was 634days. Melanoma patients received brain directed radiation relatively less   frequently following the start of PD-1 inhibitor treatment. CONCLUSIONS:  Incorporation of palliative radiation does not preclude favorable outcomes in  patients treated with PD-1 inhibitors; patients irradiated after the start of  PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of  note, patients irradiated for brain metastases demonstrate favorable outcomes  compared with historical controls.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001186	28662869	Clinical research	NSCLC, melanoma, and RCC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	137	N/A	A retrospective cohort study	Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation.	 Radiother Oncol	 BACKGROUND AND PURPOSE: Patients with metastatic melanoma, renal cell carcinoma  (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune  checkpoint blockade targeting the programed death (PD)-1 receptor, often with  palliative radiation therapy. Outcome data are limited in this population.  MATERIAL AND METHODS: We retrospectively reviewed consecutive patients with  metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy   at four centers. RESULTS: We identified 137 patients who received radiation and  PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and  121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received  radiation following the start of PD-1 blockade, 25 continued to receive PD-1  inhibition for a median of 179days and survived for a median of 238 additional  days. Median survival following first course of radiation for brain metastases  was 634days. Melanoma patients received brain directed radiation relatively less   frequently following the start of PD-1 inhibitor treatment. CONCLUSIONS:  Incorporation of palliative radiation does not preclude favorable outcomes in  patients treated with PD-1 inhibitors; patients irradiated after the start of  PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of  note, patients irradiated for brain metastases demonstrate favorable outcomes  compared with historical controls.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001187	28662869	Clinical research	NSCLC, melanoma, and RCC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); radiotherapy (NCIT:C15313); 	137	N/A	A retrospective cohort study	Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation.	 Radiother Oncol	 BACKGROUND AND PURPOSE: Patients with metastatic melanoma, renal cell carcinoma  (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune  checkpoint blockade targeting the programed death (PD)-1 receptor, often with  palliative radiation therapy. Outcome data are limited in this population.  MATERIAL AND METHODS: We retrospectively reviewed consecutive patients with  metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy   at four centers. RESULTS: We identified 137 patients who received radiation and  PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and  121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received  radiation following the start of PD-1 blockade, 25 continued to receive PD-1  inhibition for a median of 179days and survived for a median of 238 additional  days. Median survival following first course of radiation for brain metastases  was 634days. Melanoma patients received brain directed radiation relatively less   frequently following the start of PD-1 inhibitor treatment. CONCLUSIONS:  Incorporation of palliative radiation does not preclude favorable outcomes in  patients treated with PD-1 inhibitors; patients irradiated after the start of  PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of  note, patients irradiated for brain metastases demonstrate favorable outcomes  compared with historical controls.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001188	28662869	Clinical research	NSCLC, melanoma, and RCC	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	137	N/A	A retrospective cohort study	Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation.	 Radiother Oncol	 BACKGROUND AND PURPOSE: Patients with metastatic melanoma, renal cell carcinoma  (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune  checkpoint blockade targeting the programed death (PD)-1 receptor, often with  palliative radiation therapy. Outcome data are limited in this population.  MATERIAL AND METHODS: We retrospectively reviewed consecutive patients with  metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy   at four centers. RESULTS: We identified 137 patients who received radiation and  PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and  121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received  radiation following the start of PD-1 blockade, 25 continued to receive PD-1  inhibition for a median of 179days and survived for a median of 238 additional  days. Median survival following first course of radiation for brain metastases  was 634days. Melanoma patients received brain directed radiation relatively less   frequently following the start of PD-1 inhibitor treatment. CONCLUSIONS:  Incorporation of palliative radiation does not preclude favorable outcomes in  patients treated with PD-1 inhibitors; patients irradiated after the start of  PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of  note, patients irradiated for brain metastases demonstrate favorable outcomes  compared with historical controls.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001189	28662869	Clinical research	NSCLC, melanoma, and RCC	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); radiotherapy (NCIT:C15313); 	137	N/A	A retrospective cohort study	Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Radiation and PD-1 inhibition: Favorable outcomes after brain-directed radiation.	 Radiother Oncol	 BACKGROUND AND PURPOSE: Patients with metastatic melanoma, renal cell carcinoma  (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune  checkpoint blockade targeting the programed death (PD)-1 receptor, often with  palliative radiation therapy. Outcome data are limited in this population.  MATERIAL AND METHODS: We retrospectively reviewed consecutive patients with  metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy   at four centers. RESULTS: We identified 137 patients who received radiation and  PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and  121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received  radiation following the start of PD-1 blockade, 25 continued to receive PD-1  inhibition for a median of 179days and survived for a median of 238 additional  days. Median survival following first course of radiation for brain metastases  was 634days. Melanoma patients received brain directed radiation relatively less   frequently following the start of PD-1 inhibitor treatment. CONCLUSIONS:  Incorporation of palliative radiation does not preclude favorable outcomes in  patients treated with PD-1 inhibitors; patients irradiated after the start of  PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of  note, patients irradiated for brain metastases demonstrate favorable outcomes  compared with historical controls.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001190	28665741	Case report	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Radiotherapy (NCIT:C15313); pembrolizumab (DB09037); 	1	N/A	Case	Complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 3	 A rapid and systemic complete response to stereotactic body radiation therapy and  pembrolizumab in a patient with metastatic renal cell carcinoma.	 Cancer Biol Ther	 Stereotactic body radiation therapy (SBRT) of local tumor would induce an  abscopal effect that has been observed in several kinds of human cancers; one  important mechanism may involve the improved activation of the host immune  system. The immune checkpoint inhibitor can overcome immune tolerance and enhance  the activation of antitumor T cells. The combined treatment of SBRT and  checkpoint inhibitor may represent a new promising therapeutic approach. Herein,   we reported a patient with metastatic renal cell carcinoma (RCC) treated with  concurrent SBRT and anti-PD-1 antibody, pembrolizumab, by which the patient  achieved an amazingly systemic complete response in only 2.2 months after  starting treatment. This case report indicates that the advanced RCC may benefit   from the combining treatment of local SBRT and PD-1 inhibitor and provide a  useful paradigm worthy of establishing a clinical trial for patients with  advanced renal cell carcinoma.
CANIT0001191	28668860	Case report	Locally recurrent MSI-high colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Gastrocutaneous fistula	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Gastrocutaneous Fistula in a Patient with Locally Recurrent MSI-High Colorectal  Cancer: Local Complications Arising from Therapeutic Response to Immune  Checkpoint Blockade.	 Anticancer Res	 Colorectal cancers with high microsatellite instability (MSI-H) have distinct  clinical features in terms of their prognosis, recurrence patterns, and  sensitivity to immunotherapeutic agents. We present the case of a woman with a  left-sided MSI-H colon cancer who had repeated recurrences concentrated  exclusively in the left upper quadrant of the abdomen, including gastric  involvement. Despite multiple surgical resections, radiation, and several lines  of chemotherapy, her disease eventually eroded through the chest wall. Treatment   with an immune checkpoint inhibitor produced a rapid clinical response with  significant tumor necrosis; however, this necessitated surgical debridement that   ultimately led to a large gastrocutaneous fistula. This case highlights the  importance of recognizing locoregional tumor-associated complications that may  result from robust therapeutic responses to immuno-oncology drugs, which are  increasingly being used in clinical practice today.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001192	28668874	Clinical research	Non-small cell carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	Low prognostic nutritional index were  associated with early termination of nivolumab monotherapy, suggesting they might  be useful biomarkers for treatment selection.	N/A	N/A	N/A	Prognostic nutritional index (NCIT:C25597); 	Pretreatment prognostic nutritional index	Disease status	 2017 Jul	 Immunological Status May Predict Response to Nivolumab in Non-small Cell Lung  Cancer without Driver Mutations.	 Anticancer Res	 BACKGROUND/AIM: It remains challenging to select patients with non-small cell  carcinoma (NSCLC) for nivolumab monotherapy. We evaluated whether early  termination of nivolumab monotherapy correlated with pretreatment  neutrophil/lymphocyte ratio (NLR) and prognostic nutritional index (PNI).  PATIENTS AND METHODS: Twenty patients received nivolumab monotherapy for NSCLC  with wild-type epidermal growth factor receptor (EGFR) and anaplastic lymphoma  kinase (ALK) during 2016. Early termination and continued therapy were defined as  </=5 and >/=6 cycles of monotherapy, respectively. RESULTS: Early termination and  continued therapy groups included 9 and 11 patients, respectively. High  pretreatment NLR and low pretreatment PNI were significantly associated with  early termination of nivolumab, both in an overall analysis (p<0.001 and p=0.016)  and in subgroup analyses of patients with performance scores of 0-1 and >/=30  days of pretreatment drug holidays. CONCLUSION: High NLR and low PNI were  associated with early termination of nivolumab monotherapy, suggesting they might  be useful biomarkers for treatment selection.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001193	28668874	Clinical research	Non-small cell carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	High neutrophil-to-lymphocyte ratios and low PNI were  associated with early termination of nivolumab monotherapy, suggesting they might  be useful biomarkers for treatment selection.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Jul	 Immunological Status May Predict Response to Nivolumab in Non-small Cell Lung  Cancer without Driver Mutations.	 Anticancer Res	 BACKGROUND/AIM: It remains challenging to select patients with non-small cell  carcinoma (NSCLC) for nivolumab monotherapy. We evaluated whether early  termination of nivolumab monotherapy correlated with pretreatment  neutrophil/lymphocyte ratio (NLR) and prognostic nutritional index (PNI).  PATIENTS AND METHODS: Twenty patients received nivolumab monotherapy for NSCLC  with wild-type epidermal growth factor receptor (EGFR) and anaplastic lymphoma  kinase (ALK) during 2016. Early termination and continued therapy were defined as  </=5 and >/=6 cycles of monotherapy, respectively. RESULTS: Early termination and  continued therapy groups included 9 and 11 patients, respectively. High  pretreatment NLR and low pretreatment PNI were significantly associated with  early termination of nivolumab, both in an overall analysis (p<0.001 and p=0.016)  and in subgroup analyses of patients with performance scores of 0-1 and >/=30  days of pretreatment drug holidays. CONCLUSION: High NLR and low PNI were  associated with early termination of nivolumab monotherapy, suggesting they might  be useful biomarkers for treatment selection.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001194	28670746	Case report	Metastatic squamous cell carcinoma of the anal canal	Squamous cell anal canal carcinoma	EFO:1000081	Anus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Good outcome with HPV circulating tumor DNA decreased	N/A	N/A	N/A	HPV (NCIT:C14226); 	HPV circulating tumor DNA levels	Microbiota	 2017 Oct 15	 HPV circulating tumor DNA to monitor the efficacy of anti-PD-1 therapy in  metastatic squamous cell carcinoma of the anal canal: A case report.	 Int J Cancer	 Squamous cell carcinoma of the anal canal (SCCA) is a rare HPV-associated cancer   with limited sensitivity to standard chemotherapy. In a phase 2 study, nivolumab,  an anti PD-1 immune checkpoint inhibitor, demonstrated significant efficacy as  single-agent therapy in metastatic SCCA patients. Nevertheless, imaging  assessment by standard RECIST criteria of the efficacy of immune therapy can be  difficult in some patients due to tumor immune cell infiltration, and biomarkers   of treatment efficacy are needed. We have previously developed a quantitative  droplet digital PCR (ddPCR) technique to detect HPV circulating tumor DNA (HPV  ctDNA), with excellent sensitivity and specificity. Here, we report, for the  first time, the kinetics of HPV ctDNA during therapy in a patient with metastatic  SCCA, who obtained sustained partial response to single-agent nivolumab. We  observed an early and very significant decrease of HPV ctDNA during therapy from   the baseline level of 3713 copies/ml plasma to 564 copies/ml plasma at 4 weeks,  and 156 copies/ml at 6 weeks, followed by a plateau. This observation provides  proof-of-concept that HPV ctDNA can be used as a noninvasive early dynamic  biomarker to monitor the efficacy of new immunotherapy agents.CI  - (c) 2017 UICC.
CANIT0001195	28673798	Case report	Sarcomatoid transformation of chromophobe renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Rapid response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Rapid Response to Nivolumab in a Patient With Sarcomatoid Transformation of  Chromophobe Renal Cell Carcinoma.	 Clin Genitourin Cancer	Unable to provide
CANIT0001196	28674287	Case report	Advanced colon cancer with focal recurrence	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Myasthenia gravis and myositis	N/A	N/A	N/A	N/A	N/A	 2017 Jul 29	 A case of myasthenia gravis and myositis induced by nivolumab.	 Rinsho Shinkeigaku	 A 74-year-old woman, who developed advanced colon cancer with focal recurrence,  received two courses of a low dose of nivolumab. Five days after the second  course she noticed bilateral ptosis. Her symptoms rapidly progressed to  generalized manifestations including limb and neck weakness, dyspnea, and myalgia  within the following two weeks. Neurological and laboratory findings supported  the diagnosis of myasthenia gravis and myositis induced by nivolumab. The  combination immunotherapy including oral prednisolone, intravenous immunoglobulin  and plasma exchange with noninvasive positive-pressure ventilation successfully  avoid tracheal intubation. Nivolumab, one of the immune checkpoint inhibitors, is  the anti-programmed cell death-1 (PD-1) protein monoclonal antibody, which is  effective for various cancers. Since the immune checkpoint inhibitors are going  to be used widely, it is important to recognize the specific subtype of  myasthenia gravis for neurologists.
CANIT0001197	28675691	Case report	Congenital pigment synthesizing metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	She is now over a year out from initial diagnosis, continuing on nivolumab, with stable disease.	The patient tolerated this treatment well with minimal toxicity.	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 PD-1 inhibition in congenital pigment synthesizing metastatic melanoma.	 Pediatr Blood Cancer	 A newborn female child was born with a congenital pigment synthesizing melanoma  of the scalp. Further workup revealed metastatic disease within the liver, lungs,  and left tibia. Whole exome sequencing was performed on multiple samples that  revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low  allelic frequency but no v-Raf murine sarcoma viral oncogene homolog B (BRAF),  NF-1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was   initiated with the programmed cell death protein 1 inhibitor nivolumab. The  patient tolerated this treatment well with minimal toxicity. She is now over a  year out from initial diagnosis, continuing on nivolumab, with stable disease.CI  - (c) 2017 Wiley Periodicals, Inc.
CANIT0001198	28678991	Case report	Relapsed metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Nivolumab therapy for treatment-related vitiligo in a patient with relapsed metastatic melanoma.	Vitiligo	N/A	N/A	N/A	N/A	N/A	 2017 Sep 1	 Nivolumab Therapy for Treatment-Related Vitiligo in a Patient With Relapsed  Metastatic Melanoma.	 JAMA Dermatol	Unable to provide
CANIT0001199	28679408	Case report	Pulmonary adenocarcinoma with symptomatic brain metastasis	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus high-dose oral corticosteroid	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); corticosteroid (NCIT:C2322); 	1	N/A	Case	Partial response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul 6	 Partial response of pulmonary adenocarcinoma with symptomatic brain metastasis to  nivolumab plus high-dose oral corticosteroid: a case report.	 J Med Case Rep	 BACKGROUND: Nivolumab, a monoclonal antibody targeting the programmed death-1  receptor, is indicated in locally advanced or metastatic non-small cell lung  cancer, with progression after platinum-based chemotherapy. Up-to-now, few data  are available concerning brain activity of this treatment and concomitant use of   corticosteroids. CASE PRESENTATION: A 64-year-old caucasian man with a pulmonary   adenocarcinoma associated with brain metastases received four courses of  nivolumab in concomitance with a high dose of corticosteroids for his neurologic   symptoms. He experienced a partial response in his brain and chest with an  improvement in his general condition. Nivolumab was effective in shrinking  symptomatic brain metastases, and metastases at other sites, in a patient with  non-small cell lung cancer and first-line chemotherapy failure. The effect of  nivolumab was obtained despite concomitant high-dose corticosteroid therapy.  Combined nivolumab and high-dose corticosteroid therapy did not induce unexpected  adverse events. CONCLUSION: Nivolumab and concomitant high-dose corticosteroid  therapy was found to be efficient and well tolerated.
CANIT0001200	28679767	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	160	N/A	N/A	Objective response or durable disease control was noted in 24% of patients with advanced NSCLC treated with commercial PD-1 inhibitors. A tumor burden increase of <20% from baseline during therapy was associated with longer OS, proposing a practical marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with  PD-1 inhibitors.	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	Tumor burden	Disease status	 2017 Oct 1	 Tumor Response Dynamics of Advanced Non-small Cell Lung Cancer Patients Treated  with PD-1 Inhibitors: Imaging Markers for Treatment Outcome.	 Clin Cancer Res	 Purpose: We evaluated tumor burden dynamics in patients with advanced non-small  cell lung cancer (NSCLC) treated with commercial PD-1 inhibitors to identify  imaging markers associated with improved overall survival (OS).Experimental  Design: The study included 160 patients with advanced NSCLC treated with  commercial nivolumab or pembrolizumab monotherapy as a part of clinical care.  Tumor burden dynamics were studied for the association with OS.Results: Tumor  burden change at best overall response (BOR) ranged from -100% to +278% (median,   +3.5%). Response rate (RR) was 18% (29/160). Current and former smokers had a  higher RR than never smokers (P = 0.04). Durable disease control for at least 6  months was noted in 26 patients (16%), which included 10 patients with stable  disease as BOR. Using a landmark analysis, patients with <20% tumor burden  increase from baseline within 8 weeks of therapy had longer OS than patients with  >/=20% increase (median OS, 12.4 vs. 4.6 months, P < 0.001). Patients with <20%  tumor burden increase throughout therapy had significantly reduced hazards of  death (HR, 0.24; Cox P < 0.0001) after adjusting for smoking (HR, 0.86; P = 0.61)  and baseline tumor burden (HR, 1.55; P = 0.062), even though some patients met  criteria for RECIST progression while on therapy. One patient (0.6%) had atypical  response pattern consistent with pseudoprogression.Conclusions: Objective  response or durable disease control was noted in 24% of patients with advanced  NSCLC treated with commercial PD-1 inhibitors. A tumor burden increase of <20%  from baseline during therapy was associated with longer OS, proposing a practical  marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with  PD-1 inhibitors. Clin Cancer Res; 23(19); 5737-44. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001201	28679767	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	160	N/A	N/A	Objective response or durable disease control was noted in 24% of patients with advanced NSCLC treated with commercial PD-1 inhibitors. A tumor burden increase of <20% from baseline during therapy was associated with longer OS, proposing a practical marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with  PD-1 inhibitors.	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	Tumor burden	Disease status	 2017 Oct 1	 Tumor Response Dynamics of Advanced Non-small Cell Lung Cancer Patients Treated  with PD-1 Inhibitors: Imaging Markers for Treatment Outcome.	 Clin Cancer Res	 Purpose: We evaluated tumor burden dynamics in patients with advanced non-small  cell lung cancer (NSCLC) treated with commercial PD-1 inhibitors to identify  imaging markers associated with improved overall survival (OS).Experimental  Design: The study included 160 patients with advanced NSCLC treated with  commercial nivolumab or pembrolizumab monotherapy as a part of clinical care.  Tumor burden dynamics were studied for the association with OS.Results: Tumor  burden change at best overall response (BOR) ranged from -100% to +278% (median,   +3.5%). Response rate (RR) was 18% (29/160). Current and former smokers had a  higher RR than never smokers (P = 0.04). Durable disease control for at least 6  months was noted in 26 patients (16%), which included 10 patients with stable  disease as BOR. Using a landmark analysis, patients with <20% tumor burden  increase from baseline within 8 weeks of therapy had longer OS than patients with  >/=20% increase (median OS, 12.4 vs. 4.6 months, P < 0.001). Patients with <20%  tumor burden increase throughout therapy had significantly reduced hazards of  death (HR, 0.24; Cox P < 0.0001) after adjusting for smoking (HR, 0.86; P = 0.61)  and baseline tumor burden (HR, 1.55; P = 0.062), even though some patients met  criteria for RECIST progression while on therapy. One patient (0.6%) had atypical  response pattern consistent with pseudoprogression.Conclusions: Objective  response or durable disease control was noted in 24% of patients with advanced  NSCLC treated with commercial PD-1 inhibitors. A tumor burden increase of <20%  from baseline during therapy was associated with longer OS, proposing a practical  marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with  PD-1 inhibitors. Clin Cancer Res; 23(19); 5737-44. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001202	28682883	Case report	Squamous cell lung carcinoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Myasthenia gravis	N/A	N/A	N/A	N/A	N/A	 2017 Jul	 Nivolumab-induced myasthenia gravis in a patient with squamous cell lung  carcinoma: Case report.	 Medicine (Baltimore)	 RATIONALE: Nivolumab (Nivo) is an immune checkpoint inhibitor that has been used   to treat advanced melanoma, nonsmall cell lung carcinoma, and renal cell  carcinoma since 2015. Nivo is associated with several side effects, including  hepatitis, pneumonitis, acute renal failure, endocrine disorder, and other  immune-related adverse events. Here, we describe the case of a 65-year-old man  with squamous cell lung carcinoma who developed myasthenia gravis (MG) after a  third Nivo infusion. PATIENT CONCERNS: A 65-year-old man with advanced squamous  cell lung carcinoma developed ptosis, diplopia, drop head, and general weakness 5  days after a third Nivo infusion. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: We  diagnosed him with Nivo-related MG and myositis based on clinical symptoms,  elevation of muscle enzymes, negativity for autoantibodies and exclusion of other  diagnoses. Steroid treatment with methylprednisolone 1 mg/kg/d and pyridostigmine  60 mg twice a day was administered beginning at admission; however, the patient's  condition progressively worsened, despite treatment. Respiratory failure  developed 2 weeks after admission, and his family declined the use of a  mechanical ventilator. The patient died on day 27 after the third Nivo infusion.   LESSONS: Nivo-related MG should be highly suspected in patients who develop  ptosis, diplopia, and general weakness. The corresponding treatments include  discontinuation of Nivo and steroid treatment with plasmapheresis. The disease  course may be rapid and fatal. This report stresses the importance of awareness  of this rare and lethal adverse effect while using nivolomab immunotherapy.
CANIT0001203	28683452	Case report	Hodgkin's lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Graft-versus-host disease	N/A	N/A	N/A	N/A	N/A	2017	 Potential Role of the PD-1/PD-L1 Axis in the Immune Regulation of Chronic GVHD.	 Oncol Res Treat	 BACKGROUND: Antibodies blocking the PD-1/PD-L1 axis have been shown to have  substantial antitumor effects also in the treatment of Hodgkin's lymphoma (HL)  relapsing after conventional chemotherapy or even autologous hematopoietic stem  cell transplantation (autoHSCT). In the case of allogeneic HSCT (alloHSCT), this   treatment bears the risk of inducing graft-versus-host disease (GVHD). So far,  only a small number of patients who developed acute GVHD after PD-1 antibody  administration are described in the literature. CASE REPORTS: We herein report  the cases of 2 HL patients after alloHSCT who both responded well to the therapy;  however, 1 patient developed chronic GVHD (cGVHD) within 3 days of administration  of nivolumab. This patient already had a history of cGVHD and interestingly  showed manifestations at the very same sites. The other patient never showed any   signs of cGVHD, even with the administration of 13 cycles of anti-PD-1 therapy  and large doses of donor lymphocytes. CONCLUSION: The rapid reappearance of cGVHD  after blockade of PD-1 implies an important role of PD-1/PD-L1 in peripheral  immune tolerance in cGVHD after alloHSCT and warrants further investigation.CI  - (c) 2017 S. Karger GmbH, Freiburg.
CANIT0001204	28689773	Clinical research	Devil facial tumour disease (DFTD)	Devil facial tumour disease	N/A	Skin	TLR7 (Q9NYK1); TLR3 (O15455); 	TLR7; TLR3	Imiquimod plus poly-ICLC	N/A	Immune checkpoint therapy plus Tumor vaccine 	Imiquimod (DB00724); poly-ICLC (NCIT:C1198); 	8	N/A	N/A	Our results support the conserved nature of TLR signaling across mammalian species. PolyICLC and imiquimod will be trialed as immune adjuvants in future DFTD vaccine formulations.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2017 Nov	 The toll-like receptor ligands Hiltonol((R)) (polyICLC) and imiquimod effectively  activate antigen-specific immune responses in Tasmanian devils (Sarcophilus  harrisii).	 Dev Comp Immunol	 Devil facial tumour disease (DFTD) describes two genetically distinct  transmissible tumours that pose a significant threat to the survival of the  Tasmanian devil. A prophylactic vaccine could protect devils from DFTD  transmission. For this vaccine to be effective, potent immune adjuvants will be  required. Toll-like receptors (TLRs) promote robust immune responses in human  cancer studies and are highly conserved across mammalian species. In this study,   we investigated the proficiency of TLR ligands for immune activation in the  Tasmanian devil using in vitro mononuclear cell stimulations and in vivo  immunisation trials with a model antigen. We identified two such TLR ligands,  polyICLC (Hiltonol((R))) (TLR3) and imiquimod (TLR7), that in combination induced  significant IFNG production from Tasmanian devil lymphocytes in vitro.  Immunisation with these ligands and the model antigen keyhole limpet haemocyanin   activated robust antigen-specific primary, secondary and long-term memory IgG  responses. Our results support the conserved nature of TLR signaling across  mammalian species. PolyICLC and imiquimod will be trialed as immune adjuvants in   future DFTD vaccine formulations.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001205	28698009	Clinical research	Epithelial ovarian cancer, Primary peritoneal carcinoma etc.	Ovarian carcinoma	EFO:0001075	Ovary	IDO1 (P14902); 	IDO1; 	Epacadostat	Tamoxifen	Immune checkpoint therapy	Tamoxifen (DB00675); epacadostat (DB11717); 	22	20	A randomised, open-label, phase II	No significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.	The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples.	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat  (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125  relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or  fallopian tube cancer.	 Gynecol Oncol	 OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune  tolerance in ovarian cancer. This study investigated efficacy and safety of the  IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with  biochemical-only recurrence (CA-125 elevation) following complete remission after  first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or  fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255),   patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily  for successive 28-day cycles and stratified by time since completion of  first-line chemotherapy to first CA-125 elevation (3 to <12 or >/=12months). The   primary endpoint was investigator-assessed progression-free survival (PFS; RECIST  v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer  InterGroup criteria), overall survival, safety, and tolerability. RESULTS: The  study was terminated primarily due to slow accrual and lack of evidence of  superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months  for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable  patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifen patients had confirmed  CA-125 responses. The most common treatment-emergent adverse event was fatigue  (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed  with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%).  Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known  mechanism of action. IDO1 expression was observed in 94% of archival tumour  samples. CONCLUSIONS: This first report of immunotherapy evaluation in  biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in  ovarian cancer found no significant difference in efficacy between epacadostat  and tamoxifen. Epacadostat was generally well tolerated.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001206	28698009	Clinical research	Epithelial ovarian cancer, Primary peritoneal carcinoma etc.	Peritoneal carcinoma	MONDO:0015686	Soft tissue	IDO1 (P14902); 	IDO1; 	Epacadostat	Tamoxifen	Immune checkpoint therapy	Tamoxifen (DB00675); epacadostat (DB11717); 	22	20	A randomised, open-label, phase II	No significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.	The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples.	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat  (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125  relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or  fallopian tube cancer.	 Gynecol Oncol	 OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune  tolerance in ovarian cancer. This study investigated efficacy and safety of the  IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with  biochemical-only recurrence (CA-125 elevation) following complete remission after  first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or  fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255),   patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily  for successive 28-day cycles and stratified by time since completion of  first-line chemotherapy to first CA-125 elevation (3 to <12 or >/=12months). The   primary endpoint was investigator-assessed progression-free survival (PFS; RECIST  v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer  InterGroup criteria), overall survival, safety, and tolerability. RESULTS: The  study was terminated primarily due to slow accrual and lack of evidence of  superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months  for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable  patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifen patients had confirmed  CA-125 responses. The most common treatment-emergent adverse event was fatigue  (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed  with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%).  Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known  mechanism of action. IDO1 expression was observed in 94% of archival tumour  samples. CONCLUSIONS: This first report of immunotherapy evaluation in  biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in  ovarian cancer found no significant difference in efficacy between epacadostat  and tamoxifen. Epacadostat was generally well tolerated.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001207	28707403	Clinical research	Advanced metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	40	10	N/A	Our study showed that different anti-melanoma systemic therapies have different effects on the pigmentation of melanocytic lesions. BRAF inhibitor may have the propensity to cause darkening while D&T therapy and anti-PD1 caused lightening compared with controls.	In the control group, 19% of naevi lightened, 64% did not change and 17% darkened. Only the BRAF inhibitor group showed more darkened lesions than controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more lightened (49%) and fewer darkened naevi (9%) than controls, but differences were not significant.	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Melanocytic lesion evolution patterns with targeted therapies and immunotherapies  for advanced metastatic melanoma: An observational study.	 Australas J Dermatol	 BACKGROUND/OBJECTIVES: Various cutaneous side-effects have been reported with  anti-melanoma systemic therapies. This study investigated the changes in  melanocytic lesion pigmentation in patients on four different therapies. METHODS:  We analysed the serial dermatoscopic photographs of atypical melanocytic lesions   taken from patients with advanced metastatic melanoma on four different systemic   therapies (selective BRAF-inhibitor monotherapy, dabrafenib combined with  trametinib [D&T], anti-programmed cell death protein 1 [anti-PD1] therapies, and   anti-PD1 combined with ipilimumab) seen from February 2013 to May 2016. We  compared these changes with the melanocytic lesions of 10 control patients.  RESULTS: In the control group, 19% of naevi lightened, 64% did not change and 17%  darkened. Only the BRAF inhibitor group showed more darkened lesions than  controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T   therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups  (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more  lightened (49%) and fewer darkened naevi (9%) than controls, but differences were  not significant. CONCLUSIONS: Our study showed that different anti-melanoma  systemic therapies have different effects on the pigmentation of melanocytic  lesions. BRAF inhibitor may have the propensity to cause darkening while D&T  therapy and anti-PD1 caused lightening compared with controls. The findings  emphasise the importance of regular dermatological monitoring in specialised  clinics for patients on anti-melanoma systemic therapy. Clinicians should expect   changes in the global pigmentation of melanocytic lesions but be suspicious of  lesions with structural changes.CI  - (c) 2017 The Australasian College of Dermatologists.
CANIT0001208	28707403	Clinical research	Advanced metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	40	10	N/A	Our study showed that different anti-melanoma systemic therapies have different effects on the pigmentation of melanocytic lesions. BRAF inhibitor may have the propensity to cause darkening while D&T therapy and anti-PD1 caused lightening compared with controls.	In the control group, 19% of naevi lightened, 64% did not change and 17% darkened. Only the BRAF inhibitor group showed more darkened lesions than controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more lightened (49%) and fewer darkened naevi (9%) than controls, but differences were not significant.	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Melanocytic lesion evolution patterns with targeted therapies and immunotherapies  for advanced metastatic melanoma: An observational study.	 Australas J Dermatol	 BACKGROUND/OBJECTIVES: Various cutaneous side-effects have been reported with  anti-melanoma systemic therapies. This study investigated the changes in  melanocytic lesion pigmentation in patients on four different therapies. METHODS:  We analysed the serial dermatoscopic photographs of atypical melanocytic lesions   taken from patients with advanced metastatic melanoma on four different systemic   therapies (selective BRAF-inhibitor monotherapy, dabrafenib combined with  trametinib [D&T], anti-programmed cell death protein 1 [anti-PD1] therapies, and   anti-PD1 combined with ipilimumab) seen from February 2013 to May 2016. We  compared these changes with the melanocytic lesions of 10 control patients.  RESULTS: In the control group, 19% of naevi lightened, 64% did not change and 17%  darkened. Only the BRAF inhibitor group showed more darkened lesions than  controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T   therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups  (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more  lightened (49%) and fewer darkened naevi (9%) than controls, but differences were  not significant. CONCLUSIONS: Our study showed that different anti-melanoma  systemic therapies have different effects on the pigmentation of melanocytic  lesions. BRAF inhibitor may have the propensity to cause darkening while D&T  therapy and anti-PD1 caused lightening compared with controls. The findings  emphasise the importance of regular dermatological monitoring in specialised  clinics for patients on anti-melanoma systemic therapy. Clinicians should expect   changes in the global pigmentation of melanocytic lesions but be suspicious of  lesions with structural changes.CI  - (c) 2017 The Australasian College of Dermatologists.
CANIT0001209	28707403	Clinical research	Advanced metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	40	10	N/A	Our study showed that different anti-melanoma systemic therapies have different effects on the pigmentation of melanocytic lesions. BRAF inhibitor may have the propensity to cause darkening while D&T therapy and anti-PD1 caused lightening compared with controls.	In the control group, 19% of naevi lightened, 64% did not change and 17% darkened. Only the BRAF inhibitor group showed more darkened lesions than controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more lightened (49%) and fewer darkened naevi (9%) than controls, but differences were not significant.	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Melanocytic lesion evolution patterns with targeted therapies and immunotherapies  for advanced metastatic melanoma: An observational study.	 Australas J Dermatol	 BACKGROUND/OBJECTIVES: Various cutaneous side-effects have been reported with  anti-melanoma systemic therapies. This study investigated the changes in  melanocytic lesion pigmentation in patients on four different therapies. METHODS:  We analysed the serial dermatoscopic photographs of atypical melanocytic lesions   taken from patients with advanced metastatic melanoma on four different systemic   therapies (selective BRAF-inhibitor monotherapy, dabrafenib combined with  trametinib [D&T], anti-programmed cell death protein 1 [anti-PD1] therapies, and   anti-PD1 combined with ipilimumab) seen from February 2013 to May 2016. We  compared these changes with the melanocytic lesions of 10 control patients.  RESULTS: In the control group, 19% of naevi lightened, 64% did not change and 17%  darkened. Only the BRAF inhibitor group showed more darkened lesions than  controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T   therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups  (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more  lightened (49%) and fewer darkened naevi (9%) than controls, but differences were  not significant. CONCLUSIONS: Our study showed that different anti-melanoma  systemic therapies have different effects on the pigmentation of melanocytic  lesions. BRAF inhibitor may have the propensity to cause darkening while D&T  therapy and anti-PD1 caused lightening compared with controls. The findings  emphasise the importance of regular dermatological monitoring in specialised  clinics for patients on anti-melanoma systemic therapy. Clinicians should expect   changes in the global pigmentation of melanocytic lesions but be suspicious of  lesions with structural changes.CI  - (c) 2017 The Australasian College of Dermatologists.
CANIT0001210	28715523	Case report	Recurrent conjunctival melanoma	Conjunctival melanoma	EFO:1000204	Eye	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Good response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Pembrolizumab for Recurrent Conjunctival Melanoma.	 JAMA Ophthalmol	Unable to provide
CANIT0001211	28716069	Case report	Angiosarcoma	Angiosarcoma	EFO:0003968	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Although occasional  responses to immunotherapy have been reported for sarcomas, this case report  demonstrates that angiosarcoma can express PD-L1 and have a sustained response to  PD-1 directed therapy.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2017 Jul 18	 Angiosarcoma treated successfully with anti-PD-1 therapy - a case report.	 J Immunother Cancer	 BACKGROUND: Angiosarcomas are tumors of malignant endothelial origin that have a   poor prognosis with a five-year survival of less than 40%. These tumors can be  found in all age groups, but are more common in older patients; with the  cutaneous form most common in older white men. Combined modality therapy  including surgery and radiation appears to have a better outcome than each  modality alone. When metastatic, agents such as liposomal doxorubicin, paclitaxel  and ifosfamide have activity but it is short-lived and not curative.  Immunotherapy targeting either the PD-1 receptor or PD-L1 ligand has recently  been shown to have activity in multiple cancers including melanoma, renal, and  non-small lung cancer. Although these agents have been used in sarcoma therapy,  their ability to treat angiosarcoma has not been reported. CASE PRESENTATION:  Here we describe the case of a 63-year-old man who presented initially with  angiosarcoma of the nose and received surgery for the primary. Over 4 years he  had recurrent disease in the face and liver and was treated with nab-paclitaxel,   surgery, and radioembolization, but continued to have progressive disease. His  tumor was found to express PD-L1 and he received off-label pembrolizumab 2 mg/kg   every 21 days for 13 cycles with marked shrinkage of his liver disease and no new  facial lesions. Secondary to this therapy he developed hepatitis and has been  treated with decreasing doses of prednisone. During the 8 months off therapy he  has developed no new or progressive lesions. CONCLUSIONS: Although occasional  responses to immunotherapy have been reported for sarcomas, this case report  demonstrates that angiosarcoma can express PD-L1 and have a sustained response to  PD-1 directed therapy.
CANIT0001212	28716097	Case report	In transit metastases from cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Regression of multifocoal in transit melanoma metastases	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Jul 18	 Regression of multifocoal in transit melanoma metastases after palliative  resection of dominant masses and 2 years after treatment with ipilimumab.	 J Immunother Cancer	 BACKGROUND: Spontaneous regression of metastatic melanoma and delayed responses  more than one year after treatment with ipilimumab are rarely seen. CASE  PRESENTATION: Here, we present the case of a patient with in transit metastases  from cutaneous melanoma on his right lower extremity who achieved complete  regression of all metastatic lesions 13 months after the first of two consecutive  palliative resections of dominant masses and more than two years after treatment   with ipilimumab. CONCLUSION: The exact cause of our patient's sudden onset of  tumor regression remains speculative. We hypothesize that the operative trauma  followed by the postoperative infections augmented an innate immune response.
CANIT0001213	28716137	Case report	Recurrent lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); durvalumab (DB11714); 	1	N/A	Case	N/A	Progressive hypoventilation due to mixed CD8+ and CD4+ lymphocytic polymyositis	N/A	N/A	N/A	N/A	N/A	 2017 Jul 18	 Progressive hypoventilation due to mixed CD8(+) and CD4(+) lymphocytic  polymyositis following tremelimumab - durvalumab treatment.	 J Immunother Cancer	 BACKGROUND: The combination of CTLA-4 and PD-L1 inhibitors has a manageable  adverse effect profile, although rare immune-related adverse events (irAE) can  occur. CASE PRESENTATION: We describe an autoimmune polymyositis following a  partial response to combination tremelimumab and durvalumab for the treatment of   recurrent lung adenocarcinoma. Radiography revealed significant reduction in all   metastases; however, the patient developed progressive neuromuscular  hypoventilation due to lymphocytic destruction of the diaphragmatic musculature.   Serologic testing revealed a low level of de novo circulating antibodies against   striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy  with a mixed CD8(+) and CD4(+) lymphocyte infiltrate, indicative of inflammatory   myopathy. CONCLUSIONS: This case supports the hypothesis that muscle tissue is a   target for lymphocytic infiltration in immune checkpoint inhibitor-associated  polymyositis. Further insights into the autoimmune mechanism of PM will hopefully  contribute to the prevention and treatment of this phenomenon.
CANIT0001214	28726535	Case report	Mismatch repair deficient metastatic colon cancer and urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Pembrolizumab followed by atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); pembrolizumab (DB09037); 	1	N/A	Case	As the patient in 2016 was ineligible for clinical trials he received immune checkpoint anti-PD-1 therapy with pembrolizumab (200 mg every 3 weeks), on compassionate use basis, after the failure of second-line treatment. The patient's CEA initially responded to pembrolizumab for 4 months and then kept rising for 5 months before mildly declining again. His treatment was then switched to anti-PD-L1 therapy with atezolizumab as it was approved for urothelial carcinoma at that time, and his CEA declined again.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Sep 2	 Mismatch repair deficient metastatic colon cancer and urothelial cancer: A case  report of sequential immune checkpoint therapy.	 Cancer Biol Ther	 A major recent advance in cancer therapy involves the use of immune checkpoint  therapy for tumors with mismatch repair deficiency, as they have a high tumor  mutation load and neoantigen burden. Approximately 4% of advanced colorectal  cancer harbors a mismatch repair deficiency. When mismatch repair deficiency  exists in the germline, there is increased susceptibility to a variety of cancers  including colorectal cancer, uterine cancer, urothelial carcinoma, and skin  cancer. Herein we report the case of a 62-year-old man with mismatch repair  deficient metastatic colorectal adenocarcinoma, urothelial carcinoma and a  history of sebaceous carcinomas. As the patient in 2016 was ineligible for  clinical trials he received immune checkpoint anti-PD-1 therapy with  pembrolizumab (200 mg every 3 weeks), on compassionate use basis, after the  failure of second-line treatment. The patient's CEA initially responded to  pembrolizumab for 4 months and then kept rising for 5 months before mildly  declining again. His treatment was then switched to anti-PD-L1 therapy with  atezolizumab as it was approved for urothelial carcinoma at that time, and his  CEA declined again. This case raises interesting questions about caring for  patients with mismatch repair deficient colorectal cancer, including the role of   PD-L1 therapy, sequencing of immunotherapy, relying on CEA trends and determining  future therapies after progression on pembrolizumab.
CANIT0001215	28729154	Clinical research	Previously treated advanced malignant mesothelioma	Mesothelioma	EFO:0000588	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	Placebo	Immune checkpoint therapy	Tremelimumab (DB11771); 	382	189	A multicentre, international, randomised, double-blind, placebo-controlled phase IIb trial	Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors.	Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient.	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Tremelimumab as second-line or third-line treatment in relapsed malignant  mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind,  placebo-controlled phase 2b trial.	 Lancet Oncol	 BACKGROUND: New therapeutic strategies for malignant mesothelioma are urgently  needed. In the DETERMINE study, we investigated the effects of the  cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody  tremelimumab in patients with previously treated advanced malignant mesothelioma.  METHODS: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at  105 study centres across 19 countries in patients with unresectable pleural or  peritoneal malignant mesothelioma who had progressed after one or two previous  systemic treatments for advanced disease. Eligible patients were aged 18 years or  older with Eastern Cooperative Oncology Group performance status of 0 or 1 and  measurable disease as defined in the modified Response Evaluation Criteria In  Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1   for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of  three, stratified by European Organisation for Research and Treatment of Cancer  status (low risk vs high risk), line of therapy (second line vs third line), and   anatomic site (pleural vs peritoneal), by use of an interactive voice or web  system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks  for 7 doses and every 12 weeks thereafter until a treatment discontinuation  criterion was met. The primary endpoint was overall survival in the  intention-to-treat population. Safety was assessed in all patients who received  at least one dose of study drug. The trial is ongoing but no longer recruiting  participants, and is registered with ClinicalTrials.gov, number NCT01843374.  FINDINGS: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly  assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients  received treatment (two patients in the tremelimumab group were excluded from the  safety population because they did not receive treatment). At the data cutoff  date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group  and 154 (81%) of 189 patients had died in the placebo group. Median overall  survival in the intention-to-treat population did not differ between the  treatment groups: 7.7 months (95% CI 6.8-8.9) in the tremelimumab group and 7.3  months (5.9-8.7) in the placebo group (hazard ratio 0.92 [95% CI 0.76-1.12],  p=0.41). Treatment-emergent adverse events of grade 3 or worse occurred in 246  (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in  the placebo group; the most common were dyspnoea (34 [9%] patients in the  tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58  [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious  adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one  [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis   (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%)  of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo  group; those leading to the death of more than one patient were mesothelioma  (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group),  dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]),  myocardial infarction (three [1%] vs none), lung infection (three [1%] patients  vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs  none). Treatment-related adverse events leading to death occurred in five (1%)  patients in the tremelimumab group and none in the placebo group. The causes of  death were lung infection in one patient, intestinal perforation and small  intestinal obstruction in one patient; colitis in two patients, and neuritis and   skin ulcer in one patient. INTERPRETATION: Tremelimumab did not significantly  prolong overall survival compared with placebo in patients with previously  treated malignant mesothelioma. The safety profile of tremelimumab was consistent  with the known safety profile of CTLA-4 inhibitors. Investigations into whether  immunotherapy combination regimens can provide greater efficacy than  monotherapies in malignant mesothelioma are ongoing. FUNDING: AstraZeneca.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001216	28733892	Clinical research	Metastatic or recurrent NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); durvalumab (DB11714); 	41	N/A	N/A	Pseudoprogression was not frequently observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of immune-checkpoint inhibitors. Given the small number of patients studied, further study is warranted on whether treatment with immune-checkpoint inhibitors beyond RECIST progression benefits patients with advanced NSCLC.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2017 Sep	 Comparison of RECIST to immune-related response criteria in patients with  non-small cell lung cancer treated with immune-checkpoint inhibitors.	 Cancer Chemother Pharmacol	 PURPOSE: Given that immune-related response in non-small cell lung cancer (NSCLC)  has not been well evaluated, we assessed tumor response using the response  evaluation criteria in solid tumors, version 1.1 (RECIST v1.1) and immune-related  response criteria (irRC) to identify atypical responses in patients with advanced  NSCLC treated with immunotherapeutic agents. METHODS: Patients received  immune-checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, and  durvalumab plus tremelimumab) to treat metastatic or recurrent NSCLC after failed  platinum-based chemotherapy. Tumor response was assessed according to both RECIST  v1.1 and irRC. RESULTS: Responses by 41 patients were analyzed. The overall  response rate (ORR) was 29.2% (95% CI 17.6-44.5) assessed by RECIST v1.1 and  34.1% (95% CI 21.6-49.4) by irRC, showing similar results from the two methods (p  = 0.923). Two patients (4.9%) were defined as having progressive disease as  assessed by RECIST but not by irRC. The patients eventually experienced tumor  regression, suggesting delayed pseudoprogression. For all patients, the median  PFS was 5.1 months (95% CI 3.4-6.7) and OS was 18.3 months (95% CI 6.7-29.8). In   multivariate analysis, ex- or current smokers (HR 0.34, p = 0.14) and EGFR  mutation negativity (HR 0.16, p = 0.05) were associated with significantly longer  PFS. CONCLUSION: Our study found that pseudoprogression was not frequently  observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of  immune-checkpoint inhibitors. Given the small number of patients studied, further  study is warranted on whether treatment with immune-checkpoint inhibitors beyond   RECIST progression benefits patients with advanced NSCLC.
CANIT0001217	28733892	Clinical research	Metastatic or recurrent NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	41	N/A	N/A	Pseudoprogression was not frequently observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of immune-checkpoint inhibitors. Given the small number of patients studied, further study is warranted on whether treatment with immune-checkpoint inhibitors beyond RECIST progression benefits patients with advanced NSCLC.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2017 Sep	 Comparison of RECIST to immune-related response criteria in patients with  non-small cell lung cancer treated with immune-checkpoint inhibitors.	 Cancer Chemother Pharmacol	 PURPOSE: Given that immune-related response in non-small cell lung cancer (NSCLC)  has not been well evaluated, we assessed tumor response using the response  evaluation criteria in solid tumors, version 1.1 (RECIST v1.1) and immune-related  response criteria (irRC) to identify atypical responses in patients with advanced  NSCLC treated with immunotherapeutic agents. METHODS: Patients received  immune-checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, and  durvalumab plus tremelimumab) to treat metastatic or recurrent NSCLC after failed  platinum-based chemotherapy. Tumor response was assessed according to both RECIST  v1.1 and irRC. RESULTS: Responses by 41 patients were analyzed. The overall  response rate (ORR) was 29.2% (95% CI 17.6-44.5) assessed by RECIST v1.1 and  34.1% (95% CI 21.6-49.4) by irRC, showing similar results from the two methods (p  = 0.923). Two patients (4.9%) were defined as having progressive disease as  assessed by RECIST but not by irRC. The patients eventually experienced tumor  regression, suggesting delayed pseudoprogression. For all patients, the median  PFS was 5.1 months (95% CI 3.4-6.7) and OS was 18.3 months (95% CI 6.7-29.8). In   multivariate analysis, ex- or current smokers (HR 0.34, p = 0.14) and EGFR  mutation negativity (HR 0.16, p = 0.05) were associated with significantly longer  PFS. CONCLUSION: Our study found that pseudoprogression was not frequently  observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of  immune-checkpoint inhibitors. Given the small number of patients studied, further  study is warranted on whether treatment with immune-checkpoint inhibitors beyond   RECIST progression benefits patients with advanced NSCLC.
CANIT0001218	28733892	Clinical research	Metastatic or recurrent NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	41	N/A	N/A	Pseudoprogression was not frequently observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of immune-checkpoint inhibitors. Given the small number of patients studied, further study is warranted on whether treatment with immune-checkpoint inhibitors beyond RECIST progression benefits patients with advanced NSCLC.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2017 Sep	 Comparison of RECIST to immune-related response criteria in patients with  non-small cell lung cancer treated with immune-checkpoint inhibitors.	 Cancer Chemother Pharmacol	 PURPOSE: Given that immune-related response in non-small cell lung cancer (NSCLC)  has not been well evaluated, we assessed tumor response using the response  evaluation criteria in solid tumors, version 1.1 (RECIST v1.1) and immune-related  response criteria (irRC) to identify atypical responses in patients with advanced  NSCLC treated with immunotherapeutic agents. METHODS: Patients received  immune-checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, and  durvalumab plus tremelimumab) to treat metastatic or recurrent NSCLC after failed  platinum-based chemotherapy. Tumor response was assessed according to both RECIST  v1.1 and irRC. RESULTS: Responses by 41 patients were analyzed. The overall  response rate (ORR) was 29.2% (95% CI 17.6-44.5) assessed by RECIST v1.1 and  34.1% (95% CI 21.6-49.4) by irRC, showing similar results from the two methods (p  = 0.923). Two patients (4.9%) were defined as having progressive disease as  assessed by RECIST but not by irRC. The patients eventually experienced tumor  regression, suggesting delayed pseudoprogression. For all patients, the median  PFS was 5.1 months (95% CI 3.4-6.7) and OS was 18.3 months (95% CI 6.7-29.8). In   multivariate analysis, ex- or current smokers (HR 0.34, p = 0.14) and EGFR  mutation negativity (HR 0.16, p = 0.05) were associated with significantly longer  PFS. CONCLUSION: Our study found that pseudoprogression was not frequently  observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of  immune-checkpoint inhibitors. Given the small number of patients studied, further  study is warranted on whether treatment with immune-checkpoint inhibitors beyond   RECIST progression benefits patients with advanced NSCLC.
CANIT0001219	28733892	Clinical research	Metastatic or recurrent NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	41	N/A	N/A	Pseudoprogression was not frequently observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of immune-checkpoint inhibitors. Given the small number of patients studied, further study is warranted on whether treatment with immune-checkpoint inhibitors beyond RECIST progression benefits patients with advanced NSCLC.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2017 Sep	 Comparison of RECIST to immune-related response criteria in patients with  non-small cell lung cancer treated with immune-checkpoint inhibitors.	 Cancer Chemother Pharmacol	 PURPOSE: Given that immune-related response in non-small cell lung cancer (NSCLC)  has not been well evaluated, we assessed tumor response using the response  evaluation criteria in solid tumors, version 1.1 (RECIST v1.1) and immune-related  response criteria (irRC) to identify atypical responses in patients with advanced  NSCLC treated with immunotherapeutic agents. METHODS: Patients received  immune-checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, and  durvalumab plus tremelimumab) to treat metastatic or recurrent NSCLC after failed  platinum-based chemotherapy. Tumor response was assessed according to both RECIST  v1.1 and irRC. RESULTS: Responses by 41 patients were analyzed. The overall  response rate (ORR) was 29.2% (95% CI 17.6-44.5) assessed by RECIST v1.1 and  34.1% (95% CI 21.6-49.4) by irRC, showing similar results from the two methods (p  = 0.923). Two patients (4.9%) were defined as having progressive disease as  assessed by RECIST but not by irRC. The patients eventually experienced tumor  regression, suggesting delayed pseudoprogression. For all patients, the median  PFS was 5.1 months (95% CI 3.4-6.7) and OS was 18.3 months (95% CI 6.7-29.8). In   multivariate analysis, ex- or current smokers (HR 0.34, p = 0.14) and EGFR  mutation negativity (HR 0.16, p = 0.05) were associated with significantly longer  PFS. CONCLUSION: Our study found that pseudoprogression was not frequently  observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of  immune-checkpoint inhibitors. Given the small number of patients studied, further  study is warranted on whether treatment with immune-checkpoint inhibitors beyond   RECIST progression benefits patients with advanced NSCLC.
CANIT0001220	28734029	Case report	Metastatic clear cell carcinoma with dialysis treatment	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A remarkable improvement without any adverse events	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Successful treatment of metastatic clear cell carcinoma with nivolumab in a  patient receiving dialysis treatment.	 Int J Urol	 The efficacy and safety of nivolumab for patients receiving dialysis treatment  has not been established yet. Herein, we describe a patient on dialysis  successfully treated with nivolumab as seventh-line therapy for metastatic renal   cell carcinoma. Before initiating nivolumab, he had respiratory discomfort  induced by a lesion occluding the left intermediate bronchus that originated from  the metastatic lymph node behind the tracheal bifurcation. Four weeks after  nivolumab was initiated, his symptom remarkably improved, and the occlusion  disappeared according to the bronchoscopy examination. The effectiveness and  safety of nivolumab has continued for 6 months. There are few cases in which  nivolumab has been given to patients on dialysis. In the present case, nivolumab   was given to a patient on dialysis, and it resulted in a remarkable improvement  without any adverse events.CI  - (c) 2017 The Japanese Urological Association.
CANIT0001221	28734759	Clinical research	Metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	74	N/A	A multicentre, open-label, phase II trial	Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients.	The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator.	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2017 Sep	 Nivolumab in patients with metastatic DNA mismatch repair-deficient or  microsatellite instability-high colorectal cancer (CheckMate 142): an open-label,  multicentre, phase 2 study.	 Lancet Oncol	 BACKGROUND: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite  instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment  with conventional chemotherapy and exhibits high levels of tumour neoantigens,  tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features  are associated with the response to PD-1 blockade in other tumour types.  Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in  patients with dMMR/MSI-H metastatic colorectal cancer. METHODS: In this ongoing,   multicentre, open-label, phase 2 trial, we enrolled adults (aged >/=18 years)  with histologically confirmed recurrent or metastatic colorectal cancer locally  assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight  countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the  USA). Eligible patients had progressed on or after, or been intolerant of, at  least one previous line of treatment, including a fluoropyrimidine and  oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks  until disease progression, death, unacceptable toxic effects, or withdrawal from   study. The primary endpoint was investigator-assessed objective response as per  Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who  received at least one dose of study drug were included in all analyses. This  trial is registered with ClinicalTrials.gov, number NCT02060188. FINDINGS: Of the  74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40  (54%) had received three or more previous treatments. At a median follow-up of  12.0 months (IQR 8.6-18.0), 23 (31.1%, 95% CI 20.8-42.9) of 74 patients achieved   an investigator-assessed objective response and 51 (69%, 57-79) patients had  disease control for 12 weeks or longer. Median duration of response was not yet  reached; all responders were alive, and eight had responses lasting 12 months or   longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62-95). The most common grade   3 or 4 drug-related adverse events were increased concentrations of lipase (six  [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of  these deaths were deemed to be treatment related by the investigator.  INTERPRETATION: Nivolumab provided durable responses and disease control in  pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a  new treatment option for these patients. FUNDING: Bristol-Myers Squibb.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001222	28736218	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	101	N/A	A retrospective cohort study	Decreased relative lymphocyte count is associated with G3/4 and lung/GI immune-related adverse events.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Relative lymphocyte counts	Cell percentage/counts in blood	 2017 Nov	 Fluctuations in routine blood count might signal severe immune-related adverse  events in melanoma patients treated with nivolumab.	 J Dermatol Sci	 BACKGROUND: Although nivolumab significantly prolongs survival of metastatic  melanoma, about 10% of patients experience severe, even fatal immune-related  adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great  interest. OBJECTIVE: We aimed to correlate changes in routine blood count  parameters to the occurrence of serious irAEs (grade 3/4 [G3/4] or  lung/gastrointestinal [lung/GI] irAEs) in patients with melanoma who were treated  with nivolumab. METHODS: We retrospectively analyzed data from 101 patient with  melanoma treated with nivolumab from 8 institutes in Japan. We used logistic  regression analyses to investigate associations between severe irAEs and  fluctuations in routine blood count parameters (total white blood cell [WBC]  count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during  the treatment. Receiver-operating characteristic curve was used to determine a  cutoff value for the blood count parameters and area under the curve (AUC).  RESULTS: Univariate analysis revealed that G3/4 irAEs were associated with  increased total WBC count (P=0.034, cutoff value=+27%, AUC=0.68, odds ratio  [OR]=1.58) and decreased relative lymphocyte count (RLC, P=0.042, cutoff  value=-23%, AUC=0.65, OR=1.65). However, multivariate analysis showed that the  same factors, increased WBC count (P=0.014, cutoff value=+59.1%, AUC=0.79,  OR=6.04) and decreased RLC (P=0.012, cutoff value=-32.3%, AUC=0.81, OR=5.01) were  independent factors associated with lung/GI irAEs. CONCLUSIONS: Our results  suggest that increased WBC count and decreased RLC are associated with G3/4 and  lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence   was noticed and, therefore, these factors are not predictive, however, they could  be a signal of severe irAE occurrence in patients with melanoma treated with  nivolumab.CI  - Copyright (c) 2017 Japanese Society for Investigative Dermatology. Published by  Elsevier B.V. All rights reserved.
CANIT0001223	28736218	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	101	N/A	A retrospective cohort study	Increased white blood cell count is associated with G3/4 and lung/GI immune-related adverse events.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	White blood cell counts	Cell percentage/counts in blood	 2017 Nov	 Fluctuations in routine blood count might signal severe immune-related adverse  events in melanoma patients treated with nivolumab.	 J Dermatol Sci	 BACKGROUND: Although nivolumab significantly prolongs survival of metastatic  melanoma, about 10% of patients experience severe, even fatal immune-related  adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great  interest. OBJECTIVE: We aimed to correlate changes in routine blood count  parameters to the occurrence of serious irAEs (grade 3/4 [G3/4] or  lung/gastrointestinal [lung/GI] irAEs) in patients with melanoma who were treated  with nivolumab. METHODS: We retrospectively analyzed data from 101 patient with  melanoma treated with nivolumab from 8 institutes in Japan. We used logistic  regression analyses to investigate associations between severe irAEs and  fluctuations in routine blood count parameters (total white blood cell [WBC]  count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during  the treatment. Receiver-operating characteristic curve was used to determine a  cutoff value for the blood count parameters and area under the curve (AUC).  RESULTS: Univariate analysis revealed that G3/4 irAEs were associated with  increased total WBC count (P=0.034, cutoff value=+27%, AUC=0.68, odds ratio  [OR]=1.58) and decreased relative lymphocyte count (RLC, P=0.042, cutoff  value=-23%, AUC=0.65, OR=1.65). However, multivariate analysis showed that the  same factors, increased WBC count (P=0.014, cutoff value=+59.1%, AUC=0.79,  OR=6.04) and decreased RLC (P=0.012, cutoff value=-32.3%, AUC=0.81, OR=5.01) were  independent factors associated with lung/GI irAEs. CONCLUSIONS: Our results  suggest that increased WBC count and decreased RLC are associated with G3/4 and  lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence   was noticed and, therefore, these factors are not predictive, however, they could  be a signal of severe irAE occurrence in patients with melanoma treated with  nivolumab.CI  - Copyright (c) 2017 Japanese Society for Investigative Dermatology. Published by  Elsevier B.V. All rights reserved.
CANIT0001224	28736235	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	69	N/A	N/A	HLA-A*26 allele is correlated with response to nivolumab therapy (odds ratio = 4.93, P = 0.028, Fisher exact test).	N/A	N/A	N/A	HLA (P04439); 	HLA-A*26	Mutational status	 2017 Nov	 HLA-A*26 Is Correlated With Response to Nivolumab in Japanese Melanoma Patients.	 J Invest Dermatol	Unable to provide
CANIT0001225	28737580	Case report	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Pulmonary sarcoidosis	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Nivolumab-Induced Development of Pulmonary Sarcoidosis in Renal Cell Carcinoma.	 Clin Nucl Med	 A 64-year-old woman with metastatic clear cell renal carcinoma who had been on  nivolumab immunotherapy for 10 months was referred for a FDG PET scan to monitor   disease progress. New bilateral mediastinal and hilar FDG-avid lymphadenopathy  was noted. Pathology on subsequent mediastinal nodal biopsy showed well-formed  epithelioid granulomas with no evidence of malignancy consistent with  sarcoidosis. This case illustrates that pulmonary sarcoidosis can be induced by  immunotherapy in the treatment of renal cell carcinoma.
CANIT0001226	28737620	Case report	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Sarcoidosis	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma.	 J Immunother	 Immune checkpoint inhibitors represent the newest treatment for stage IV  melanoma. These agents are generally well tolerated, however severe  immune-related adverse effects have been noted in a small, but clinically  significant percentage of patients. Specifically, sarcoidosis is a known  potential complication following anti-CTLA-4 therapy. We present 2 cases of  pulmonary and cutaneous sarcoidosis developing in patients with stage IV  melanoma. Both patients were treated with ipilimumab and anti-PD-1 therapy, and  both experienced good oncologic responses to treatment; neither had evidence of  preexisting sarcoidosis. Of note, both patients developed sarcoidosis only after   undergoing immune checkpoint inhibitor therapy. In 1 patient, sarcoidosis  developed after initiation of anti-PD-1 therapy, 3 months after the last dose of   anti-CTLA-4 monotherapy, suggesting a synergistic immune dysmodulating effect of   both checkpoint inhibitors. Ultimately, both patients' symptoms and radiologic  findings resolved with corticosteroid treatment, and both patients have tolerated  retreatment with PD-1 inhibitors. Sarcoidosis is a rare complication of immune  checkpoint inhibitors and can manifest with severe pulmonary manifestations.  However, sarcoidosis in this setting is responsive to corticosteroids and does  not necessarily recur with retreatment. It is yet unclear whether the development  of sarcoidosis in these patients represents unmasking of preexisting autoimmune  tendencies or is a marker of oncologic response.
CANIT0001227	28737620	Case report	Stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab followed by nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Sarcoidosis	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma.	 J Immunother	 Immune checkpoint inhibitors represent the newest treatment for stage IV  melanoma. These agents are generally well tolerated, however severe  immune-related adverse effects have been noted in a small, but clinically  significant percentage of patients. Specifically, sarcoidosis is a known  potential complication following anti-CTLA-4 therapy. We present 2 cases of  pulmonary and cutaneous sarcoidosis developing in patients with stage IV  melanoma. Both patients were treated with ipilimumab and anti-PD-1 therapy, and  both experienced good oncologic responses to treatment; neither had evidence of  preexisting sarcoidosis. Of note, both patients developed sarcoidosis only after   undergoing immune checkpoint inhibitor therapy. In 1 patient, sarcoidosis  developed after initiation of anti-PD-1 therapy, 3 months after the last dose of   anti-CTLA-4 monotherapy, suggesting a synergistic immune dysmodulating effect of   both checkpoint inhibitors. Ultimately, both patients' symptoms and radiologic  findings resolved with corticosteroid treatment, and both patients have tolerated  retreatment with PD-1 inhibitors. Sarcoidosis is a rare complication of immune  checkpoint inhibitors and can manifest with severe pulmonary manifestations.  However, sarcoidosis in this setting is responsive to corticosteroids and does  not necessarily recur with retreatment. It is yet unclear whether the development  of sarcoidosis in these patients represents unmasking of preexisting autoimmune  tendencies or is a marker of oncologic response.
CANIT0001228	28746020	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Pancytopenia	N/A	N/A	N/A	N/A	N/A	2017	 Pembrolizumab-Induced Pancytopenia: A Case Report.	 Perm J	 INTRODUCTION: Programmed death receptor-1 blockade with pembrolizumab is approved  by the US Food and Drug Administration to treat patients with metastatic  melanoma. Activating T cells to fight cancer may cause immune-mediated adverse  events. Pembrolizumab-induced pancytopenia has not been previously reported in  the medical literature, to our knowledge. CASE PRESENTATION: A 52-year-old  Caucasian woman with a diagnosis of metastatic melanoma of the rectum experienced  multiple adverse events along her course of therapy with pembrolizumab, ranging  from colitis, hepatitis, gastritis, and vitiligo after the fifth cycle of  pembrolizumab; to knee synovitis after the 14th cycle; and to severe pancytopenia  after the 18th cycle of pembrolizumab. Severe pancytopenia improved after  high-dose corticosteroids and a 5-day course of intravenous immunoglobulin  therapy. DISCUSSION: In our case, pembrolizumab-induced Grade 4 pancytopenia  resolved via a combination of corticosteroids and intravenous immunoglobulins.  Pancytopenia reached a nadir in 10 weeks, and it took 16 weeks for meaningful  recovery.
CANIT0001229	28751414	Case report	Non-small cell lung cancer patients with poor performance status and major leukocytosis	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Lazarus syndrome	N/A	N/A	N/A	N/A	N/A	2017 Jul 27	Lazarus syndrome in nonsmall cell lung cancer patients with poor performance status and major leukocytosis following nivolumab treatment.	Eur Respir J	Unable to provide
CANIT0001230	28753231	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab, dabrafenib plus trametinib followed by ipilimumab	N/A	Immune checkpoint therapy	Trametinib (DB08911); dabrafenib (DB08912); pembrolizumab (DB09037); ipilimumab (DB06186); 	4	N/A	Case	Lichenoid inflammation with incidental suprabasilar acantholysis or vesiculation	Four patients presented with interface dermatitis with microscopic intraepidermal clefts. In 2 patients, the clefts were well developed and had some acantholytic cells while the other 2 appeared to be spongiosis or inflammation related. Immunofluorescence was negative in 1 patient. None of them had clinical findings in keeping with paraneoplastic pemphigus (PP) and the symptoms improved with either topical corticosteroid or withdrawal of immunotherapy.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 PD-1 inhibitor-associated lichenoid inflammation with incidental suprabasilar  acantholysis or vesiculation-Report of 4 cases.	 J Cutan Pathol	 BACKGROUND: Immune checkpoint agents targeting programmed cell death-1 protein  (PD1) or cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) receptors are  increasingly utilized in treatment of advanced malignancies. However, these  immunotherapies are commonly associated with idiosyncratic cutaneous adverse  reactions. Thus, recognition and awareness of these reactions are necessary.  METHODS: We reviewed the skin biopsies of all patients on anti-PD1 therapy with  or without ipilimumab who developed lichenoid inflammation and included those  with microscopic suprabasal or intraepidermal clefts. RESULTS: Four patients  presented with interface dermatitis with microscopic intraepidermal clefts. In 2   patients, the clefts were well developed and had some acantholytic cells while  the other 2 appeared to be spongiosis or inflammation related. Immunofluorescence  was negative in 1 patient. None of them had clinical findings in keeping with  paraneoplastic pemphigus (PP) and the symptoms improved with either topical  corticosteroid or withdrawal of immunotherapy. CONCLUSIONS: Lichenoid drug  reaction occurring in patients receiving anti-PD1 therapy may be associated with   microscopic suprabasal or intraepidermal clefting. The clinical course was  similar to lichenoid drug reactions without clefting even though some lesions may  resemble PP microscopically.CI  - (c) 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001231	28754096	Case report	Relapsed natural killer/T-cell lymphoma	Mature t-cell and nk-cell non-hodgkin lymphoma	MONDO:0000430	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Clinical complete remission	The only adverse event was soreness of the upper limb joints and muscles.	N/A	N/A	N/A	N/A	N/A	 2017 Jul 28	 Successful treatment with anti-programmed-death-1 antibody in a relapsed natural   killer/T-cell lymphoma patient with multi-line resistance: a case report.	 BMC Cancer	 BACKGROUND: Extranodal natural killer/T-cell lymphoma (NKTCL), nasal type, is an   aggressive malignancy with poor prognosis. Currently, there is no recommended  standard therapy for relapsed NKTCL. CASE PRESENTATION: A 37-year-old woman with   lymphadenopathy was diagnosed with NKTCL by biopsy of an enlarged lymph node on  the right side of her neck. Enhanced computed tomography revealed no metastasis.   For this patient, we performed continuous chemotherapy followed by radiotherapy;   however, nodule biopsy showed metastases in her lower limbs 3 months after  radiotherapy, which confirmed disease progression. Unfortunately, the patient(')   s temperature was persistently high and her skin ulcers could not be controlled  well using multi-line treatment. Therefore, we attempted treatment with the  anti-programmed-death-1 (PD-1) antibody, pembrolizumab. Surprisingly, the patient  achieved clinical complete remission (CR) after four cycles of pembrolizumab  treatment, despite having persistent detectable Epstein-Barr virus (EBV) DNA.  Other molecular monitoring techniques were unavailable for this patient owing to   the retrospective nature of the study. The only adverse event was soreness of the  upper limb joints and muscles. CONCLUSION: This relapsed NKTCL case treated with   pembrolizumab showed that multimodal therapy including pembrolizumab would be  partially or totally effective for relapsed NKTCL.
CANIT0001232	28756224	Basic research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	RMP1-14	N/A	Immune checkpoint therapy	RMP1-14 (NCIT:C128037); 	Cell lines/ animal models	N/A	Basic research	Our results suggest that anti-PD-1 antibody treatment has little effect on afatinib-induced lung injury.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2017 Sep 23	 Treatment with a programmed cell death-1-specific antibody has little effect on  afatinib- and naphthalene-induced acute pneumonitis in mice.	 Biochem Biophys Res Commun	 Although several antibodies developed to target programmed cell death-1 (PD-1)  and its ligand (PD-L1) have demonstrated great promise for the treatment of  non-small cell lung cancer (NSCLC), and other malignancies, these therapeutic  antibodies can cause pneumonitis. Furthermore, epidermal growth factor  receptor-tyrosine kinase inhibitor (EGFR-TKI)-induced pneumonitis was reported  after treatment with anti PD-1 antibodies. We previously demonstrated that mice  with naphthalene-induced airway epithelial injury developed severe  gefitinib-induced pneumonitis through a neutrophil-dependent mechanism. The  present study aimed to investigate whether treatment with afatinib, an EGFR-TKI  that effectively targets EGFR mutation-positive NSCLC, and anti PD-1 antibodies  induces pneumonitis in mice. C57BL/6J mice were treated intraperitoneally with  naphthalene (200 mg/kg) on day 0. Afatinib (20 mg/kg) was administered orally on   days -1 to 13. An anti-PD-1 antibody (0.2 mg/mice) was also administered  intraperitoneally every 3 days from day 1 until day 13. The bronchoalveolar  lavage fluid (BALF) and lung tissues were sampled on day 14. As observed  previously with gefitinib, afatinib significantly increased the severity of  histopathologic findings and the level of protein in BALF on day 14, compared to   treatment with naphthalene alone. A combined anti-PD-1 antibody and afatinib  treatment after naphthalene administration had yielded the same histopathological  grade of lung inflammation as did afatinib treatment alone. Our results suggest  that anti-PD-1 antibody treatment has little effect on afatinib-induced lung  injury.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001233	28774862	Case report	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Nivolumab enhances the inflammation of the irradiation field	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Nivolumab Enhances the Inflammation of the Irradiation Field in Advanced  Non-Small Cell Lung Cancer.	 J Thorac Oncol	Unable to provide
CANIT0001234	28778931	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Cerebellar dysfunction due to severe hypothyroidism induced by pembrolizumab	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Hypothyroid ataxia complicating monoclonal antibody therapy.	 Pract Neurol	 We present a case of cerebellar dysfunction due to severe hypothyroidism induced   by pembrolizumab, a member of the 'immune checkpoint inhibitor' class of cancer  immunotherapies. Thyroxine replacement completely resolved his symptoms and  signs. We also discuss the neurological immune-related complications of  checkpoint inhibitors.CI  - (c) Article author(s) (or their employer(s) unless otherwise stated in the text  of the article) 2017. All rights reserved. No commercial use is permitted unless   otherwise expressly granted.
CANIT0001235	28778959	Case report	Anaplastic Thyroid Cancer	Anaplastic thyroid carcinoma	EFO:1000595	Thyroid	PD-1 (Q15116); BRAF (P15056); 	PD-1; BRAF	Nivolumab plus vemurafenib	N/A	Immune checkpoint therapy plus Target therapy	Vemurafenib (DB08881); nivolumab (DB09035); 	1	N/A	Case	Exceptional Response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Exceptional Response with Immunotherapy in a Patient with Anaplastic Thyroid  Cancer.	 Oncologist	 Chemotherapy with or without radiation is the standard therapy for anaplastic  thyroid cancer (ATC), although the response rate is not high and not durable. We   describe a 62-year-old male who was diagnosed with ATC and initially treated with  a thyroidectomy and lymph node dissection, followed by chemotherapy. Next  generation sequencing was then performed to guide therapy and the tumor was found  to have BRAF and programmed death-ligand 1 (PD-L1) positivity that was  subsequently treated with vemurafenib and nivolumab. This led to substantial  regression of tumor nodules. Genomic sequencing-based approaches to identify  therapeutic targets has potential for improving outcomes. Currently, the patient   continues to be in complete radiographic and clinical remission 20 months after  beginning treatment with nivolumab. KEY POINTS: Programmed death-1 (PD-1)/PD-L1  immunotherapy has shown evidence of durable responses in certain malignancies  such as melanoma, lung cancer, and renal cell carcinoma.PD-L1 positive tumors  promote autoimmunity against the tumor; therefore, PD-1/PD-L1 blockade may be  beneficial.Molecular profiling could possibly result in improved targeted therapy  for certain malignancies.CI  - (c) AlphaMed Press 2017.
CANIT0001236	28780994	Case report	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	Cell lines	N/A	Case	N/A	Cardiogenic shock	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2017 Dec	 Cardiogenic shock in a patient being treated with atezolizumab for metastatic  non-small cell lung cancer.	 Lung Cancer	Unable to provide
CANIT0001237	28783540	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Gamma-Knife followed by ipilimumab	Gamma-Knife	Radiotherapy followed by Immune checkpoint therapy	Gamma-knife (NCIT:C15382); ipilimumab (DB06186); 	76	29	A retrospective cohort study	In real-life MM pts with BMs, a strategy aiming at controlling BM with GK together with TT and/or TT seems to achieve unprecedented survival rates.	N/A	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2017 Oct	 Survival of melanoma patients treated with targeted therapy and immunotherapy  after systematic upfront control of brain metastases by radiosurgery.	 Eur J Cancer	 BACKGROUND: Targeted therapy (TT) and immunotherapies (ITs) have dramatically  improved survival in metastatic melanoma (MM). However, their efficacy on brain  metastasis (BM) remains limited and poorly documented. PATIENTS AND METHODS:  Retrospective cohort of consecutive MM patients (pts) with BMs, all  systematically upfront treated by Gamma-Knife (GK) at first BM and retreated in  case of new BMs, from 2010 to 2015 at the time when ipilimumab BRAF +/- MEK  inhibitors and anti-PD1 were introduced in practice. Survival after 1st GK  (OSGK1) according to prognostic factors and treatment. RESULTS: Among 179  consecutive pts treated by GK, 109 received IT and/or TT after the 1st GK. Median  OSGK1 was 10.95 months and 1- and 2-year survival rates were 49.5% and 27.4%,  respectively, versus a median overall survival (OS) of 2.29 months (p < .001) in   those who did not receive IT or TT. In pts who initially had a single BM, median   OS and 1- and 2-year survival rates were 14.46 months, 66.7% and 43.4%,  respectively; in pts with 2-3 BMs: 8.85 months, 46.4% and 31%, respectively; in  pts with >3 BMs: 7.25 months, 37.2% and 11.9%, respectively. Multivariate  analysis for OSGK1 confirmed that IT and TT were significantly and highly  protective. Best OSGK1 was observed in BRAF-wild-type pts receiving anti-PD1 or  in BRAF-mutated pts receiving BRAF-inhibitors and anti-PD1 (12.26 and 14.82  months, respectively). CONCLUSION: In real-life MM pts with BMs, a strategy  aiming at controlling BM with GK together with TT and/or TT seems to achieve  unprecedented survival rates.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001238	28788102	Clinical research	Metastatic basal cell carcinoma	Basal cell carcinoma	EFO:0004193	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	N/A	Since immunotherapy response rates are  higher in patients with more genomically complex tumors, our observations suggest  that, in contrast with the premise of earlier treatment is better, which holds  true for targeted and cytotoxic therapies, immunotherapy may be better suited to   more advanced disease. Near complete remission but developed new primary cutaneous basal cell carcinomas.	N/A	N/A	N/A	More advanced disease (NCIT:C9270); 	More advanced disease	Disease status	 2017 Jul 31	 Appearance of New Cutaneous Superficial Basal Cell Carcinomas during Successful  Nivolumab Treatment of Refractory Metastatic Disease: Implications for  Immunotherapy in Early Versus Late Disease.	 Int J Mol Sci	 Metastatic basal cell carcinoma may be treated with hedgehog pathway inhibitors,   including vismodegib and sonidegib. However, patients can demonstrate resistance   to these agents. We describe a man with metastatic basal cell carcinoma who did  not respond well to vismodegib and sonidegib. Next generation sequencing of his  metastatic liver tumor demonstrated a high tumor mutational burden (103 mutations  per megabase) and the genomic amplification of PD-L1, both of which are features   that predict response to anti-PD1/PD-L1 immunotherapy. Treatment with nivolumab,   an anti-PD1 checkpoint inhibitor, resulted in near complete remission. Yet, he  developed new primary cutaneous basal cell carcinomas while receiving  immunotherapy and while his metastatic disease showed an ongoing response. His  new superficial skin cancer had a lower tumor mutational burden (45 mutations per  megabase) than the metastatic disease. Since immunotherapy response rates are  higher in patients with more genomically complex tumors, our observations suggest  that, in contrast with the premise of earlier treatment is better, which holds  true for targeted and cytotoxic therapies, immunotherapy may be better suited to   more advanced disease.
CANIT0001239	28794361	Case report	Unresectable sinonasal melanoma	Sinonasal undifferentiated carcinoma	EFO:1000527	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Complete response	Acute fibrinous and organizing pneumonia	N/A	N/A	N/A	N/A	N/A	 2017 Sep 1	 Nivolumab-induced Acute Fibrinous and Organizing Pneumonia (AFOP).	 Intern Med	 Although nivolumab is known to cause immune-related interstitial lung diseases  (ILD), the detailed characteristics of ILD are still not fully understood. A  68-year-old man was treated with nivolumab because of unresectable sinonasal  melanoma, he achieved a complete response soon after the initiation of the  therapy and a complete response was thereafter maintained for 30 weeks until the   patient experienced dyspnea of subacute onset. CT images revealed patchy  infiltrates and ground-glass opacifications. The bronchoalveolar lavage fluid  (BALF) contained elevated percentages of lymphocytes (53%) and neutrophils (30%).  A transbronchial lung biopsy revealed intraalveolar fibrin balls without hyaline   membranes, which was considered to be consistent with the pattern of acute  fibrinous and organizing pneumonia (AFOP). This is the first report of AFOP  induced by nivolumab.
CANIT0001240	28807048	Case report	1 melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Poor prognosis	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 15	 Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1   inhibitors: a case series.	 J Immunother Cancer	 BACKGROUND: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained  increasing attention across many solid tumors and hematologic malignancies due to  their efficacy and favorable toxicity profile. With more than 1 agent now  FDA-approved in a wide variety of tumor types, and with others in clinical  trials, it is becoming more common that patients present to clinic for potential   treatment with a second PD-1/PD-L1 inhibitor. CASE PRESENTATION: In this report,   we present two patients with renal cell carcinoma and one with melanoma who  received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1  inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all   cases) and all had progressive disease as their best response to the subsequent  PD-1 inhibitor. The reported clinical information focuses on the course of the  disease and the responses to all treatment regimens. CONCLUSIONS: Clinicians  should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of   clinical trials until there is sufficient data to support this practice  routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are  needed to validate the efficacy and safety of these drugs in the second line or  later setting. Furthermore, ongoing efforts that aim to identify mechanisms of  resistance to immunotherapy will be informative and may ultimately assist  physicians in select the optimal treatment following progression on PD-1/PD-L1  inhibitor.
CANIT0001241	28807048	Case report	1 melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Poor prognosis	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 15	 Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1   inhibitors: a case series.	 J Immunother Cancer	 BACKGROUND: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained  increasing attention across many solid tumors and hematologic malignancies due to  their efficacy and favorable toxicity profile. With more than 1 agent now  FDA-approved in a wide variety of tumor types, and with others in clinical  trials, it is becoming more common that patients present to clinic for potential   treatment with a second PD-1/PD-L1 inhibitor. CASE PRESENTATION: In this report,   we present two patients with renal cell carcinoma and one with melanoma who  received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1  inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all   cases) and all had progressive disease as their best response to the subsequent  PD-1 inhibitor. The reported clinical information focuses on the course of the  disease and the responses to all treatment regimens. CONCLUSIONS: Clinicians  should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of   clinical trials until there is sufficient data to support this practice  routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are  needed to validate the efficacy and safety of these drugs in the second line or  later setting. Furthermore, ongoing efforts that aim to identify mechanisms of  resistance to immunotherapy will be informative and may ultimately assist  physicians in select the optimal treatment following progression on PD-1/PD-L1  inhibitor.
CANIT0001242	28807048	Case report	2 renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	Poor prognosis	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 15	 Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1   inhibitors: a case series.	 J Immunother Cancer	 BACKGROUND: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained  increasing attention across many solid tumors and hematologic malignancies due to  their efficacy and favorable toxicity profile. With more than 1 agent now  FDA-approved in a wide variety of tumor types, and with others in clinical  trials, it is becoming more common that patients present to clinic for potential   treatment with a second PD-1/PD-L1 inhibitor. CASE PRESENTATION: In this report,   we present two patients with renal cell carcinoma and one with melanoma who  received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1  inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all   cases) and all had progressive disease as their best response to the subsequent  PD-1 inhibitor. The reported clinical information focuses on the course of the  disease and the responses to all treatment regimens. CONCLUSIONS: Clinicians  should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of   clinical trials until there is sufficient data to support this practice  routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are  needed to validate the efficacy and safety of these drugs in the second line or  later setting. Furthermore, ongoing efforts that aim to identify mechanisms of  resistance to immunotherapy will be informative and may ultimately assist  physicians in select the optimal treatment following progression on PD-1/PD-L1  inhibitor.
CANIT0001243	28807048	Case report	2 renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Case	Poor prognosis	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 15	 Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1   inhibitors: a case series.	 J Immunother Cancer	 BACKGROUND: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained  increasing attention across many solid tumors and hematologic malignancies due to  their efficacy and favorable toxicity profile. With more than 1 agent now  FDA-approved in a wide variety of tumor types, and with others in clinical  trials, it is becoming more common that patients present to clinic for potential   treatment with a second PD-1/PD-L1 inhibitor. CASE PRESENTATION: In this report,   we present two patients with renal cell carcinoma and one with melanoma who  received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1  inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all   cases) and all had progressive disease as their best response to the subsequent  PD-1 inhibitor. The reported clinical information focuses on the course of the  disease and the responses to all treatment regimens. CONCLUSIONS: Clinicians  should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of   clinical trials until there is sufficient data to support this practice  routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are  needed to validate the efficacy and safety of these drugs in the second line or  later setting. Furthermore, ongoing efforts that aim to identify mechanisms of  resistance to immunotherapy will be informative and may ultimately assist  physicians in select the optimal treatment following progression on PD-1/PD-L1  inhibitor.
CANIT0001244	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	ADAM17 (P78536); 	ADAM17 expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001245	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	CDK2 (P24941); 	CDK2 expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001246	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	CDKN2A (P42771); 	CDKN2A expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001247	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	DPP4 (P27487); 	DPP4 expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001248	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	HER2 (P04626); 	HER2 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001249	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	HLA (P04439); 	HLA-DRA expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001250	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	ICOS (Q9Y6W8); 	ICOS expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001251	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	ITGA4 (P13612); 	ITGA4 expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001252	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	LARGE1 (O95461); 	LARGE expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001253	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	MYC (P01106); 	MYC expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001254	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	NAB2 (Q15742); 	NAB2 expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001255	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	NRAS (P01111); 	NRAS expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001256	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	RhoC (P08134); 	RhoC expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001257	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	TGFB (P01137); 	TGFB1 expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001258	28807052	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	360	N/A	A retrospective cohort study	This is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response.	N/A	N/A	N/A	TIMP1 (P01033); 	TIMP1 expression on tumor cells	Gene expression signature on/in tumor cell	 2017 Aug 15	 Whole-blood RNA transcript-based models can predict clinical response in two  large independent clinical studies of patients with advanced melanoma treated  with the checkpoint inhibitor, tremelimumab.	 J Immunother Cancer	 BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates  clinical efficacy in a subset of advanced melanoma patients. An unmet clinical  need exists for blood-based response-predictive gene signatures to facilitate  clinically effective and cost-efficient use of such immunotherapeutic  interventions. METHODS: Peripheral blood samples were collected in PAXgene(R)  tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a  worldwide, multicenter phase III study (discovery dataset). A central panel of  radiologists determined objective response using RECIST criteria. Gene expression  for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene  pre-treatment response-predictive classifier model was identified. An independent  population (N = 150) of refractory melanoma patients receiving tremelimumab after  chemotherapy enrolled in a worldwide phase II study (validation dataset). The  classifier model, using the same genes, coefficients and constants for objective   response and one-year survival after treatment, was applied to the validation  dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17,  CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC,  TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence   interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence  interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set.  This model was validated in the validation set with AUCs of 0.62 (95% confidence   interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year  survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our  knowledge, this is the largest blood-based biomarker study of a checkpoint  inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA  classifier model that predicts clinical response. The data suggest that the model  captures a biological signature representative of genes needed for a robust  anti-cancer immune response. It also identifies non-responders to tremelimumab at  baseline prior to treatment.
CANIT0001259	28813164	Clinical research	Extensive-stage small-cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A multicohort, phase Ib open-label	The safety of pembrolizumab was consistent with the known safety profile in other tumor types. Pembrolizumab demonstrated promising antitumor activity in patients with pretreated, PD-L1-expressing SCLC.	All 24 patients experienced AEs; the most common were asthenia (n = 7), fatigue (n = 7), and cough (n = 6). Two patients experienced grade 3 to 5 treatment-related AEs: one patient had elevated bilirubin, and one patient had asthenia, grade 5 colitis, and intestinal ischemia.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2017 Dec 1	 Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results  From the Phase Ib KEYNOTE-028 Study.	 J Clin Oncol	 Purpose The safety and efficacy of pembrolizumab, a humanized monoclonal antibody  against programmed death 1 (PD-1), were assessed in patients with programmed  death ligand 1 (PD-L1)-expressing extensive-stage small-cell lung cancer (SCLC)  in the multicohort, phase Ib open-label KEYNOTE-028 study ( ClinicalTrials.gov  identifier: NCT02054806). Methods Patients with SCLC received pembrolizumab 10  mg/kg every 2 weeks for 24 months or until disease progression or intolerable  toxicity occurred. PD-L1 expression was assessed by immunohistochemistry.  PD-L1-positive patients had membranous PD-L1 expression in >/= 1% of tumor and  associated inflammatory cells or positive staining in stroma. Response was  assessed by investigator per Response Evaluation Criteria in Solid Tumors version  1.1 every 8 weeks for the first 6 months and every 12 weeks thereafter. Adverse  events (AEs) were reported per the National Cancer Institute Common Terminology  Criteria for Adverse Events, version 4.0. Primary end points were safety,  tolerability, and objective response rate (ORR). Secondary end points included  progression-free survival, overall survival, and duration of response. Results  Twenty-four patients with PD-L1-expressing SCLC were enrolled and received at  least one pembrolizumab dose. At the data cutoff date (June 20, 2016), the median  follow-up duration was 9.8 months (range, 0.5 to 24 months). All 24 patients  experienced AEs; the most common were asthenia (n = 7), fatigue (n = 7), and  cough (n = 6). Two patients experienced grade 3 to 5 treatment-related AEs: one  patient had elevated bilirubin, and one patient had asthenia, grade 5 colitis,  and intestinal ischemia. One patient had a complete response, and seven patients   had partial responses, resulting in an ORR of 33% (95% CI, 16% to 55%).  Conclusion The safety of pembrolizumab was consistent with the known safety  profile in other tumor types. Pembrolizumab demonstrated promising antitumor  activity in patients with pretreated, PD-L1-expressing SCLC.
CANIT0001260	28816150	Clinical research	Brain metastases from melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); radiotherapy (NCIT:C15313); 	16	N/A	A phase I clinical trial 	Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity.	A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 1	 Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or  Radiosurgery for Melanoma Patients With Brain Metastases.	 Int J Radiat Oncol Biol Phys	 PURPOSE: We performed a phase 1 study to determine the maximum tolerable dose and  safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain  radiation therapy (WBRT) in patients with brain metastases from melanoma. METHODS  AND MATERIALS: Based on the intracranial disease burden, patients underwent WBRT   (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks,  starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated   to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine  the maximum tolerable dose of ipilimumab combined with radiation therapy. The  secondary endpoints were overall survival, intracranial and extracranial control,  progression-free survival, and toxicity. The ClinicalTrials.gov registration  number is NCT01703507. RESULTS: The characteristics of the 16 patients enrolled  between 2011 and 2014 were mean age, 60 years; median number of brain metastases,  2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT  (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median  follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to   2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient  experienced grade 3 neurotoxicity before ipilimumab administration. Ten  additional grade 3 toxicities were reported, with gastrointestinal toxicities  (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The  median progression-free survival and overall survival in arm A was 2.5 months and  8 months and in arm B was 2.1 months and not reached, respectively. CONCLUSIONS:   Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early  because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No  patient experienced dose-limiting toxicity. Larger studies, including those with   combination checkpoint inhibitor therapy and SRS, are warranted.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001261	28817753	Clinical research	Locally advanced or metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	191	N/A	A phase I/II open-label	Favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC	Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis).	N/A	N/A	N/A	N/A	N/A	 2017 Sep 14	 Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial  Carcinoma: Updated Results From a Phase 1/2 Open-label Study.	 JAMA Oncol	 Importance: The data reported herein were accepted for assessment by the US Food   and Drug Administration for Biologics License Application under priority review  to establish the clinical benefit of durvalumab as second-line therapy for  locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent  US approval. Objective: To report a planned update of the safety and efficacy of   durvalumab in patients with locally advanced/metastatic UC. Design, Setting, and   Participants: This is an ongoing phase 1/2 open-label study of 191 adult patients  with histologically or cytologically confirmed locally advanced/metastatic UC  whose disease had progressed on, were ineligible for, or refused prior  chemotherapy from 60 sites in 9 countries as reported herein. Intervention:  Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2  weeks, for up to 12 months or until progression, starting another anticancer  therapy, or unacceptable toxic effects. Main Outcomes and Measures: Primary end  points were safety and confirmed objective response rate (ORR) per blinded  independent central review (Response Evaluation Criteria In Solid Tumors  [RECIST], version 1.1). Results: A total of 191 patients with UC had received  treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78   months (range, 0.4-25.9 months). The median age of patients was 67.0 years and  most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4  disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum).  The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete  responses. Responses were early (median time to response, 1.41 months), durable  (median duration of response not reached), and observed regardless of programmed   cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%]   and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative  expression of PD-L1, respectively). Median progression-free survival and overall   survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1  months to not estimable), respectively; the 1-year overall survival rate was 55%   (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4  treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4   immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led   to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that  led to death (autoimmune hepatitis and pneumonitis). Conclusions and Relevance:  Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and   an encouraging and manageable safety profile in patients with locally  advanced/metastatic UC. Trial Registration: clinicaltrials.gov Identifier:  NCT01693562.
CANIT0001262	28818548	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	N/A	Obstructive findings in the lungs, which easily cause infections, may be an important risk factor for nivolumab-induced ILD.	Severe acute interstitial lung disease	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Severe acute interstitial lung disease after nivolumab in three non-small cell  lung cancer patients with imaging findings of airway obstruction adjacent to lung  tumors.	 J Infect Chemother	 Nivolumab has been associated with unique adverse events known as immune-related   adverse events. Although interstitial lung disease (ILD) is a life-threatening  immune-related adverse event, the risk of ILD during nivolumab treatment is  unclear. In this report, we encountered three patients with stage IV non-small  cell lung cancer with signs of lung obstruction caused by tumor-mediated  compression on imaging who developed acute ILD within 10 days of commencing  nivolumab treatment. The first case involved a 74-year-old Japanese female  never-smoker, the second a 67-year-old Japanese female never-smoker, and the  third a 75-year-old Japanese female current-smoker. The first patient was  administered nivolumab as third-line chemotherapy, the second was administered  nivolumab as fifth-line chemotherapy, and the third was administered nivolumab as  second-line chemotherapy. Regardless of aggressive treatments for ILD, 2 of 3  patients died. The findings of these cases suggest that obstructive findings in  the lungs, which easily cause infections, may be an important risk factor for  nivolumab-induced ILD.CI  - Copyright (c) 2017 Japanese Society of Chemotherapy and The Japanese Association   for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
CANIT0001263	28819833	Case report	Metastatic clear cell renal cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Lymphocytic myocarditis	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 [Lymphocytic myocarditis in a patient with metastatic clear cell renal cell  carcinoma treated with Nivolumab].	 Pathologe	 Immune checkpoint inhibitors against the PD-1 protein offer a new therapy option   for many solid cancers. We report a patient with metastatic renal cell cancer  treated with Nivolumab. As a rare immune-mediated adverse event, we describe a  fatal lymphocytic myocarditis two weeks after starting immune therapy. The cause   of death was first diagnosed at autopsy. This case report underlines the  importance and need of clinical autopsies as an instrument of quality assurance  and detection of rare therapy-induced adverse effects.
CANIT0001264	28821685	Clinical research	Solid tumors(5 Melanoma, 6 Non-small cell lung cancer, 1 colon cancer)	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	12	N/A	A retrospective cohort study	The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.	Myasthenia gravis with myositis and myocarditis	N/A	N/A	N/A	N/A	N/A	 2017 Sep 12	 Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan.	 Neurology	 OBJECTIVE: To report the clinical features of myasthenia gravis (MG) induced by  treatment with immune checkpoint inhibitors using 2-year safety databases based  on postmarketing surveys in Japan. METHODS: We studied 10,277 patients with  cancer who had received monotherapy with either nivolumab or ipilimumab between  September 2014 and August 2016. As the control group, 105 patients with  idiopathic MG were used. RESULTS: There were 12 MG cases (0.12%) among 9,869  patients with cancer who had been treated with nivolumab, but none among 408  patients treated with ipilimumab. These 12 patients included 6 men and 6 women  with a mean age of 73.5 +/- 6.3 years. MG onset occurred in the early phase after  nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG)  included 4 patients with mild involvement and 8 patients with severe involvement.  Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG  than idiopathic MG. Ten patients were positive for anti-acetylcholine receptor  antibodies. Serum creatine kinase levels were markedly elevated to an average  level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had   myocarditis, with 1 of these patients having both. Immunosuppressive therapy was   effective. Postintervention status showed that pharmacologic remission or minimal  manifestations were obtained in 4 patients; however, 2 patients died.  Immune-related adverse events triggered by nivolumab impaired the patients' daily  living activity. CONCLUSIONS: The prompt and correct recognition of MG following   treatment with immune checkpoint inhibitors in patients with cancer is important.CI  - (c) 2017 American Academy of Neurology.
CANIT0001265	28821685	Clinical research	Solid tumors(5 Melanoma, 6 Non-small cell lung cancer, 1 colon cancer)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	12	N/A	A retrospective cohort study	The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.	Myasthenia gravis with myositis and myocarditis	N/A	N/A	N/A	N/A	N/A	 2017 Sep 12	 Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan.	 Neurology	 OBJECTIVE: To report the clinical features of myasthenia gravis (MG) induced by  treatment with immune checkpoint inhibitors using 2-year safety databases based  on postmarketing surveys in Japan. METHODS: We studied 10,277 patients with  cancer who had received monotherapy with either nivolumab or ipilimumab between  September 2014 and August 2016. As the control group, 105 patients with  idiopathic MG were used. RESULTS: There were 12 MG cases (0.12%) among 9,869  patients with cancer who had been treated with nivolumab, but none among 408  patients treated with ipilimumab. These 12 patients included 6 men and 6 women  with a mean age of 73.5 +/- 6.3 years. MG onset occurred in the early phase after  nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG)  included 4 patients with mild involvement and 8 patients with severe involvement.  Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG  than idiopathic MG. Ten patients were positive for anti-acetylcholine receptor  antibodies. Serum creatine kinase levels were markedly elevated to an average  level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had   myocarditis, with 1 of these patients having both. Immunosuppressive therapy was   effective. Postintervention status showed that pharmacologic remission or minimal  manifestations were obtained in 4 patients; however, 2 patients died.  Immune-related adverse events triggered by nivolumab impaired the patients' daily  living activity. CONCLUSIONS: The prompt and correct recognition of MG following   treatment with immune checkpoint inhibitors in patients with cancer is important.CI  - (c) 2017 American Academy of Neurology.
CANIT0001266	28821685	Clinical research	Solid tumors(5 Melanoma, 6 Non-small cell lung cancer, 1 colon cancer)	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	12	N/A	A retrospective cohort study	The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.	Myasthenia gravis with myositis and myocarditis	N/A	N/A	N/A	N/A	N/A	 2017 Sep 12	 Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan.	 Neurology	 OBJECTIVE: To report the clinical features of myasthenia gravis (MG) induced by  treatment with immune checkpoint inhibitors using 2-year safety databases based  on postmarketing surveys in Japan. METHODS: We studied 10,277 patients with  cancer who had received monotherapy with either nivolumab or ipilimumab between  September 2014 and August 2016. As the control group, 105 patients with  idiopathic MG were used. RESULTS: There were 12 MG cases (0.12%) among 9,869  patients with cancer who had been treated with nivolumab, but none among 408  patients treated with ipilimumab. These 12 patients included 6 men and 6 women  with a mean age of 73.5 +/- 6.3 years. MG onset occurred in the early phase after  nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG)  included 4 patients with mild involvement and 8 patients with severe involvement.  Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG  than idiopathic MG. Ten patients were positive for anti-acetylcholine receptor  antibodies. Serum creatine kinase levels were markedly elevated to an average  level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had   myocarditis, with 1 of these patients having both. Immunosuppressive therapy was   effective. Postintervention status showed that pharmacologic remission or minimal  manifestations were obtained in 4 patients; however, 2 patients died.  Immune-related adverse events triggered by nivolumab impaired the patients' daily  living activity. CONCLUSIONS: The prompt and correct recognition of MG following   treatment with immune checkpoint inhibitors in patients with cancer is important.CI  - (c) 2017 American Academy of Neurology.
CANIT0001267	28824067	Case report	Metastatic lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Anti-CTLA-4 therapy may target Tregs in vivo	Isolated adrenocorticotropic hormone deficiency	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Isolated Adrenocorticotropic Hormone Deficiency Caused by Nivolumab in a Patient   with Metastatic Lung Cancer.	 Intern Med	 Nivolumab has promising efficacy for treating various advanced malignant tumors,   although it has been reported to induce a wide range of autoimmune adverse  effects. We herein report the case of a patient with metastatic lung  adenocarcinoma who developed adrenal insufficiency after 12 cycles of nivolumab  treatment. Endocrine test results supported a diagnosis of isolated  adrenocorticotropic hormone deficiency due to hypophysitis, and replacement  therapy using hydrocortisone has been successful. Although hypophysitis is a rare  immune-related adverse event that is associated with nivolumab therapy, clinical   awareness is essential, as this condition can be life-threatening and requires  prompt treatment.
CANIT0001268	28825378	Case report	Relapsed extensive stage small cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Autoimmune hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Jan	 Immunotherapy-induced autoimmune hypophysitis.	 J Oncol Pharm Pract	 Autoimmune hypophysitis is an immune-related adverse event of immune checkpoint  inhibitors. In this article, we present the case of a 58-year-old female patient   who presented to the emergency room with gradually worsening nonspecific symptoms  of headache, nausea, vomiting and decreased oral intake of one week duration. The  patient had been diagnosed with relapsed extensive stage small cell lung cancer.   She was being treated with a combination of ipilimumab and nivolumab after  progression on chemotherapy. Gadolinium-enhanced magnetic resonance imaging of  head revealed pituitary enlargement up to 1.5 cm and pituitary stalk enlargement   up to 4 mm consistent with hypophysitis. The patient was treated with  corticosteroids resulting in rapid resolution of her symptoms. The objective of  our report is to highlight this rare but important adverse event associated with   checkpoint inhibitors, and discuss its clinical features, diagnostic work-up and   treatment.
CANIT0001269	28833116	Case report	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Fatal Myocarditis	Here we present a fatal case of active myocarditis in a 55-year-old man with non-small-cell lung cancer which occurred following monotherapy with the PD-1 inhibitor nivolumab (Opdivo). He presented with acute right-sided heart failure and died 1 day after admission. Postmortem examination revealed multiple gelatinous lesions in the myocardium of the interventricular septum and the bilateral atria and ventricles which had microscopic features diagnostic of myocarditis. Subsequent studies failed to identify an infectious cause. Immune checkpoint inhibitors are an increasingly common addition to anticancer regimens and they should be considered in the evaluation of acute myocarditis.	N/A	N/A	N/A	N/A	N/A	 2018 May	 Fatal Myocarditis Following Treatment with the PD-1 Inhibitor Nivolumab.	 J Forensic Sci	 Therapeutic antibodies targeting the programmed cell death protein 1 (PD-1)  pathway function as immune checkpoint inhibitors, allowing the immune system to  recognize tumors which otherwise escape immune surveillance. However, these  agents can also elicit an autoimmune response by inhibiting the ability of  non-neoplastic tissues and regulatory cells to suppress the immune system. Here  we present a fatal case of active myocarditis in a 55-year-old man with  non-small-cell lung cancer which occurred following monotherapy with the PD-1  inhibitor nivolumab (Opdivo). He presented with acute right-sided heart failure  and died 1 day after admission. Postmortem examination revealed multiple  gelatinous lesions in the myocardium of the interventricular septum and the  bilateral atria and ventricles which had microscopic features diagnostic of  myocarditis. Subsequent studies failed to identify an infectious cause. Immune  checkpoint inhibitors are an increasingly common addition to anticancer regimens   and they should be considered in the evaluation of acute myocarditis.CI  - (c) 2017 American Academy of Forensic Sciences.
CANIT0001270	28838208	Case report	Metastatic non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Diffuse pseudoprogression	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Aug 1	 Diffuse pseudoprogression in a patient with metastatic non-small-cell lung cancer  treated with Nivolumab.	 Ann Oncol	Unable to provide
CANIT0001271	28838377	Clinical research	Advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	6	N/A	N/A	Nivolumab therapy may be feasible in NSCLC patients with mild idiopathic interstitial pneumonia (IIP).	None experienced drug-related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of nivolumab treatment. Furthermore, none of the patients had pneumonitis of any grade.	N/A	N/A	Idiopathic interstitial pneumonia (NCIT:C35714); 	Idiopathic interstitial pneumonia	Adverse events	 2017 Sep	 A pilot trial of nivolumab treatment for advanced non-small cell lung cancer  patients with mild idiopathic interstitial pneumonia.	 Lung Cancer	 INTRODUCTION: Nivolumab has demonstrated efficacy against metastatic non-small  cell lung cancer (NSCLC). However, immune-related adverse events can occur, among  which pneumonitis is relatively common. Lung cancer patients with idiopathic  interstitial pneumonia (IIP) have a higher risk of pneumonitis associated with  anticancer therapy. We hypothesized that the benefit of nivolumab may outweigh  the risks of pneumonitis in patients with NSCLC who have mild IIP. We performed a  pilot trial to evaluate the safety of nivolumab in NSCLC patients with mild IIP.   METHODS: Previously treated, inoperable NSCLC patients with mild IIP were  enrolled. Mild IIP was defined as having a predicted vital capacity >/=80% and a   possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern on  chest high-resolution computed tomography. Patients received nivolumab at a dose   of 3mg/kg biweekly. RESULTS: Six patients were enrolled in this trial between  April 2016 and December 2016. None experienced drug-related nonhematologic grade   3/4 or hematologic grade 4 adverse events in the 12 weeks following the  initiation of nivolumab treatment. Furthermore, none of the patients had  pneumonitis of any grade. At the time of analysis, all patients were alive, and 3  had experienced a partial response. CONCLUSIONS: Nivolumab therapy may be  feasible in NSCLC patients with mild IIP. (Trial registration number:  UMIN000022037).CI  - Copyright (c) 2017. Published by Elsevier B.V.
CANIT0001272	28838390	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	52	N/A	N/A	Elevated pre-treatment neutrophil-to-lymphocyte ratio (NLR) is associated with shorter OS and PFS and with lower response rates in patients with metastatic NSCLC treated with nivolumab independently of other prognostic factors.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Sep	 Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as  prognostic markers in patients with non-small cell lung cancer (NSCLC) treated  with nivolumab.	 Lung Cancer	 OBJECTIVES: Immunotherapy with the programmed death receptor-1 (PD-1) antibody  nivolumab has changed the field of metastatic non-small cell lung cancer (NSCLC)   treatment. Nivolumab shows better outcome compared to standard second line  chemotherapy, but reliable prognostic markers are lacking. High  neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are  markers of host inflammation and associated with worse overall survival (OS) in  several tumor types, but have not been analysed extensively in lung cancer in the  era of immunotherapy. METHODS: Patients with metastatic NSCLC treated with  nivolumab were enrolled. Pre-treatment NLR and PLR were calculated by division of  neutrophils and platelets by lymphocytes measured in peripheral blood. Cox  regression analyses were conducted to study the prognostic role of NLR and PLR on  OS and progression free survival (PFS). Logistic regression was used to study the  association of NLR and PLR. The combined impact of NLR and other known prognostic  factors was explored with multivariable regression. RESULTS: Fifty-two patients  were included. Elevated NLR was associated with worse OS (HR for log(NLR)=3.64,  95% CI 1.78-7.46, p<0.001) and lower response rates (OR for log(NLR)=0.17, 95% CI  0.04-0.68, p=0.013). There was no significant association with PFS (HR for  log(NLR)=1.46, 95% CI=0.91-2.34, p=0.114). The AUC for the prediction of 10-month  survival using log(NLR) was 0.738, the AUC for the prediction of response to  nivolumab was 0.776. Relationships with PLR were similar. NLR and PLR didn't  correlate with other known prognostic factors (i.e histology, tobacco use, ECOG  performance status,) in our cohort. Inclusion of NLR in multivariable models with  these other factors significantly improved the prediction of OS. CONCLUSION:  Elevated pre-treatment NLR and PLR are associated with shorter OS and PFS and  with lower response rates in patients with metastatic NSCLC treated with  nivolumab independently of other prognostic factors.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001273	28838390	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	52	N/A	N/A	Elevated pre-treatment platelet-to-lymphocyte ratio (PLR) is associated with shorter OS and PFS and with lower response rates in patients with metastatic NSCLC treated with nivolumab independently of other prognostic factors.	N/A	N/A	N/A	Platelet-to-lymphocyte ratios (EFO:0008446); 	Platelet-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Sep	 Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as  prognostic markers in patients with non-small cell lung cancer (NSCLC) treated  with nivolumab.	 Lung Cancer	 OBJECTIVES: Immunotherapy with the programmed death receptor-1 (PD-1) antibody  nivolumab has changed the field of metastatic non-small cell lung cancer (NSCLC)   treatment. Nivolumab shows better outcome compared to standard second line  chemotherapy, but reliable prognostic markers are lacking. High  neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are  markers of host inflammation and associated with worse overall survival (OS) in  several tumor types, but have not been analysed extensively in lung cancer in the  era of immunotherapy. METHODS: Patients with metastatic NSCLC treated with  nivolumab were enrolled. Pre-treatment NLR and PLR were calculated by division of  neutrophils and platelets by lymphocytes measured in peripheral blood. Cox  regression analyses were conducted to study the prognostic role of NLR and PLR on  OS and progression free survival (PFS). Logistic regression was used to study the  association of NLR and PLR. The combined impact of NLR and other known prognostic  factors was explored with multivariable regression. RESULTS: Fifty-two patients  were included. Elevated NLR was associated with worse OS (HR for log(NLR)=3.64,  95% CI 1.78-7.46, p<0.001) and lower response rates (OR for log(NLR)=0.17, 95% CI  0.04-0.68, p=0.013). There was no significant association with PFS (HR for  log(NLR)=1.46, 95% CI=0.91-2.34, p=0.114). The AUC for the prediction of 10-month  survival using log(NLR) was 0.738, the AUC for the prediction of response to  nivolumab was 0.776. Relationships with PLR were similar. NLR and PLR didn't  correlate with other known prognostic factors (i.e histology, tobacco use, ECOG  performance status,) in our cohort. Inclusion of NLR in multivariable models with  these other factors significantly improved the prediction of OS. CONCLUSION:  Elevated pre-treatment NLR and PLR are associated with shorter OS and PFS and  with lower response rates in patients with metastatic NSCLC treated with  nivolumab independently of other prognostic factors.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001274	28838401	Case report	EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Lack of response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung  cancer adenocarcinoma sub-type transformed to small cell lung cancer.	 Lung Cancer	 Small cell transformation is a rare but well recognised mechanism of acquired  resistance to EGFR-TKI therapy in EGFR-mutated NSCLC, but optimal drug therapy  thereof is unknown. Nivolumab has demonstrated activity in relapsed de novo small  cell lung cancer in early phase trials. Here, we report a case of transformed  EGFR-mutant SCLC treated with nivolumab with no benefit.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001275	28838713	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	79	N/A	N/A	Liver metastasis is associated with poor progression-free survival in patients with non-small cell lung cancer treated with nivolumab.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2017 Sep	 Liver Metastasis Is Associated with Poor Progression-Free Survival in Patients  with Non-Small Cell Lung Cancer Treated with Nivolumab.	 J Thorac Oncol	Unable to provide
CANIT0001276	28838715	Case report	Primary lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Abscopal effect	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Abscopal Effect of Nivolumab in a Patient with Primary Lung Cancer.	 J Thorac Oncol	Unable to provide
CANIT0001277	28844598	Case report	Metastatic renal cell 	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Indeed, the patient once again developed grade 3 liver function test abnormalities, but treatment with just two doses yielded a significant reduction in tumor burden.Here, we extend the utility of measuring declining ctDNA velocity as a predictor of immunotherapy response to clear cell RCC, with a rapid decline in cumulative mutant allele fraction in the current case from 2.43% to 0%. The current case thus not only suggests the potential for nivolumab rechallenge in the face of prior immune-related adverse events in mRCC, but also suggests the utility of ctDNA velocity as an early surrogate of immunotherapy response.	Grade 3 hepatoxicity	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels 	Metabolite	 2018 Feb	 Exceptional Response to Nivolumab Rechallenge in Metastatic Renal Cell Carcinoma   with Parallel Changes in Genomic Profile.	 Eur Urol	Unable to provide
CANIT0001278	28845909	Case report	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Plantar erythema and pulmonary infiltrate	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Nivolumab infusion reaction manifesting as plantar erythema and pulmonary  infiltrate in a lung cancer patient.	 Thorac Cancer	 Infusion reaction is an adverse event of therapeutic monoclonal antibodies.  Nivolumab, an anti-programmed death-1 antibody, directly activates T cells, which  could probably interact with endothelial cells. The etiology of infusion reaction  induced by nivolumab may differ from that of other antibodies; however, the  detailed clinical features are unknown. We report a case of lung cancer treated  with nivolumab, in which the infusion reaction manifested as plantar erythema,  followed by a transient local pulmonary infiltrate around the tumor. Physicians  should be aware that an infusion reaction induced by anti-programmed death-1  antibodies could appear as local cutaneous and pulmonary adverse events.CI  - (c) 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and   John Wiley & Sons Australia, Ltd.
CANIT0001279	28854067	Clinical research	Advanced squamous non-small-cell lung cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus chemotherapy	Chemotherapy plus placebo	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); 	388	361	A standard treatment controlled	The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies.	Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 20	 Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in  Advanced Squamous Non-Small-Cell Lung Cancer.	 J Clin Oncol	 Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor  prognosis and limited treatment options. This randomized, double-blind, phase III  study investigated the efficacy and safety of first-line ipilimumab or placebo  plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods   Patients with stage IV or recurrent chemotherapy-naive squamous NSCLC were  randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded  ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule  comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6  and then, after induction treatment, ipilimumab or placebo maintenance every 12  weeks for patients with stable disease or better. The primary end point was  overall survival (OS) in patients receiving at least one dose of blinded study  therapy. Results Of 956 randomly assigned patients, 749 received at least one  dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388;  chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy  plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio,  0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6  months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade  3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and  TRAEs leading to discontinuation were numerically higher with chemotherapy plus  ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo   (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with  chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo.  Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong   OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The  safety profile of chemotherapy plus ipilimumab was consistent with that observed   in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab   in combination with nivolumab in this population.
CANIT0001280	28855356	Clinical research	Chordoma, colorectal cancer, breast cancer, lung cancer, ovarian cancer etc.	Breast cancer	MONDO:0007254	Breast	TBXT (O15178); 	TBXT; 	Poxviral TRICOM-based vaccine	N/A	Tumor vaccine	Poxviral TRICOM-based vaccine (NCIT:C2667); 	38	N/A	A phase I trial 	The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients.	No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and grade 2. 	N/A	N/A	Brachyury (O15178); T-Lymphocyte (NCIT:C12476); 	Brachyury-specific T-cell 	Gene expression signature on/in immune cell	 2017 Nov 15	 Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the  Transcription Factor Brachyury.	 Clin Cancer Res	 Purpose: The transcription factor brachyury has been shown in preclinical studies  to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance  to therapy of human tumor cells. This study describes the characterization of a  Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for  brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3,  designated TRICOM) and a phase I study with this vaccine.Experimental Design:  Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define  their ability to activate brachyury-specific T cells. A dose-escalation phase I  study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define   safety and to identify brachyury-specific T-cell responses.Results:  MVA-brachyury-TRICOM-infected human DCs activated CD8(+) and CD4(+) T cells  specific against the self-antigen brachyury in vitro No dose-limiting toxicities   were observed due to vaccine in cancer patients at any of the three dose levels.   One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea)  resolved without intervention and did not recur with subsequent vaccine. All  other AEs related to vaccine were transient and </=grade 2. Brachyury-specific  T-cell responses were observed at all dose levels and in most  patients.Conclusions: The MVA-brachyury-TRICOM vaccine directed against a  transcription factor known to mediate EMT can be administered safely in patients   with advanced cancer and can activate brachyury-specific T cells in vitro and in   patients. Further studies of this vaccine in combination therapies are warranted   and planned. Clin Cancer Res; 23(22); 6833-45. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001281	28855356	Clinical research	Chordoma, colorectal cancer, breast cancer, lung cancer, ovarian cancer etc.	Chordoma	Orphanet:178	Nervous system	TBXT (O15178); 	TBXT; 	Poxviral TRICOM-based vaccine	N/A	Tumor vaccine	Poxviral TRICOM-based vaccine (NCIT:C2667); 	38	N/A	A phase I trial 	The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients.	No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and grade 2. 	N/A	N/A	Brachyury (O15178); T-Lymphocyte (NCIT:C12476); 	Brachyury-specific T-cell 	Gene expression signature on/in immune cell	 2017 Nov 15	 Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the  Transcription Factor Brachyury.	 Clin Cancer Res	 Purpose: The transcription factor brachyury has been shown in preclinical studies  to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance  to therapy of human tumor cells. This study describes the characterization of a  Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for  brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3,  designated TRICOM) and a phase I study with this vaccine.Experimental Design:  Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define  their ability to activate brachyury-specific T cells. A dose-escalation phase I  study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define   safety and to identify brachyury-specific T-cell responses.Results:  MVA-brachyury-TRICOM-infected human DCs activated CD8(+) and CD4(+) T cells  specific against the self-antigen brachyury in vitro No dose-limiting toxicities   were observed due to vaccine in cancer patients at any of the three dose levels.   One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea)  resolved without intervention and did not recur with subsequent vaccine. All  other AEs related to vaccine were transient and </=grade 2. Brachyury-specific  T-cell responses were observed at all dose levels and in most  patients.Conclusions: The MVA-brachyury-TRICOM vaccine directed against a  transcription factor known to mediate EMT can be administered safely in patients   with advanced cancer and can activate brachyury-specific T cells in vitro and in   patients. Further studies of this vaccine in combination therapies are warranted   and planned. Clin Cancer Res; 23(22); 6833-45. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001282	28855356	Clinical research	Chordoma, colorectal cancer, breast cancer, lung cancer, ovarian cancer etc.	Colorectal cancer	EFO:0005842	Intestines	TBXT (O15178); 	TBXT; 	Poxviral TRICOM-based vaccine	N/A	Tumor vaccine	Poxviral TRICOM-based vaccine (NCIT:C2667); 	38	N/A	A phase I trial 	The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients.	No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and grade 2. 	N/A	N/A	Brachyury (O15178); T-Lymphocyte (NCIT:C12476); 	Brachyury-specific T-cell 	Gene expression signature on/in immune cell	 2017 Nov 15	 Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the  Transcription Factor Brachyury.	 Clin Cancer Res	 Purpose: The transcription factor brachyury has been shown in preclinical studies  to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance  to therapy of human tumor cells. This study describes the characterization of a  Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for  brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3,  designated TRICOM) and a phase I study with this vaccine.Experimental Design:  Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define  their ability to activate brachyury-specific T cells. A dose-escalation phase I  study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define   safety and to identify brachyury-specific T-cell responses.Results:  MVA-brachyury-TRICOM-infected human DCs activated CD8(+) and CD4(+) T cells  specific against the self-antigen brachyury in vitro No dose-limiting toxicities   were observed due to vaccine in cancer patients at any of the three dose levels.   One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea)  resolved without intervention and did not recur with subsequent vaccine. All  other AEs related to vaccine were transient and </=grade 2. Brachyury-specific  T-cell responses were observed at all dose levels and in most  patients.Conclusions: The MVA-brachyury-TRICOM vaccine directed against a  transcription factor known to mediate EMT can be administered safely in patients   with advanced cancer and can activate brachyury-specific T cells in vitro and in   patients. Further studies of this vaccine in combination therapies are warranted   and planned. Clin Cancer Res; 23(22); 6833-45. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001283	28855356	Clinical research	Chordoma, colorectal cancer, breast cancer, lung cancer, ovarian cancer etc.	Lung carcinoma	EFO:0001071	Lung	TBXT (O15178); 	TBXT; 	Poxviral TRICOM-based vaccine	N/A	Tumor vaccine	Poxviral TRICOM-based vaccine (NCIT:C2667); 	38	N/A	A phase I trial 	The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients.	No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and grade 2. 	N/A	N/A	Brachyury (O15178); T-Lymphocyte (NCIT:C12476); 	Brachyury-specific T-cell 	Gene expression signature on/in immune cell	 2017 Nov 15	 Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the  Transcription Factor Brachyury.	 Clin Cancer Res	 Purpose: The transcription factor brachyury has been shown in preclinical studies  to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance  to therapy of human tumor cells. This study describes the characterization of a  Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for  brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3,  designated TRICOM) and a phase I study with this vaccine.Experimental Design:  Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define  their ability to activate brachyury-specific T cells. A dose-escalation phase I  study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define   safety and to identify brachyury-specific T-cell responses.Results:  MVA-brachyury-TRICOM-infected human DCs activated CD8(+) and CD4(+) T cells  specific against the self-antigen brachyury in vitro No dose-limiting toxicities   were observed due to vaccine in cancer patients at any of the three dose levels.   One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea)  resolved without intervention and did not recur with subsequent vaccine. All  other AEs related to vaccine were transient and </=grade 2. Brachyury-specific  T-cell responses were observed at all dose levels and in most  patients.Conclusions: The MVA-brachyury-TRICOM vaccine directed against a  transcription factor known to mediate EMT can be administered safely in patients   with advanced cancer and can activate brachyury-specific T cells in vitro and in   patients. Further studies of this vaccine in combination therapies are warranted   and planned. Clin Cancer Res; 23(22); 6833-45. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001284	28855356	Clinical research	Chordoma, colorectal cancer, breast cancer, lung cancer, ovarian cancer etc.	Ovarian carcinoma	EFO:0001075	Ovary	TBXT (O15178); 	TBXT; 	Poxviral TRICOM-based vaccine	N/A	Tumor vaccine	Poxviral TRICOM-based vaccine (NCIT:C2667); 	38	N/A	A phase I trial 	The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients.	No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and grade 2. 	N/A	N/A	Brachyury (O15178); T-Lymphocyte (NCIT:C12476); 	Brachyury-specific T-cell 	Gene expression signature on/in immune cell	 2017 Nov 15	 Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the  Transcription Factor Brachyury.	 Clin Cancer Res	 Purpose: The transcription factor brachyury has been shown in preclinical studies  to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance  to therapy of human tumor cells. This study describes the characterization of a  Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for  brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3,  designated TRICOM) and a phase I study with this vaccine.Experimental Design:  Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define  their ability to activate brachyury-specific T cells. A dose-escalation phase I  study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define   safety and to identify brachyury-specific T-cell responses.Results:  MVA-brachyury-TRICOM-infected human DCs activated CD8(+) and CD4(+) T cells  specific against the self-antigen brachyury in vitro No dose-limiting toxicities   were observed due to vaccine in cancer patients at any of the three dose levels.   One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea)  resolved without intervention and did not recur with subsequent vaccine. All  other AEs related to vaccine were transient and </=grade 2. Brachyury-specific  T-cell responses were observed at all dose levels and in most  patients.Conclusions: The MVA-brachyury-TRICOM vaccine directed against a  transcription factor known to mediate EMT can be administered safely in patients   with advanced cancer and can activate brachyury-specific T cells in vitro and in   patients. Further studies of this vaccine in combination therapies are warranted   and planned. Clin Cancer Res; 23(22); 6833-45. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001285	28858075	Clinical research	Metastatic melanoma  (pembrolizumab (n=28) or nivolumab (n=31))	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	Nivolumab	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	17	42	A retrospective cohort study	The combination of RT and anti-PD-1 immunotherapy is well tolerated and leads to a significant higher tumor response rate within and outside the irradiated field, which is emphasized by the first reported case of an abscopal effect in solid tumors.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Concurrent radiotherapy for patients with metastatic melanoma and receiving  anti-programmed-death 1 therapy: a safe and effective combination.	 Melanoma Res	 A combination of immune-checkpoint inhibitors and radiation therapy (RT)  represents a promising therapeutic strategy in part mediated by the abscopal  effect, but clinical experience related to this combination remains scarce.  Clinical data and patterns of treatment were retrospectively collected from all  consecutive patients with metastatic melanoma and receiving programmed-death 1  (PD-1) immune-checkpoint inhibitors. Survival data, best overall response, and  acute and delayed toxicities (graded according to Common Terminology Criteria for  Adverse Events, v 4.3) were compared between patients receiving concurrent RT  (IR) or no irradiation (NIR). Fifty-nine patients received anti-PD-1  immunotherapy [pembrolizumab (n=28) or nivolumab (n=31)] between August 2014 and   December 2015 at our institution. Among these, 29% (n=17) received palliative RT   for a total of 21 sites, with a mean dose of 30 Gy delivered in 10 fractions.  Acute and late toxicity profiles were similar in the two groups. After a 10-month  median follow-up, the objective response rate (complete or partial response) was   significantly higher in the IR group versus the NIR group (64.7 vs. 33.3%,  P=0.02) and one complete responder after RT was compatible with an abscopal  effect. The 6-month disease-free survival and overall survival rates for the NIR   group versus the IR group were 49.7 versus 64.7% (P=0.32) and 58.8 versus 76.4%  (P=0.42), respectively. We report here that the combination of RT and anti-PD-1  immunotherapy is well tolerated and leads to a significant higher tumor response   rate within and outside the irradiated field, which is emphasized by the first  reported case of an abscopal effect in solid tumors.
CANIT0001286	28858075	Clinical research	Metastatic melanoma  (pembrolizumab (n=28) or nivolumab (n=31))	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus radiotherapy	Pembrolizumab	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); radiotherapy (NCIT:C15313); 	17	42	A retrospective cohort study	The combination of RT and anti-PD-1 immunotherapy is well tolerated and leads to a significant higher tumor response rate within and outside the irradiated field, which is emphasized by the first reported case of an abscopal effect in solid tumors.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Concurrent radiotherapy for patients with metastatic melanoma and receiving  anti-programmed-death 1 therapy: a safe and effective combination.	 Melanoma Res	 A combination of immune-checkpoint inhibitors and radiation therapy (RT)  represents a promising therapeutic strategy in part mediated by the abscopal  effect, but clinical experience related to this combination remains scarce.  Clinical data and patterns of treatment were retrospectively collected from all  consecutive patients with metastatic melanoma and receiving programmed-death 1  (PD-1) immune-checkpoint inhibitors. Survival data, best overall response, and  acute and delayed toxicities (graded according to Common Terminology Criteria for  Adverse Events, v 4.3) were compared between patients receiving concurrent RT  (IR) or no irradiation (NIR). Fifty-nine patients received anti-PD-1  immunotherapy [pembrolizumab (n=28) or nivolumab (n=31)] between August 2014 and   December 2015 at our institution. Among these, 29% (n=17) received palliative RT   for a total of 21 sites, with a mean dose of 30 Gy delivered in 10 fractions.  Acute and late toxicity profiles were similar in the two groups. After a 10-month  median follow-up, the objective response rate (complete or partial response) was   significantly higher in the IR group versus the NIR group (64.7 vs. 33.3%,  P=0.02) and one complete responder after RT was compatible with an abscopal  effect. The 6-month disease-free survival and overall survival rates for the NIR   group versus the IR group were 49.7 versus 64.7% (P=0.32) and 58.8 versus 76.4%  (P=0.42), respectively. We report here that the combination of RT and anti-PD-1  immunotherapy is well tolerated and leads to a significant higher tumor response   rate within and outside the irradiated field, which is emphasized by the first  reported case of an abscopal effect in solid tumors.
CANIT0001287	28858175	Case report	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Fulminant type 1 diabetes	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Fulminant type 1 diabetes after adjuvant ipilimumab therapy in cutaneous  melanoma.	 Melanoma Res	Unable to provide
CANIT0001288	28870955	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	Although increasing the risk of interstitial lung disease (ILD), a history of radiation pneumonitis before nivolumab also contributes to the prolongation of PFS after nivolumab.	N/A	N/A	N/A	Radiation-induced pneumonitis (NCIT:C27932); 	Radiation pneumonitis	Adverse events	 2017 Sep	 Correlation of Radiation Pneumonitis History Before Nivolumab with Onset of  Interstitial Lung Disease and Progression-free Survival of Patients with  Pre-treated Advanced Non-small Cell Lung Cancer.	 Anticancer Res	 BACKGROUND/AIM: Nivolumab has a promising efficacy for patients with  non-small-cell lung cancer (NSCLC) as second-line or later treatment, and after  radiotherapy as abscopal effect. However, the effects of radiation pneumonitis  history before nivolumab have not been clarified. Therefore, we retrospectively  analyzed the correlation of a history of radiation pneumonitis before nivolumab  with onset of interstitial lung disease (ILD) and progression-free survival (PFS)  after nivolumab treatment in patients with previously treated NSCLC. PATIENTS AND  METHODS: A total of 201 patients treated with nivolumab were retrospectively  reviewed. We collected clinical data of patients at the time of starting  nivolumab and we evaluated ILD incidence and PFS in relation to patient  characteristics, including radiation pneumonitis history. RESULTS: The median age  was 68 years; 135 patients were men, 157 had a smoking history, and 153 had  performance status of 0 or 1. Thirty-four patients experienced radiation  pneumonitis before nivolumab, and 50 patients received radiotherapy to the chest   (31 patients received curative radiotherapy). The overall median PFS was 2.8  months and the overall ILD rate was 12.4%. Higher ILD incidence was observed in  the group with a history of radiation pneumonitis (26.5%) compared to the group  without radiation pneumonitis (9.6%). The median PFS was 3.6 and 2.3 months,  respectively. On multivariate analysis, a history of radiation pneumonitis was  also significantly correlated with good PFS (p=0.023). CONCLUSION: Although  increasing the risk of ILD, a history of radiation pneumonitis before nivolumab  also contributes to the prolongation of PFS after nivolumab.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001289	28871578	Case report	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Secondary adrenal insufficiency	N/A	N/A	N/A	N/A	N/A	 2017 Sep 20	 Secondary Adrenal Insufficiency Following Nivolumab Therapy in a Patient with  Metastatic Renal Cell Carcinoma.	 Tokai J Exp Clin Med	 Currently, nivolumab (an anti-programmed cell death-1 receptor monoclonal  antibody) is available for many types of advanced cancers in Japan. However,  there have been few detailed case reports about endocrine-related adverse events   of this therapy. Here, we report a patient with metastatic renal cell carcinoma  who presented with secondary adrenal insufficiency following nivolumab therapy.  Endocrinological assessment by rapid adrenocorticotropic hormone (ACTH) and  corticotropin-releasing hormone (CRH) tests revealed that the patient's disorder   was a secondary adrenal insufficiency due to pituitary dysfunction. Moreover, the  results of the thyrotropin-releasing hormone (TRH), luteinizing hormone-releasing  hormone (LH-RH) and growth hormone-releasing peptide-2 (GHRP-2) tests showed that  only the ACTH function was destroyed (isolated ACTH deficiency). The magnetic  resonance imaging (MRI) findings of hypophysitis, which is the major cause of  isolated ACTH deficiency, usually demonstrate enlargement of the pituitary gland.  However, the MRI findings of our case showed no abnormalities of the pituitary  gland and stalk. Therefore, not only oncologists, but also other specialists,  including doctors in emergency units, should have knowledge of this specific  feature. Our clinical observation could be useful to avoid a delay in diagnosis  and to treat life-threatening adverse effects of nivolumab therapy, such as  secondary adrenal insufficiency.
CANIT0001290	28872489	Case report	Cardiac metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Pure red cell aplasia	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 A case of pure red cell aplasia during nivolumab therapy for cardiac metastatic  melanoma.	 Melanoma Res	 Nivolumab is an antibody against programmed cell death 1 and functions as an  immune checkpoint inhibitor for various malignancies, including unresectable  melanomas. Nivolumab causes several immune-related adverse events, which  typically include skin rash, pneumonitis, thyroid dysfunction, hepatitis, and  colitis; in rare cases, anemia may be present. There are several reports of  autoimmune hemolytic anemia that has developed in response to nivolumab; however,  there are few reports of pure red cell aplasia (PRCA). We describe a patient who   developed PRCA during nivolumab administration. A 70-year-old Japanese woman  received nivolumab for cardiac metastasis from malignant melanoma from an unknown  site. Twenty-one months after nivolumab administration (31 courses), treatment  was discontinued because she developed severe anemia. Blood test results  indicated normocytic, normochromic anemia, and reticulocytopenia, but all other  components were normal. Bone marrow aspiration showed increased megakaryocytes  and decreased erythroblasts; these findings were consistent with PRCA. Anemia  improved without recurrence after treatment with corticosteroids and blood  transfusions. The steroid dosage was reduced gradually, and to date, the patient   has not experienced recurrence of anemia. The tumor decreased in size and the  patient has shown a continued response to treatment with decrease in disease for   3 years. Although it is unclear how nivolumab causes PRCA, hematological  toxicities have been reported in patients treated with immunotherapy drugs. PRCA   might be an unrecognized immune-mediated adverse event that did not manifest  during the clinical trial phase.
CANIT0001291	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Esophageal adenocarcinoma	EFO:0000478	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001292	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Esophageal adenocarcinoma	EFO:0000478	Esophagus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001293	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Leiomyosarcoma	EFO:0000564	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001294	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Leiomyosarcoma	EFO:0000564	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001295	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001296	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001297	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001298	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001299	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Peritoneal mesothelioma	EFO:1000467	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001300	28873125	Clinical research	Melanoma, lung adenocarcinoma, esophageal adenocarcinoma, leiomyosarcoma, peritoneal mesothelioma etc.	Peritoneal mesothelioma	EFO:1000467	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	347	N/A	A single-center retrospective cohort study	Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.	Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Neurological Complications Associated With Anti-Programmed Death 1 (PD-1)  Antibodies.	 JAMA Neurol	 Importance: Neurological complications are an increasingly recognized consequence  of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of  solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical  spectrum and optimum treatment approach are not established. Objective: To  investigate the frequency, clinical spectrum, and optimum treatment approach to  neurological complications associated with anti-PD-1 therapy. Design, Setting,  and Participants: This single-center, retrospective cohort study was conducted  from either September or December 2014 (the approval dates of the study drugs by   the US Food and Drug Administration) to May 19, 2016. All patients receiving  anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy  Database. Patients with development of neurological symptoms within 12 months of   anti-PD-1 therapy were included. Patients with neurological complications  directly attributable to metastatic disease or other concurrent cancer-related  treatments were excluded. Main Outcomes and Measures: Clinical and pathological  characteristics, time to development of neurological symptoms, and modified  Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1  monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute   onset of neurological complications. Seven patients were receiving pembrolizumab,  and 3 patients were receiving nivolumab. The patients included 8 men and 2 women.  Their median age was 71 years (age range, 31-78 years). Neurological  complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1  inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4),  cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear  ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included  axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent  neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to  maximum symptom severity varied from 1 day to more than 3 months. The median mRS   score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients  experienced other systemic immune-mediated complications, including  hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with  anti-PD-1 antibodies was discontinued in 7 patients. Treatment included  corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange   (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One  patient with severe necrotizing myopathy died. Conclusions and Relevance:  Neurological adverse events associated with anti-PD-1 therapy have a diverse  phenotype, with more frequent neuromuscular complications. Although rare, they  will likely be encountered with increasing frequency as anti-PD-1 therapy expands  to other cancers. The time of onset is unpredictable, and evolution may be rapid   and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy  is recommended. In some cases, immune rescue treatment may be required.
CANIT0001301	28877632	Case report	Metastatic cholangiocarcinoma	Cholangiocarcinoma	EFO:0005221	Bilie duct	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Type 1 diabetes	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 Case report: pembrolizumab-induced Type 1 diabetes in a patient with metastatic  cholangiocarcinoma.	 Immunotherapy	 BACKGROUND: Immune checkpoint inhibitors are novel cancer therapies associated  with numerous autoimmune toxicities, some of which are only now being  appreciated. CASE PRESENTATION: A 67-year old female with metastatic  cholangiocarcinoma and no prior history of diabetes was treated with leucovorin,   fluorouracil, oxaliplatin and pembrolizumab. After eight cycles, she developed  new onset type 1 diabetes mellitus with positive glutamic acid decarboxylase  antibody titers. Conclusions: To our knowledge, this is the first reported case  of PD-1 inhibitor associated Type 1 diabetes mellitus in a patient with  cholangiocarcinoma and supports others' experiences that PD-1 inhibition can  cause a spectrum of autoimmune adverse events that require clinical monitoring  and periodic screenings.
CANIT0001302	28879531	Case report	NK/T cell lymphoma failing L-asparaginase	Lymphoma	EFO:0000574	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Case	The high efficacy of nivolumab in this series and pembrolizumab in previous patients confirms that PD1 blockade is an important strategy in NK/T cell lymphomas.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing  L-asparaginase: efficacy and safety.	 Ann Hematol	Unable to provide
CANIT0001303	28880972	Clinical research	Metastatic colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 plus cyclophosphamide	Cyclophosphamide	Tumor vaccine plus Chemotherapy	Cyclophosphamide (DB00531); MVA-5T4 vaccine (NCIT:C49087); 	18	9	A randomized clinical trial	This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects.	No grade 3 or 4 adverse events were observed.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 12	 Effect of Modified Vaccinia Ankara-5T4 and Low-Dose Cyclophosphamide on Antitumor  Immunity in Metastatic Colorectal Cancer: A Randomized Clinical Trial.	 JAMA Oncol	 Importance: The success of immunotherapy with checkpoint inhibitors is not  replicated in most cases of colorectal cancer; therefore, different strategies  are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of  cases of metastatic colorectal cancer (mCRC). Preliminary data using modified  vaccinia Ankara-5T4 (MVA-5T4) in mCRC demonstrated that it safely induced  serologic and T-cell responses. Objective: To determine whether antitumor  immunity in mCRC could be increased using MVA-5T4, metronomic low-dose  cyclophosphamide, or a combination of both treatments. Design, Setting, and  Participants: In this randomized clinical trial, 55 patients with inoperable mCRC  and prior stable disease after standard chemotherapy were enrolled at a single  center and randomized to watch and wait (n = 9), cyclophosphamide treatment only   (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide  (n = 18). Patients were enrolled and treated from July 9, 2012, through February   8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed  based on intention to treat. Interventions: Patients randomized to a  cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15  to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection  at a dose of 1 x 109 50% tissue culture infectious dose on treatment days 22, 36,  50, 64, 78, and 106. Main Outcomes and Measures: The predefined primary end point  was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody   levels) generated at treatment week 7. Secondary end points included analysis of   the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall   survival (OS). Results: Fifty-two patients (38 men and 14 women; mean [SD] age,  64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody  immune responses were significantly increased in the MVA-5T4 (83.41 [36.09]  relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P =  .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide  depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently  prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P   = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients,  resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI,  0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P   = .008). No grade 3 or 4 adverse events were observed. Conclusions and Relevance:  This initial randomized clinical immunotherapy study demonstrates a significant  survival benefit in mCRC. Prior depletion of regulatory T cells by  cyclophosphamide did not increase immune responses generated by MVA-5T4  vaccination; however, cyclophosphamide and MVA-5T4 each independently induced  beneficial antitumor immune responses, resulting in prolonged survival without  toxic effects. Larger clinical trials are planned to further validate these data.  Trial Registration: isrctn.org Identifier: ISRCTN54669986.
CANIT0001304	28880972	Clinical research	Metastatic colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	5T4 (Q13641); 	5T4; 	MVA-5T4 plus cyclophosphamide	MVA-5T4 vaccine	Tumor vaccine plus Chemotherapy	Cyclophosphamide (DB00531); MVA-5T4 vaccine (NCIT:C49087); 	18	19	A randomized clinical trial	This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects.	No grade 3 or 4 adverse events were observed.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 12	 Effect of Modified Vaccinia Ankara-5T4 and Low-Dose Cyclophosphamide on Antitumor  Immunity in Metastatic Colorectal Cancer: A Randomized Clinical Trial.	 JAMA Oncol	 Importance: The success of immunotherapy with checkpoint inhibitors is not  replicated in most cases of colorectal cancer; therefore, different strategies  are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of  cases of metastatic colorectal cancer (mCRC). Preliminary data using modified  vaccinia Ankara-5T4 (MVA-5T4) in mCRC demonstrated that it safely induced  serologic and T-cell responses. Objective: To determine whether antitumor  immunity in mCRC could be increased using MVA-5T4, metronomic low-dose  cyclophosphamide, or a combination of both treatments. Design, Setting, and  Participants: In this randomized clinical trial, 55 patients with inoperable mCRC  and prior stable disease after standard chemotherapy were enrolled at a single  center and randomized to watch and wait (n = 9), cyclophosphamide treatment only   (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide  (n = 18). Patients were enrolled and treated from July 9, 2012, through February   8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed  based on intention to treat. Interventions: Patients randomized to a  cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15  to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection  at a dose of 1 x 109 50% tissue culture infectious dose on treatment days 22, 36,  50, 64, 78, and 106. Main Outcomes and Measures: The predefined primary end point  was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody   levels) generated at treatment week 7. Secondary end points included analysis of   the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall   survival (OS). Results: Fifty-two patients (38 men and 14 women; mean [SD] age,  64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody  immune responses were significantly increased in the MVA-5T4 (83.41 [36.09]  relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P =  .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide  depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently  prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P   = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients,  resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI,  0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P   = .008). No grade 3 or 4 adverse events were observed. Conclusions and Relevance:  This initial randomized clinical immunotherapy study demonstrates a significant  survival benefit in mCRC. Prior depletion of regulatory T cells by  cyclophosphamide did not increase immune responses generated by MVA-5T4  vaccination; however, cyclophosphamide and MVA-5T4 each independently induced  beneficial antitumor immune responses, resulting in prolonged survival without  toxic effects. Larger clinical trials are planned to further validate these data.  Trial Registration: isrctn.org Identifier: ISRCTN54669986.
CANIT0001305	28881488	Case report	Pleomorphic carcinomas of the lung	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Case	Effective to some extent	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Case series of pleomorphic carcinomas of the lung treated with nivolumab.	 Thorac Cancer	 Pleomorphic carcinoma (PC) of the lung is a rare type of non-small cell lung  cancer, exhibiting aggressive behavior and resistance to chemotherapy and  radiotherapy. A previous study reported that PCs expressed high levels of PD-L1,   suggesting the potential efficacy of immune checkpoint inhibitors in these  tumors. We retrospectively reviewed the clinical records of three patients with  PC of the lung treated with nivolumab: a 59-year-old woman (Case 1), a  66-year-old man (Case 2), and an 83-year-old man (Case 3). PD-L1 was highly  expressed in their tumor cells. Two cases showed a partial response with long  progression-free survival. However, in Case 2, brain and bone metastases  progressed during nivolumab treatment in spite of high PD-L1 expression. This  case series indicates that nivolumab is effective to some extent for PC of the  lung. However, the clinical course of patients treated with nivolumab should be  carefully observed, even when PD-L1 is highly expressed.CI  - (c) 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and   John Wiley & Sons Australia, Ltd.
CANIT0001306	28882978	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	64	N/A	A retrospective cohort study	Thyroglobulin antibody levels at baseline may be predictive of hypothyroidism.	Of the 64 patients enrolled, 5 (7.8%) developed hypothyroidism after treatment with nivolumab. The thyroid peroxidase and thyroglobulin antibodies were significantly positive in patients who developed primary hypothyroidism.	N/A	N/A	Thyroglobulin antibody (P01266); 	Thyroglobulin antibody	Gene expression signature in serum	 2017 Sep-Oct	 Predictive Factors of Nivolumab-induced Hypothyroidism in Patients with Non-small  Cell Lung Cancer.	 In Vivo	 BACKGROUND/AIM: Although immune checkpoint inhibitors play an important role in  the therapy of lung cancer, they are associated with various immune-related  adverse events and predictive factors of them are unclear. In this study, we  investigated predictive factors of nivolumab-induced hypothyroidism which is one   of the adverse events in patients with lung cancer. PATIENTS AND METHODS:  Patients with non-small-cell lung cancer who were administered nivolumab at our  hospital between December 2015 and May 2016 were retrospectively enrolled. The  thyroid-stimulating hormone, free triiodothyronine, free thyroxine, thyroid  peroxidase (TPO) antibody, and thyroglobulin antibody levels of each patient were  analyzed. RESULTS: Of the 64 patients enrolled, 5 (7.8%) developed hypothyroidism  after treatment with nivolumab. The TPO and thyroglobulin antibodies were  significantly positive in patients who developed primary hypothyroidism.  CONCLUSION: TPO and thyroglobulin antibody levels at baseline may be predictive  of hypothyroidism.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001307	28882978	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	64	N/A	A retrospective cohort study	Thyroid peroxidase level at baseline may be predictive of hypothyroidism.	Of the 64 patients enrolled, 5 (7.8%) developed hypothyroidism after treatment with nivolumab. The thyroid peroxidase and thyroglobulin antibodies were significantly positive in patients who developed primary hypothyroidism.	N/A	N/A	Thyroid peroxidase (P07202); 	Thyroid peroxidase	Gene expression signature on/in tumor cell	 2017 Sep-Oct	 Predictive Factors of Nivolumab-induced Hypothyroidism in Patients with Non-small  Cell Lung Cancer.	 In Vivo	 BACKGROUND/AIM: Although immune checkpoint inhibitors play an important role in  the therapy of lung cancer, they are associated with various immune-related  adverse events and predictive factors of them are unclear. In this study, we  investigated predictive factors of nivolumab-induced hypothyroidism which is one   of the adverse events in patients with lung cancer. PATIENTS AND METHODS:  Patients with non-small-cell lung cancer who were administered nivolumab at our  hospital between December 2015 and May 2016 were retrospectively enrolled. The  thyroid-stimulating hormone, free triiodothyronine, free thyroxine, thyroid  peroxidase (TPO) antibody, and thyroglobulin antibody levels of each patient were  analyzed. RESULTS: Of the 64 patients enrolled, 5 (7.8%) developed hypothyroidism  after treatment with nivolumab. The TPO and thyroglobulin antibodies were  significantly positive in patients who developed primary hypothyroidism.  CONCLUSION: TPO and thyroglobulin antibody levels at baseline may be predictive  of hypothyroidism.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001308	28885881	Clinical research	Stage III non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Chemoradiotherapy followed by durvalumab	Chemoradiotherapy followed by placebo	Chemotherapy followed by Immune checkpoint therapy	Durvalumab (DB11714); 	473	236	A randomized, double-blind, international, phase III PACIFIC study	Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored  durvalumab, and safety was similar between the groups.	Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events.	N/A	N/A	N/A	N/A	N/A	 2017 Nov 16	 Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.	 N Engl J Med	 BACKGROUND: Most patients with locally advanced, unresectable, non-small-cell  lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy  (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the  anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with   placebo in patients with stage III NSCLC who did not have disease progression  after two or more cycles of platinum-based chemoradiotherapy. METHODS: We  randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of  10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up   to 12 months. The study drug was administered 1 to 42 days after the patients had  received chemoradiotherapy. The coprimary end points were progression-free  survival (as assessed by means of blinded independent central review) and overall  survival (unplanned for the interim analysis). Secondary end points included  12-month and 18-month progression-free survival rates, the objective response  rate, the duration of response, the time to death or distant metastasis, and  safety. RESULTS: Of 713 patients who underwent randomization, 709 received  consolidation therapy (473 received durvalumab and 236 received placebo). The  median progression-free survival from randomization was 16.8 months (95%  confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95%  CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or   death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free  survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival   rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than  with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was   longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months).  The median time to death or distant metastasis was longer with durvalumab than  with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events   occurred in 29.9% of the patients who received durvalumab and 26.1% of those who   received placebo; the most common adverse event of grade 3 or 4 was pneumonia  (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab  group and 9.8% of those in the placebo group discontinued the study drug because   of adverse events. CONCLUSIONS: Progression-free survival was significantly  longer with durvalumab than with placebo. The secondary end points also favored  durvalumab, and safety was similar between the groups. (Funded by AstraZeneca;  PACIFIC ClinicalTrials.gov number, NCT02125461 .).
CANIT0001309	28886381	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	21	N/A	A phase 1b trial	Oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment.	Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 7	 Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves  Anti-PD-1 Immunotherapy.	 Cell	 Here we report a phase 1b clinical trial testing the impact of oncolytic  virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and  therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients  with advanced melanoma were treated with talimogene laherparepvec followed by  combination therapy with pembrolizumab. Therapy was generally well tolerated,  with fatigue, fevers, and chills as the most common adverse events. No  dose-limiting toxicities occurred. Confirmed objective response rate was 62%,  with a complete response rate of 33% per immune-related response criteria.  Patients who responded to combination therapy had increased CD8(+) T cells,  elevated PD-L1 protein expression, as well as IFNG gene expression on  several cell subsets in tumors after talimogene laherparepvec treatment. Response  to combination therapy did not appear to be associated with baseline CD8(+) T  cell infiltration or baseline IFNG signature. These findings suggest that  oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing  the tumor microenvironment. VIDEO ABSTRACT.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001310	28894934	Clinical research	Stage III melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	A retrospective cohort study	Our data suggest a correlation between the T-cell infiltration of the lymph node metastases in stage III melanoma and the response to ipilimumab once these patients progress to stage IV disease.	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	Tumor-infiltrating T-cell 	Tumor-infiltrating immune cell	 2018 Jan	 Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma  correspond to response and survival in nine patients treated with ipilimumab at  the time of stage IV disease.	 Cancer Immunol Immunother	 Prognosis of metastatic melanoma improved with the development of checkpoint  inhibitors. The role of tumor infiltrating lymphocytes (TILs) in lymph node  metastases of stage III melanoma remains unclear. We retrospectively  characterized TILs in primary melanomas and matched lymph node metastases (stage   III melanoma) of patients treated with the checkpoint inhibitor ipilimumab. Tumor  infiltrating lymphocytes were characterized for CD3, CD4, and CD8 expressions by   immunohistochemistry. 4/9 patients (44%) responded to treatment with ipilimumab  (1 complete and 2 partial remissions, 1 stable disease). All responders exhibited  CD4 and CD8 T-cell infiltration in their lymph node metastases, whereas all  non-responders did not show an infiltration of the lymph node metastasis with  TILs. The correlation between the presence and absence of TILs in responders vs.   non-responders was statistically significant (p = 0.008). Median distant  metastases free survival, i.e., progression from stage III to stage IV melanoma,   was similar in responders and non-responders (22.1 vs. 19.3 months; p = 0.462).  Median progression free and overall survival show a trend in favor of the  patients having TIL rich lymph node metastases (6.8 vs. 3.3 months, p = 0.09; and  all alive at last follow-up vs. 8.2 months, respectively, p = 0.08). Our data  suggest a correlation between the T-cell infiltration of the lymph node  metastases in stage III melanoma and the response to ipilimumab once these  patients progress to stage IV disease.
CANIT0001311	28901560	Case report	1 ovarian clear cell cancer and 1 invasive melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	2	N/A	Case	Good outcome	Erythema nodosum-like panniculitis mimicking disease recurrence	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Erythema nodosum-like panniculitis mimicking disease recurrence: A novel toxicity  from immune checkpoint blockade therapy-Report of 2 patients.	 J Cutan Pathol	 Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)  and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have  showed substantial therapeutic benefit in patients with clinically advanced solid  malignancies. However, autoimmune toxicities are common and often significant  adverse events with these agents. While rash and pruritus remain the most common   cutaneous complications in treated patients, novel dermatologic toxicities  related to immune checkpoint blockade continue to emerge as the number of  patients exposed to immunotherapy increases. Here, we describe 2 patients treated  with combination immunotherapy with ipilimumab and nivolumab who developed  painful subcutaneous nodules. Although the findings were clinically concerning  for disease recurrence, histopathologic examination of biopsies from the lesions   revealed a subcutaneous mixed septal and lobular erythema nodosum-like  panniculitis. Notably, neither patient received immunosuppressive therapy for  these lesions, which subsequently remained stable, and both patients' cancer  remained controlled. These cases show that the dermatologic toxicity profile of  immune checkpoint blockade is diverse and continues to expand, and illustrates  that recognition of such toxicities is critical to optimal patient management.CI  - (c) 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001312	28901560	Case report	1 ovarian clear cell cancer and 1 invasive melanoma	Ovarian clear cell cancer	MONDO:0000548	Ovary	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	2	N/A	Case	Good outcome	Erythema nodosum-like panniculitis mimicking disease recurrence	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Erythema nodosum-like panniculitis mimicking disease recurrence: A novel toxicity  from immune checkpoint blockade therapy-Report of 2 patients.	 J Cutan Pathol	 Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)  and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have  showed substantial therapeutic benefit in patients with clinically advanced solid  malignancies. However, autoimmune toxicities are common and often significant  adverse events with these agents. While rash and pruritus remain the most common   cutaneous complications in treated patients, novel dermatologic toxicities  related to immune checkpoint blockade continue to emerge as the number of  patients exposed to immunotherapy increases. Here, we describe 2 patients treated  with combination immunotherapy with ipilimumab and nivolumab who developed  painful subcutaneous nodules. Although the findings were clinically concerning  for disease recurrence, histopathologic examination of biopsies from the lesions   revealed a subcutaneous mixed septal and lobular erythema nodosum-like  panniculitis. Notably, neither patient received immunosuppressive therapy for  these lesions, which subsequently remained stable, and both patients' cancer  remained controlled. These cases show that the dermatologic toxicity profile of  immune checkpoint blockade is diverse and continues to expand, and illustrates  that recognition of such toxicities is critical to optimal patient management.CI  - (c) 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001313	28906278	Case report	Stage IIIa poorly differentiated carcinoma of the lung	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	HBV reactivation	N/A	N/A	N/A	N/A	N/A	 2017 Sep 24	 Hepatitis B reactivation in a long-term nonprogressor due to nivolumab therapy.	 AIDS	Unable to provide
CANIT0001314	28910131	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Atypical response	Lung tissue injury	N/A	N/A	N/A	N/A	N/A	 2017 Nov 15	 Lung Tissue Injury as an Atypical Response to Nivolumab in Non-Small Cell Lung  Cancer.	 Am J Respir Crit Care Med	Unable to provide
CANIT0001315	28910804	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Stability	Sarcoid-like side effect	N/A	N/A	N/A	N/A	N/A	2017	 EBUS-TBNA Can Distinguish Sarcoid-Like Side Effect of Nivolumab Treatment from  Tumor Progression in Non-Small Cell Lung Cancer.	 Respiration	 With the expansion of immunotherapy in the treatment of lung cancer, clinicians  have to face new clinical pictures and adapt their practice. We report the case  of a 69-year-old man diagnosed with non-small cell lung cancer using  endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and   treated with nivolumab as second-line therapy. After 8 injections of nivolumab, a  new CT and PET scan revealed massive growth and increase in metabolism of hilar  and mediastinal lymph nodes, whereas the size and metabolism of the left upper  lobe lesion were reduced. A new EBUS-TBNA was thus performed and showed an  epithelioid cell reaction compatible with sarcoidosis in the 3 punctured lymph  nodes (stations 4R, 11L, 7). In the absence of cancer evolution, nivolumab was  continued, and the CT after the twelfth injection showed stability.CI  - (c) 2017 S. Karger AG, Basel.
CANIT0001316	28912410	Case report	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Psoriasis and psoriatic arthritis	N/A	N/A	N/A	N/A	N/A	 2017 Sep	 [Psoriasis and Psoriatic Arthritis Induced by Nivolumab in a Patient with  Advanced Non-Small-Cell Lung Cancer].	 Gan To Kagaku Ryoho	 BACKGROUND: Immune checkpoint-blocking antibodies may induce specific side  effects known as immune-relatedad verse events. CASE PRESENTATION: A  66-year-oldman without any history of autoimmune disease was referredto our  hospital for treatment of lung cancer in the right upper lobe. The tumor was  diagnosed as Stage III A non-small-cell lung cancer by using bronchoscopic  biopsy, computedtomography, andFDG -PET. After a single course of cisplatin  andpemetrexed , the tumor size increasedremarkably andthe regimen was changedto  nivolumab(3mg/kg every 2 weeks). Psoriasis andpsoriatic arthritis were observed  after 4 courses of nivolumab. Nivolumab treatment continued, and the oral  administration of predni- solone(20mg/day)couldimprove psoriasis andpsoriatic  arthritis. However, the lung cancer showedprogressive disease after the 11th  course of nivolumab. CONCLUSION: Psoriasis andpsoriatic arthritis were inducedby   nivolumab in the patient without any history of autoimmune disease. It is unclear  how prednisolone affected nivolumab for the treatment of lung cancer.
CANIT0001317	28913619	Case report	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Nivolumab may cause extrahepatic cholangitis.	Extrahepatic cholangitis	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 Bile duct obstruction in a patient treated with nivolumab as second-line  chemotherapy for advanced non-small-cell lung cancer: a case report.	 Cancer Immunol Immunother	 Immune checkpoint inhibitors (ICIs) are becoming a standard therapy for  non-small-cell lung cancer in the advanced stage. As these ICIs become widely  available in clinical practice, immune-related adverse effects will become more  common. Here we report a patient with lung adenocarcinoma who was treated with  nivolumab and developed obstruction because of biliary inflammation. A  63-year-old Japanese man having lung adenocarcinoma with pleural dissemination  complained of epigastric pain on the fifth cycle of nivolumab. Computed  tomography showed wall thickening at the lower part of the bile duct and  cholecystitis. Endoscopic retrograde cholangiopancreatography was repeatedly  performed for drainage and stenting of the bile duct. Biopsies did not show  obvious malignancy. Laboratory data on day 85 demonstrated grade 3 elevation of  serum alkaline phosphatase, transaminase, and amylase levels. We initiated  high-dose oral prednisone, resulting in gradual improvement of symptoms and  laboratory data. Follow-up magnetic resonance cholangiopancreatography  demonstrated no progression of duct obstruction, which confirmed the absence of  biliary malignancy. Combined with results from previous reports, nivolumab may  cause extrahepatic cholangitis.
CANIT0001318	28916617	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	647	N/A	N/A	Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E-R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Nivolumab Exposure-Response Analyses of Efficacy and Safety in Previously Treated  Squamous or Nonsquamous Non-Small Cell Lung Cancer.	 Clin Cancer Res	 Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1  antibody with demonstrated efficacy, including durable responses and prolonged  survival, in patients with previously treated, advanced non-small cell lung  cancer (NSCLC). Exposure-response (E-R) analyses for efficacy and safety were  conducted to inform the benefit-risk assessment of nivolumab in this patient  population.Experimental Design: The analyses used clinical trial data from  patients with squamous (n = 293) or nonsquamous (n = 354) NSCLC from four  clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E-R   efficacy analyses were performed by investigating the relationship between  time-averaged nivolumab concentration after the first dose (Cavg1) and the  probability of overall survival by histology. E-R safety analyses examined  relationships between nivolumab Cavg1 and hazards of adverse events leading to  discontinuation or death (AEs-DC/D).Results: Nivolumab exposure was not  associated with overall survival [the 95% confidence interval (CI) of effect  included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555-1.16) or  nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683-1.29). Similarly, nivolumab exposure  was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI,  0.644-1.31). The risk of AEs-DC/D was similar among patients with squamous or  nonsquamous histology.Conclusions: Nivolumab monotherapy demonstrated a wide  therapeutic margin, as evidenced by relatively flat E-R relationships over the  range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W),  supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with  NSCLC. Clin Cancer Res; 23(18); 5394-405. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001319	28917814	Case report	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Late-occurring nivolumab-induced cryptogenic organising pneumonia mimicking lung progression	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Late-occurring nivolumab-induced cryptogenic organising pneumonia mimicking lung   progression in a patient with metastatic non-small cell lung cancer.	 Eur J Cancer	Unable to provide
CANIT0001320	28918779	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Acutely induced diabetes mellitus	N/A	N/A	N/A	N/A	N/A	 2017 Sep 11	 [Acutely induced diabetes mellitus in a 63-year-old female after treatment with  ipilimumab for metastatic melanoma].	 Ugeskr Laeger	 Immune checkpoint inhibitors have improved survival rate in patients with  advanced melanoma, but also have the potential to induce several adverse events.   We report on a 63-year-old woman who had advanced melanoma and was admitted with   diabetic ketoacidosis, which had occurred upon treatment with ipilimumab. On  admission, the C-peptide level was low, and the HbA1c concentration was 50 mmol/l  indicating a rapid onset of the disease. The patient had also been diagnosed with  thyroiditis. Diabetes mellitus is a rare and serious side effect of treatment  with ipilimumab, and we recommend being aware of this due to the rapid course.
CANIT0001321	28923100	Clinical research	Large cell neuroendocrine tumor	Cervical large cell neuroendocrine carcinoma	EFO:1000167	Cervix	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	N/A	Achieved a significant and durable response. Immunotherapy with  checkpoint inhibitors is an effective treatment option for patients with  metastatic LCNEC, even if PD-L1 expression is negative.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2017 Sep 19	 Checkpoint inhibitor is active against large cell neuroendocrine carcinoma with  high tumor mutation burden.	 J Immunother Cancer	 BACKGROUND: Large cell neuroendocrine tumor (LCNEC) of the lung is a rare and  aggressive tumor similar to small cell lung cancer (SCLC). Thus, it is often  treated similarly to SCLC in the front-line setting with a platinum doublet.  However, treatment for patients beyond the first line remains undefined. CASE  PRESENTATION: We report the case of a patient with stage IB LCNEC (PD-L1 negative  but positive for PD-L1 amplification and tumor mutation burden high) who  progressed after adjuvant chemotherapy after surgery and subsequent therapy with   an antibody drug conjugate targeting a neuroendocrine-specific cell surface  marker but achieved a significant and durable response with pembrolizumab, a  humanized IgG4 monoclonal anti-PD-1 antibody. CONCLUSIONS: Immunotherapy with  checkpoint inhibitors is an effective treatment option for patients with  metastatic LCNEC, even if PD-L1 expression is negative.
CANIT0001322	28923104	Clinical research	Colorectal cancer, non-small-cell lung cancer, urothelial cell cancer, and renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	N/A (N/A); 	N/A; 	Chimeric adenovirus enadenotucirev	N/A	Tumor vaccine	Chimeric adenovirus enadenotucirev (NCIT:C113786); 	17	N/A	A phase I trial 	This study provides key delivery and feasibility data to support the use of IV infusion of enadenotucirev, or therapeutic transgene-bearing derivatives of it, in clinical trials across a range of epithelial tumors, including the ongoing combination study of enadenotucirev with the checkpoint inhibitor nivolumab. It also provides insights into the potential immune-stimulating properties of enadenotucirev.	Both methods of enadenotucirev delivery were well tolerated, with no treatment-associated serious adverse events.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 19	 Phase 1 study of intravenous administration of the chimeric adenovirus  enadenotucirev in patients undergoing primary tumor resection.	 J Immunother Cancer	 BACKGROUND: Enadenotucirev (formerly ColoAd1) is a tumor-selective chimeric  adenovirus with demonstrated preclinical activity. This phase 1 Mechanism of  Action study assessed intravenous (IV) delivery of enadenotucirev in patients  with resectable colorectal cancer (CRC), non-small-cell lung cancer (NSCLC),  urothelial cell cancer (UCC), and renal cell cancer (RCC) with a comparator  intratumoral (IT) dosed CRC patient cohort. METHODS: Seventeen patients scheduled  for primary tumor resection were enrolled. IT injection of enadenotucirev (CRC  only) was administered as a single dose (</= 3 x 10(11) viral particles [vp]) on   day 1, followed by resection during days 8-15. IV infusion of enadenotucirev was   administered by three separate doses (1 x 10(12) vp) on days 1, 3, and 5,  followed by resection during days 8-15 (CRC) or days 10-25 (NSCLC, UCC, and RCC).  Enadenotucirev activity was measured using immunohistochemical staining of  nuclear viral hexon and quantitative polymerase chain reaction for viral genomic   DNA. RESULTS: Delivery of enadenotucirev was observed in most tumor samples  following IV infusion, with little or no demonstrable activity in normal tissue.   This virus delivery (by both IV and IT dosing) was accompanied by high local  CD8(+) cell infiltration in 80% of tested tumor samples, suggesting a potential  enadenotucirev-driven immune response. Both methods of enadenotucirev delivery  were well tolerated, with no treatment-associated serious adverse events.  CONCLUSIONS: This study provides key delivery and feasibility data to support the  use of IV infusion of enadenotucirev, or therapeutic transgene-bearing  derivatives of it, in clinical trials across a range of epithelial tumors,  including the ongoing combination study of enadenotucirev with the checkpoint  inhibitor nivolumab. It also provides insights into the potential  immune-stimulating properties of enadenotucirev. TRIAL REGISTRATION: This MOA  study was a phase 1, multicenter, non-randomized, open-label study to investigate  the administration of enadenotucirev in a preoperative setting  (ClinicalTrials.gov: NCT02053220).
CANIT0001323	28923104	Clinical research	Colorectal cancer, non-small-cell lung cancer, urothelial cell cancer, and renal cell cancer	Colorectal cancer	EFO:0005842	Intestines	N/A (N/A); 	N/A; 	Chimeric adenovirus enadenotucirev	N/A	Tumor vaccine	Chimeric adenovirus enadenotucirev (NCIT:C113786); 	17	N/A	A phase I trial 	This study provides key delivery and feasibility data to support the use of IV infusion of enadenotucirev, or therapeutic transgene-bearing derivatives of it, in clinical trials across a range of epithelial tumors, including the ongoing combination study of enadenotucirev with the checkpoint inhibitor nivolumab. It also provides insights into the potential immune-stimulating properties of enadenotucirev.	Both methods of enadenotucirev delivery were well tolerated, with no treatment-associated serious adverse events.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 19	 Phase 1 study of intravenous administration of the chimeric adenovirus  enadenotucirev in patients undergoing primary tumor resection.	 J Immunother Cancer	 BACKGROUND: Enadenotucirev (formerly ColoAd1) is a tumor-selective chimeric  adenovirus with demonstrated preclinical activity. This phase 1 Mechanism of  Action study assessed intravenous (IV) delivery of enadenotucirev in patients  with resectable colorectal cancer (CRC), non-small-cell lung cancer (NSCLC),  urothelial cell cancer (UCC), and renal cell cancer (RCC) with a comparator  intratumoral (IT) dosed CRC patient cohort. METHODS: Seventeen patients scheduled  for primary tumor resection were enrolled. IT injection of enadenotucirev (CRC  only) was administered as a single dose (</= 3 x 10(11) viral particles [vp]) on   day 1, followed by resection during days 8-15. IV infusion of enadenotucirev was   administered by three separate doses (1 x 10(12) vp) on days 1, 3, and 5,  followed by resection during days 8-15 (CRC) or days 10-25 (NSCLC, UCC, and RCC).  Enadenotucirev activity was measured using immunohistochemical staining of  nuclear viral hexon and quantitative polymerase chain reaction for viral genomic   DNA. RESULTS: Delivery of enadenotucirev was observed in most tumor samples  following IV infusion, with little or no demonstrable activity in normal tissue.   This virus delivery (by both IV and IT dosing) was accompanied by high local  CD8(+) cell infiltration in 80% of tested tumor samples, suggesting a potential  enadenotucirev-driven immune response. Both methods of enadenotucirev delivery  were well tolerated, with no treatment-associated serious adverse events.  CONCLUSIONS: This study provides key delivery and feasibility data to support the  use of IV infusion of enadenotucirev, or therapeutic transgene-bearing  derivatives of it, in clinical trials across a range of epithelial tumors,  including the ongoing combination study of enadenotucirev with the checkpoint  inhibitor nivolumab. It also provides insights into the potential  immune-stimulating properties of enadenotucirev. TRIAL REGISTRATION: This MOA  study was a phase 1, multicenter, non-randomized, open-label study to investigate  the administration of enadenotucirev in a preoperative setting  (ClinicalTrials.gov: NCT02053220).
CANIT0001324	28923104	Clinical research	Colorectal cancer, non-small-cell lung cancer, urothelial cell cancer, and renal cell cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	N/A (N/A); 	N/A; 	Chimeric adenovirus enadenotucirev	N/A	Tumor vaccine	Chimeric adenovirus enadenotucirev (NCIT:C113786); 	17	N/A	A phase I trial 	This study provides key delivery and feasibility data to support the use of IV infusion of enadenotucirev, or therapeutic transgene-bearing derivatives of it, in clinical trials across a range of epithelial tumors, including the ongoing combination study of enadenotucirev with the checkpoint inhibitor nivolumab. It also provides insights into the potential immune-stimulating properties of enadenotucirev.	Both methods of enadenotucirev delivery were well tolerated, with no treatment-associated serious adverse events.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 19	 Phase 1 study of intravenous administration of the chimeric adenovirus  enadenotucirev in patients undergoing primary tumor resection.	 J Immunother Cancer	 BACKGROUND: Enadenotucirev (formerly ColoAd1) is a tumor-selective chimeric  adenovirus with demonstrated preclinical activity. This phase 1 Mechanism of  Action study assessed intravenous (IV) delivery of enadenotucirev in patients  with resectable colorectal cancer (CRC), non-small-cell lung cancer (NSCLC),  urothelial cell cancer (UCC), and renal cell cancer (RCC) with a comparator  intratumoral (IT) dosed CRC patient cohort. METHODS: Seventeen patients scheduled  for primary tumor resection were enrolled. IT injection of enadenotucirev (CRC  only) was administered as a single dose (</= 3 x 10(11) viral particles [vp]) on   day 1, followed by resection during days 8-15. IV infusion of enadenotucirev was   administered by three separate doses (1 x 10(12) vp) on days 1, 3, and 5,  followed by resection during days 8-15 (CRC) or days 10-25 (NSCLC, UCC, and RCC).  Enadenotucirev activity was measured using immunohistochemical staining of  nuclear viral hexon and quantitative polymerase chain reaction for viral genomic   DNA. RESULTS: Delivery of enadenotucirev was observed in most tumor samples  following IV infusion, with little or no demonstrable activity in normal tissue.   This virus delivery (by both IV and IT dosing) was accompanied by high local  CD8(+) cell infiltration in 80% of tested tumor samples, suggesting a potential  enadenotucirev-driven immune response. Both methods of enadenotucirev delivery  were well tolerated, with no treatment-associated serious adverse events.  CONCLUSIONS: This study provides key delivery and feasibility data to support the  use of IV infusion of enadenotucirev, or therapeutic transgene-bearing  derivatives of it, in clinical trials across a range of epithelial tumors,  including the ongoing combination study of enadenotucirev with the checkpoint  inhibitor nivolumab. It also provides insights into the potential  immune-stimulating properties of enadenotucirev. TRIAL REGISTRATION: This MOA  study was a phase 1, multicenter, non-randomized, open-label study to investigate  the administration of enadenotucirev in a preoperative setting  (ClinicalTrials.gov: NCT02053220).
CANIT0001325	28923104	Clinical research	Colorectal cancer, non-small-cell lung cancer, urothelial cell cancer, and renal cell cancer	Urothelial carcinoma	EFO:0008528	Bladder	N/A (N/A); 	N/A; 	Chimeric adenovirus enadenotucirev	N/A	Tumor vaccine	Chimeric adenovirus enadenotucirev (NCIT:C113786); 	17	N/A	A phase I trial 	This study provides key delivery and feasibility data to support the use of IV infusion of enadenotucirev, or therapeutic transgene-bearing derivatives of it, in clinical trials across a range of epithelial tumors, including the ongoing combination study of enadenotucirev with the checkpoint inhibitor nivolumab. It also provides insights into the potential immune-stimulating properties of enadenotucirev.	Both methods of enadenotucirev delivery were well tolerated, with no treatment-associated serious adverse events.	N/A	N/A	N/A	N/A	N/A	 2017 Sep 19	 Phase 1 study of intravenous administration of the chimeric adenovirus  enadenotucirev in patients undergoing primary tumor resection.	 J Immunother Cancer	 BACKGROUND: Enadenotucirev (formerly ColoAd1) is a tumor-selective chimeric  adenovirus with demonstrated preclinical activity. This phase 1 Mechanism of  Action study assessed intravenous (IV) delivery of enadenotucirev in patients  with resectable colorectal cancer (CRC), non-small-cell lung cancer (NSCLC),  urothelial cell cancer (UCC), and renal cell cancer (RCC) with a comparator  intratumoral (IT) dosed CRC patient cohort. METHODS: Seventeen patients scheduled  for primary tumor resection were enrolled. IT injection of enadenotucirev (CRC  only) was administered as a single dose (</= 3 x 10(11) viral particles [vp]) on   day 1, followed by resection during days 8-15. IV infusion of enadenotucirev was   administered by three separate doses (1 x 10(12) vp) on days 1, 3, and 5,  followed by resection during days 8-15 (CRC) or days 10-25 (NSCLC, UCC, and RCC).  Enadenotucirev activity was measured using immunohistochemical staining of  nuclear viral hexon and quantitative polymerase chain reaction for viral genomic   DNA. RESULTS: Delivery of enadenotucirev was observed in most tumor samples  following IV infusion, with little or no demonstrable activity in normal tissue.   This virus delivery (by both IV and IT dosing) was accompanied by high local  CD8(+) cell infiltration in 80% of tested tumor samples, suggesting a potential  enadenotucirev-driven immune response. Both methods of enadenotucirev delivery  were well tolerated, with no treatment-associated serious adverse events.  CONCLUSIONS: This study provides key delivery and feasibility data to support the  use of IV infusion of enadenotucirev, or therapeutic transgene-bearing  derivatives of it, in clinical trials across a range of epithelial tumors,  including the ongoing combination study of enadenotucirev with the checkpoint  inhibitor nivolumab. It also provides insights into the potential  immune-stimulating properties of enadenotucirev. TRIAL REGISTRATION: This MOA  study was a phase 1, multicenter, non-randomized, open-label study to investigate  the administration of enadenotucirev in a preoperative setting  (ClinicalTrials.gov: NCT02053220).
CANIT0001326	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	39	N/A	A single-site, correlative study	Respone in patients with enriched bacteroides caccae in gut microbiota	N/A	N/A	N/A	Bacteroides caccae (NCIT:C86168); 	Bacteroides caccae	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001327	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	39	N/A	A single-site, correlative study	Respone in patients with enriched bacteroides caccae in gut microbiota	N/A	N/A	N/A	Bacteroides caccae (NCIT:C86168); 	Bacteroides caccae	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001328	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	39	N/A	A single-site, correlative study	Respone in patients with enriched bacteroides caccae in gut microbiota	N/A	N/A	N/A	Bacteroides caccae (NCIT:C86168); 	Bacteroides caccae	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001329	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	39	N/A	A single-site, correlative study	Respone in patients with enriched bacteroides caccae in gut microbiota	N/A	N/A	N/A	Bacteroides caccae (NCIT:C86168); 	Bacteroides caccae	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001330	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A single-site, correlative study	Respone in patients with enriched faecalibacterium prausnitzii in gut microbiota	N/A	N/A	N/A	Faecalibacterium prausnitzii (NCIT:C86394); 	Faecalibacterium prausnitzii	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001331	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06187); 	24	N/A	A single-site, correlative study	Respone in patients with enriched faecalibacterium prausnitzii in gut microbiota	N/A	N/A	N/A	Faecalibacterium prausnitzii (NCIT:C86394); 	Faecalibacterium prausnitzii	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001332	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A single-site, correlative study	Respone in patients with enriched faecalibacterium prausnitzii in gut microbiota	N/A	N/A	N/A	Faecalibacterium prausnitzii (NCIT:C86394); 	Faecalibacterium prausnitzii	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001333	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A single-site, correlative study	Respone in patients with enriched faecalibacterium prausnitzii in gut microbiota	N/A	N/A	N/A	Faecalibacterium prausnitzii (NCIT:C86394); 	Faecalibacterium prausnitzii	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001334	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A single-site, correlative study	Respone in patients with enriched holdemania filiformis in gut microbiota	N/A	N/A	N/A	Holdemania filiformis (NCIT:C86443); 	Holdemania filiformis in gut microbiota	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001335	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06188); 	24	N/A	A single-site, correlative study	Respone in patients with enriched holdemania filiformis in gut microbiota	N/A	N/A	N/A	Holdemania filiformis (NCIT:C86443); 	Holdemania filiformis in gut microbiota	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001336	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A single-site, correlative study	Respone in patients with enriched holdemania filiformis in gut microbiota	N/A	N/A	N/A	Holdemania filiformis (NCIT:C86443); 	Holdemania filiformis in gut microbiota	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001337	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A single-site, correlative study	Respone in patients with enriched holdemania filiformis in gut microbiota	N/A	N/A	N/A	Holdemania filiformis (NCIT:C86443); 	Holdemania filiformis in gut microbiota	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001338	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	13	N/A	A single-site, correlative study	Respone in patients with enriched dorea formicogenerans in gut microbiota	N/A	N/A	N/A	Dorea formicogenerans (NCIT:C122287); 	Dorea formicogenerans in gut microbiota	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001339	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06189); 	13	N/A	A single-site, correlative study	Respone in patients with enriched dorea formicogenerans in gut microbiota	N/A	N/A	N/A	Dorea formicogenerans (NCIT:C122287); 	Dorea formicogenerans in gut microbiota	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001340	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	13	N/A	A single-site, correlative study	Respone in patients with enriched dorea formicogenerans in gut microbiota	N/A	N/A	N/A	Dorea formicogenerans (NCIT:C122287); 	Dorea formicogenerans in gut microbiota	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001341	28923537	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	13	N/A	A single-site, correlative study	Respone in patients with enriched dorea formicogenerans in gut microbiota	N/A	N/A	N/A	Dorea formicogenerans (NCIT:C122287); 	Dorea formicogenerans in gut microbiota	Microbiota	 2017 Oct	 Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify  Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint  Therapy Efficacy in Melanoma Patients.	 Neoplasia	 This is the first prospective study of the effects of human gut microbiota and  metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma   patients. Whereas many melanoma patients exhibit profound response to ICT, there   are fewer options for patients failing ICT-particularly with BRAF-wild-type  disease. In preclinical studies, specific gut microbiota promotes regression of  melanoma in mice. We therefore conducted a study of the effects of pretreatment  gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid  Tumors response in 39 metastatic melanoma patients treated with ipilimumab,  nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67%  responses and 8% stable disease; P achieved 23% responses and 23% stable disease.  ICT responders for all types of therapies were enriched for Bacteroides caccae.  Among IN responders, the gut microbiome was enriched for Faecalibacterium  prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P  responders, the microbiome was enriched for Dorea formicogenerans. Unbiased  shotgun metabolomics revealed high levels of anacardic acid in ICT responders.  Based on these pilot studies, both additional confirmatory clinical studies and  preclinical testing of these bacterial species and metabolites are warranted to  confirm their ICT enhancing activity.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001342	28934595	Clinical research	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	73	N/A	A retrospective cohort study	In patients with Chronic obstructive pulmonary disease (COPD), Th1 cell populations were expanded in both lung and tumor microenvironments, and the presence of COPD was associated with longer progression-free intervals in patients treated with immune checkpoint inhibitors (ICIs). This has implications for understanding the immune mediators of COPD and developing novel therapies for NSCLC.	N/A	N/A	N/A	Chronic obstructive pulmonary disease (NCIT:C3199); 	Chronic obstructive pulmonary disease	Disease status	 2018 Feb 1	 Chronic Obstructive Pulmonary Disease Alters Immune Cell Composition and Immune  Checkpoint Inhibitor Efficacy in Non-Small Cell Lung Cancer.	 Am J Respir Crit Care Med	 RATIONALE: Chronic obstructive pulmonary disease (COPD) and non-small cell lung  cancer (NSCLC) are interrelated diseases with substantial mortality, and the  pathogenesis of both involves aberrant immune functioning. OBJECTIVES: To profile  immune cell composition and function in patients with NSCLC and describe the  effects of COPD on lung and tumor microenvironments. METHODS: We profiled  resected lung and tumor tissue using flow cytometry and T-cell receptor  sequencing in patients with and without COPD from a prospective cohort of  patients undergoing resection of NSCLC. A murine cigarette smoke exposure model  was used to evaluate the effect on pulmonary immune populations. A separate  retrospective cohort of patients who received immune checkpoint inhibitors (ICIs)  was analyzed, and their survival was quantified. MEASUREMENTS AND MAIN RESULTS:  We observed an increased number of IFN-gamma-producing CD8(+) and CD4(+)  (T-helper cell type 1 [Th1]) lymphocytes in the lungs of patients with COPD. In  both humans and mice, increased Th17 content was seen with smoke exposure, but  was not associated with the development or severity of COPD. COPD-affected lung  tissue displayed increased Th1 differentiation that was recapitulated in the  matching tumor sample. PD-1 (programmed cell death protein 1) expression was  increased in tumors of patients with COPD, and the presence of COPD was  associated with progression-free survival in patients treated with ICIs.  CONCLUSIONS: In patients with COPD, Th1 cell populations were expanded in both  lung and tumor microenvironments, and the presence of COPD was associated with  longer progression-free intervals in patients treated with ICIs. This has  implications for understanding the immune mediators of COPD and developing novel   therapies for NSCLC.
CANIT0001343	28934595	Clinical research	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	73	N/A	A retrospective cohort study	In patients with Chronic obstructive pulmonary disease (COPD), Th1 cell populations were expanded in both lung and tumor microenvironments, and the presence of COPD was associated with longer progression-free intervals in patients treated with immune checkpoint inhibitors (ICIs). This has implications for understanding the immune mediators of COPD and developing novel therapies for NSCLC.	N/A	N/A	N/A	Chronic obstructive pulmonary disease (NCIT:C3199); 	Chronic obstructive pulmonary disease	Disease status	 2018 Feb 1	 Chronic Obstructive Pulmonary Disease Alters Immune Cell Composition and Immune  Checkpoint Inhibitor Efficacy in Non-Small Cell Lung Cancer.	 Am J Respir Crit Care Med	 RATIONALE: Chronic obstructive pulmonary disease (COPD) and non-small cell lung  cancer (NSCLC) are interrelated diseases with substantial mortality, and the  pathogenesis of both involves aberrant immune functioning. OBJECTIVES: To profile  immune cell composition and function in patients with NSCLC and describe the  effects of COPD on lung and tumor microenvironments. METHODS: We profiled  resected lung and tumor tissue using flow cytometry and T-cell receptor  sequencing in patients with and without COPD from a prospective cohort of  patients undergoing resection of NSCLC. A murine cigarette smoke exposure model  was used to evaluate the effect on pulmonary immune populations. A separate  retrospective cohort of patients who received immune checkpoint inhibitors (ICIs)  was analyzed, and their survival was quantified. MEASUREMENTS AND MAIN RESULTS:  We observed an increased number of IFN-gamma-producing CD8(+) and CD4(+)  (T-helper cell type 1 [Th1]) lymphocytes in the lungs of patients with COPD. In  both humans and mice, increased Th17 content was seen with smoke exposure, but  was not associated with the development or severity of COPD. COPD-affected lung  tissue displayed increased Th1 differentiation that was recapitulated in the  matching tumor sample. PD-1 (programmed cell death protein 1) expression was  increased in tumors of patients with COPD, and the presence of COPD was  associated with progression-free survival in patients treated with ICIs.  CONCLUSIONS: In patients with COPD, Th1 cell populations were expanded in both  lung and tumor microenvironments, and the presence of COPD was associated with  longer progression-free intervals in patients treated with ICIs. This has  implications for understanding the immune mediators of COPD and developing novel   therapies for NSCLC.
CANIT0001344	28934595	Clinical research	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	73	N/A	A retrospective cohort study	In patients with Chronic obstructive pulmonary disease (COPD), Th1 cell populations were expanded in both lung and tumor microenvironments, and the presence of COPD was associated with longer progression-free intervals in patients treated with immune checkpoint inhibitors (ICIs). This has implications for understanding the immune mediators of COPD and developing novel therapies for NSCLC.	N/A	N/A	N/A	Chronic obstructive pulmonary disease (NCIT:C3199); 	Chronic obstructive pulmonary disease	Disease status	 2018 Feb 1	 Chronic Obstructive Pulmonary Disease Alters Immune Cell Composition and Immune  Checkpoint Inhibitor Efficacy in Non-Small Cell Lung Cancer.	 Am J Respir Crit Care Med	 RATIONALE: Chronic obstructive pulmonary disease (COPD) and non-small cell lung  cancer (NSCLC) are interrelated diseases with substantial mortality, and the  pathogenesis of both involves aberrant immune functioning. OBJECTIVES: To profile  immune cell composition and function in patients with NSCLC and describe the  effects of COPD on lung and tumor microenvironments. METHODS: We profiled  resected lung and tumor tissue using flow cytometry and T-cell receptor  sequencing in patients with and without COPD from a prospective cohort of  patients undergoing resection of NSCLC. A murine cigarette smoke exposure model  was used to evaluate the effect on pulmonary immune populations. A separate  retrospective cohort of patients who received immune checkpoint inhibitors (ICIs)  was analyzed, and their survival was quantified. MEASUREMENTS AND MAIN RESULTS:  We observed an increased number of IFN-gamma-producing CD8(+) and CD4(+)  (T-helper cell type 1 [Th1]) lymphocytes in the lungs of patients with COPD. In  both humans and mice, increased Th17 content was seen with smoke exposure, but  was not associated with the development or severity of COPD. COPD-affected lung  tissue displayed increased Th1 differentiation that was recapitulated in the  matching tumor sample. PD-1 (programmed cell death protein 1) expression was  increased in tumors of patients with COPD, and the presence of COPD was  associated with progression-free survival in patients treated with ICIs.  CONCLUSIONS: In patients with COPD, Th1 cell populations were expanded in both  lung and tumor microenvironments, and the presence of COPD was associated with  longer progression-free intervals in patients treated with ICIs. This has  implications for understanding the immune mediators of COPD and developing novel   therapies for NSCLC.
CANIT0001345	28934595	Clinical research	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	73	N/A	A retrospective cohort study	In patients with Chronic obstructive pulmonary disease (COPD), Th1 cell populations were expanded in both lung and tumor microenvironments, and the presence of COPD was associated with longer progression-free intervals in patients treated with immune checkpoint inhibitors (ICIs). This has implications for understanding the immune mediators of COPD and developing novel therapies for NSCLC.	N/A	N/A	N/A	Chronic obstructive pulmonary disease (NCIT:C3199); 	Chronic obstructive pulmonary disease	Disease status	 2018 Feb 1	 Chronic Obstructive Pulmonary Disease Alters Immune Cell Composition and Immune  Checkpoint Inhibitor Efficacy in Non-Small Cell Lung Cancer.	 Am J Respir Crit Care Med	 RATIONALE: Chronic obstructive pulmonary disease (COPD) and non-small cell lung  cancer (NSCLC) are interrelated diseases with substantial mortality, and the  pathogenesis of both involves aberrant immune functioning. OBJECTIVES: To profile  immune cell composition and function in patients with NSCLC and describe the  effects of COPD on lung and tumor microenvironments. METHODS: We profiled  resected lung and tumor tissue using flow cytometry and T-cell receptor  sequencing in patients with and without COPD from a prospective cohort of  patients undergoing resection of NSCLC. A murine cigarette smoke exposure model  was used to evaluate the effect on pulmonary immune populations. A separate  retrospective cohort of patients who received immune checkpoint inhibitors (ICIs)  was analyzed, and their survival was quantified. MEASUREMENTS AND MAIN RESULTS:  We observed an increased number of IFN-gamma-producing CD8(+) and CD4(+)  (T-helper cell type 1 [Th1]) lymphocytes in the lungs of patients with COPD. In  both humans and mice, increased Th17 content was seen with smoke exposure, but  was not associated with the development or severity of COPD. COPD-affected lung  tissue displayed increased Th1 differentiation that was recapitulated in the  matching tumor sample. PD-1 (programmed cell death protein 1) expression was  increased in tumors of patients with COPD, and the presence of COPD was  associated with progression-free survival in patients treated with ICIs.  CONCLUSIONS: In patients with COPD, Th1 cell populations were expanded in both  lung and tumor microenvironments, and the presence of COPD was associated with  longer progression-free intervals in patients treated with ICIs. This has  implications for understanding the immune mediators of COPD and developing novel   therapies for NSCLC.
CANIT0001346	28939066	Clinical research	Recurrent squamous cell carcinoma of the head and neck	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	Investigator's choice of therapy	Immune checkpoint therapy	Nivolumab (DB09035); 	23	11	A randomized, open-label, Phase III	Nivolumab demonstrated a survival advantage compared with conventional treatments in Asian patients with platinum-refractory recurrent or metastatic SCCHN, and was well tolerated.	Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC had a treatment-related adverse event, most commonly decreased appetite (21.7%), pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis, and decreased appetite (27.3% each) with IC.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 A randomized, open-label, Phase III clinical trial of nivolumab vs. therapy of  investigator's choice in recurrent squamous cell carcinoma of the head and neck:   A subanalysis of Asian patients versus the global population in checkmate 141.	 Oral Oncol	 OBJECTIVES: To assess efficacy and safety of nivolumab versus investigator's  choice of therapy (IC) in Asian patients with platinum-refractory recurrent or  metastatic squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND  METHODS: Thirty-four patients from Japan, Taiwan, Hong Kong, and Korea received  nivolumab 3mg/kg (n=23) every 2weeks or IC (n=11), as part of a global trial  (n=361), until intolerable toxicity or disease progression. The primary endpoint   was overall survival (OS). RESULTS: Median OS was 9.5months (95% confidence  interval [CI] 9.1-NR) with nivolumab and 6.2months (95% CI 2.6-NR) with IC. Seven  (30.4%) patients receiving nivolumab and six (54.5%) receiving IC died. The  hazard ratio (HR) for risk of death (nivolumab vs. IC) was 0.50 (95% CI  0.17-1.48). Median progression-free survival was 1.9months (95% CI 1.6-7.5) with   nivolumab and 1.8months (95% CI 0.4-6.1) with IC (HR 0.57 [95% CI 0.25-1.33]).  Objective response rates (complete+partial responses) were 26.1% (6/23 patients;   95% CI 10.2-48.4) for nivolumab and 0% (0/11 patients; 95% CI 0.0-28.5) for IC.  Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC  had a treatment-related adverse event, most commonly decreased appetite (21.7%),   pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis,   and decreased appetite (27.3% each) with IC. CONCLUSION: Nivolumab demonstrated a  survival advantage compared with conventional treatments in Asian patients with  platinum-refractory recurrent or metastatic SCCHN, and was well tolerated.  Clinical trial registration NCT02105636.CI  - Copyright (c) 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
CANIT0001347	28939128	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	43	N/A	A retrospective cohort study	Early immune-related adverse events are associated with a better outcome after treatment with immunotherapy. We predicted responses to nivolumab by using early immune-related adverse events.	A total of 43 patients were enrolled, including 19 patients with irAEs 2 weeks after commencement of nivolumab treatment. Common irAEs included rash, pyrexia, and diarrhea.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2017 Dec	 Early Immune-Related Adverse Events and Association with Outcome in Advanced  Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort   Study.	 J Thorac Oncol	 INTRODUCTION: Retrospective studies have shown immune-related adverse events  (irAEs) to be associated with better prognosis. However, no prospective clinical   trials have been conducted, and little is known regarding the association between  irAEs and the outcome of patients with NSCLC after treatment with immunotherapy.   METHODS: We conducted a prospective cohort study of patients with advanced NSCLC   who were treated with nivolumab between January and December 2016. The  association between clinical outcome and irAEs 2 to 6 weeks after commencement of  nivolumab treatment was investigated. IrAEs were assessed by at least three  independent medical professionals. RESULTS: A total of 43 patients were enrolled,  including 19 patients with irAEs 2 weeks after commencement of nivolumab  treatment. Common irAEs included rash, pyrexia, and diarrhea. Programmed cell  death ligand 1-positive tumor cell expression was not significantly different  between patients with and without irAEs. The objective response and disease  control rates were higher in patients with irAEs than in those without irAEs (37%  versus 17% and 74% versus 29% [p = 0.17 and p < 0.01], respectively]). Patients  with irAEs were associated with a significantly longer median progression-free  survival than those without (6.4 months [95% confidence interval: 2.5-not  reached] versus 1.5 months [95% confidence interval: 1.2-2.3] [p = 0.01]). These   findings were comparable to those for patients with and without irAEs 6 weeks  after commencement of nivolumab treatment. CONCLUSIONS: Early irAEs are  associated with a better outcome after treatment with immunotherapy. We predicted  responses to nivolumab by using early irAEs. Further research is needed to  elucidate the mechanisms of these associations.CI  - Copyright (c) 2017 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0001348	28945837	Case report	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Asthma	N/A	N/A	N/A	N/A	N/A	 2017 Nov 1	 Nivolumab-induced asthma in a patient with non-small-cell lung cancer.	 Ann Oncol	Unable to provide
CANIT0001349	28946850	Case report	Non small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	B. bronchiseptica is a pathogen that can cause serious infection in humans, especially in immunocompromised or immunoincompetent individuals. In our patient it showed unusual resistance to cephalosporins and poor sensitivity to amikacin. To our knowledge this is the first case of such an infection in a lung cancer patient undergoing treatment with nivolumab.	N/A	N/A	N/A	Bordetella bronchiseptica (NCIT:C86204); 	B. bronchiseptica	Microbiota	 2017 Sep 25	 Bordetella bronchiseptica pneumonia in a patient with lung cancer; a case report   of a rare infection.	 BMC Infect Dis	 BACKGROUND: Bordetella bronchiseptica (B.bronchiseptica) is a frequent cause of  respiratory infections in animals but rarely causes serious infection in humans.   We present a rare case of B. bronchiseptica pneumonia in a patient with lung  cancer. CASE PRESENTATION: A 52-year-old white male with non small cell lung  cancer developed fever during treatment with nivolumab. A persistent productive  cough and a deterioration in his clinical condition led to his hospitalization  for evaluation. Bronchoscopy was performed and a diagnosis of B. bronchiseptica  pneumonia was made. The infection was successfully managed by antiobiotic  therapy. CONCLUSIONS: B. bronchiseptica is a pathogen that can cause serious  infection in humans, especially in immunocompromised or immunoincompetent  individuals. In our patient it showed unusual resistance to cephalosporins and  poor sensitivity to amikacin. To our knowledge this is the first case of such an   infection in a lung cancer patient undergoing treatment with nivolumab. When B.  bronchiseptica is identified, the possibility of a nosocomial transmission must  be considered.
CANIT0001350	28949050	Clinical research	Myelodysplastic syndrome	Myelodysplastic syndrome	EFO:0000198	Blood and lymph nodes	WT1 (P19544); 	WT1; 	WT1 peptide cancer vaccine	N/A	Tumor vaccine	WT1 vaccine (NCIT:C104738); 	26	N/A	A phase I/II open-label trial	WT4869 was well tolerated in patients with myelodysplastic syndrome and preliminary data suggest that WT4869 is efficacious.	The most common adverse event was injection site reaction (61.5%). Main grade 3 or 4 adverse events were neutropenia (30.8%), febrile neutropenia, pneumonia, elevated blood creatine phosphokinase levels and hypoalbuminemia (all 7.7%). Dose-limiting toxicities occurred in 1 patient in the 50 g/dose cohort (pyrexia, muscle hemorrhage and hypoalbuminemia) and 1 patient in the 400 g/dose cohort (pneumonitis); however, the maximum tolerated dose could not be determined from this trial.	N/A	N/A	WT1 (P19544); T-Lymphocyte (NCIT:C12476); 	WT1-specific cytotoxic T lymphocyte induction	Gene expression signature on/in immune cell	 2017 Dec	 Phase 1/2 study of the WT1 peptide cancer vaccine WT4869 in patients with  myelodysplastic syndrome.	 Cancer Sci	 WT4869 is a synthetic peptide vaccine derived from the Wilms' tumor gene 1 (WT1)   protein. This phase 1/2 open-label study evaluated the safety and efficacy of  WT4869, and biomarkers for response, in patients with myelodysplastic syndrome.  WT4869 (5-1200 mug/dose) was administered intradermally every 2 weeks, according   to a 3 + 3 dose-escalation method in higher-risk (International Prognostic  Scoring System score >/=1.5) or lower-risk (score <1.5) red blood cell  transfusion-dependent patients with myelodysplastic syndrome. Twenty-six patients  were enrolled and treated (median age, 75 years; range, 32 to 89). The most  common adverse event was injection site reaction (61.5%). Main grade 3 or 4  adverse events were neutropenia (30.8%), febrile neutropenia, pneumonia, elevated  blood creatine phosphokinase levels and hypoalbuminemia (all 7.7%). Dose-limiting  toxicities occurred in 1 patient in the 50 mug/dose cohort (pyrexia, muscle  hemorrhage and hypoalbuminemia) and 1 patient in the 400 mug/dose cohort  (pneumonitis); however, the maximum tolerated dose could not be determined from  this trial. The overall response rate was 18.2%, the disease control rate was  59.1% and median overall survival was 64.71 weeks (95% confidence interval:  50.29, 142.86) as assessed by the Kaplan-Meier method. Subgroup analysis of  azacitidine-refractory patients with higher-risk myelodysplastic syndrome (11  patients) showed median overall survival of 55.71 weeks (approximately 13  months). WT1-specific cytotoxic T lymphocyte induction was observed in 11 of 25  evaluable patients. WT4869 was well tolerated in patients with myelodysplastic  syndrome and preliminary data suggest that WT4869 is efficacious. This trial was   registered at www.clinicaltrials.jp as JapicCTI-101374.CI  - (c) 2017 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0001351	28950039	Clinical research	Melanoma, renal cell cancer, nonCsmall cell lung cancer	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1018	N/A	A retrospective cohort study	Cancer immunotherapy with checkpoint inhibitors (CPIs) is associated with a multitude of immune-mediated reactions (IMRs), especially colitis and pneumonitis. Individual CPIs had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.	Adverse event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were identified by generic names, and IMRs were identified by MedDRA Preferred Terms. Empirical Bayes geometric means with corresponding 95% confidence intervals (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined as metrics with EB05  2.0. Overall, 1,018 IMR events were submitted for CPIs, corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab. The period of data collection precluded data on the most recently approved CPI agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs. Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for pembrolizumab, for which nephritis and infusion-related reactions were not reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8).	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint  Inhibitor Cancer Immunotherapies.	 Pharmacotherapy	 STUDY OBJECTIVE: Ipilimumab, pembrolizumab, and nivolumab are checkpoint  inhibitors (CPIs) that activate T-cell-mediated immune response. CPI can provide   durable benefits to some cancer patients with melanoma, renal cell cancer,  non-small cell lung cancer, or a growing list of other cancers. However, CPI  treatment is also associated with adverse immune-mediated reactions (IMRs) that  can be life-threatening. This pharmacovigilance analysis aims to characterize IMR  signals in relation to CPI treatment. DESIGN: Retrospective pharmacovigilance  disproportionality analysis. DATA SOURCE: U.S. Food and Drug Administration  Adverse Event Reporting System (FAERS). MEASUREMENTS AND MAIN RESULTS: Adverse  event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were  identified by generic names, and IMRs were identified by MedDRA Preferred Terms.   Empirical Bayes geometric means with corresponding 95% confidence intervals  (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined   as metrics with EB05 >/= 2.0. Overall, 1,018 IMR events were submitted for CPIs,   corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab.  The period of data collection precluded data on the most recently approved CPI  agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11%  hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs.  Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab,  respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for  pembrolizumab, for which nephritis and infusion-related reactions were not  reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and  individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and  pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for  CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest  signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for  nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8). CONCLUSION: Cancer  immunotherapy with CPIs is associated with a multitude of IMRs, especially  colitis and pneumonitis. Individual CPIs had variable IMR signals, and  pharmacoepidemiologic studies are required to evaluate the identified signals.CI  - (c) 2017 Pharmacotherapy Publications, Inc.
CANIT0001352	28950039	Clinical research	Melanoma, renal cell cancer, nonCsmall cell lung cancer	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1018	N/A	A retrospective cohort study	Cancer immunotherapy with checkpoint inhibitors (CPIs) is associated with a multitude of immune-mediated reactions (IMRs), especially colitis and pneumonitis. Individual CPIs had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.	Adverse event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were identified by generic names, and IMRs were identified by MedDRA Preferred Terms. Empirical Bayes geometric means with corresponding 95% confidence intervals (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined as metrics with EB05  2.0. Overall, 1,018 IMR events were submitted for CPIs, corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab. The period of data collection precluded data on the most recently approved CPI agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs. Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for pembrolizumab, for which nephritis and infusion-related reactions were not reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8).	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint  Inhibitor Cancer Immunotherapies.	 Pharmacotherapy	 STUDY OBJECTIVE: Ipilimumab, pembrolizumab, and nivolumab are checkpoint  inhibitors (CPIs) that activate T-cell-mediated immune response. CPI can provide   durable benefits to some cancer patients with melanoma, renal cell cancer,  non-small cell lung cancer, or a growing list of other cancers. However, CPI  treatment is also associated with adverse immune-mediated reactions (IMRs) that  can be life-threatening. This pharmacovigilance analysis aims to characterize IMR  signals in relation to CPI treatment. DESIGN: Retrospective pharmacovigilance  disproportionality analysis. DATA SOURCE: U.S. Food and Drug Administration  Adverse Event Reporting System (FAERS). MEASUREMENTS AND MAIN RESULTS: Adverse  event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were  identified by generic names, and IMRs were identified by MedDRA Preferred Terms.   Empirical Bayes geometric means with corresponding 95% confidence intervals  (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined   as metrics with EB05 >/= 2.0. Overall, 1,018 IMR events were submitted for CPIs,   corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab.  The period of data collection precluded data on the most recently approved CPI  agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11%  hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs.  Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab,  respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for  pembrolizumab, for which nephritis and infusion-related reactions were not  reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and  individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and  pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for  CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest  signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for  nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8). CONCLUSION: Cancer  immunotherapy with CPIs is associated with a multitude of IMRs, especially  colitis and pneumonitis. Individual CPIs had variable IMR signals, and  pharmacoepidemiologic studies are required to evaluate the identified signals.CI  - (c) 2017 Pharmacotherapy Publications, Inc.
CANIT0001353	28950039	Clinical research	Melanoma, renal cell cancer, nonCsmall cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1018	N/A	A retrospective cohort study	Cancer immunotherapy with checkpoint inhibitors (CPIs) is associated with a multitude of immune-mediated reactions (IMRs), especially colitis and pneumonitis. Individual CPIs had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.	Adverse event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were identified by generic names, and IMRs were identified by MedDRA Preferred Terms. Empirical Bayes geometric means with corresponding 95% confidence intervals (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined as metrics with EB05  2.0. Overall, 1,018 IMR events were submitted for CPIs, corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab. The period of data collection precluded data on the most recently approved CPI agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs. Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for pembrolizumab, for which nephritis and infusion-related reactions were not reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8).	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint  Inhibitor Cancer Immunotherapies.	 Pharmacotherapy	 STUDY OBJECTIVE: Ipilimumab, pembrolizumab, and nivolumab are checkpoint  inhibitors (CPIs) that activate T-cell-mediated immune response. CPI can provide   durable benefits to some cancer patients with melanoma, renal cell cancer,  non-small cell lung cancer, or a growing list of other cancers. However, CPI  treatment is also associated with adverse immune-mediated reactions (IMRs) that  can be life-threatening. This pharmacovigilance analysis aims to characterize IMR  signals in relation to CPI treatment. DESIGN: Retrospective pharmacovigilance  disproportionality analysis. DATA SOURCE: U.S. Food and Drug Administration  Adverse Event Reporting System (FAERS). MEASUREMENTS AND MAIN RESULTS: Adverse  event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were  identified by generic names, and IMRs were identified by MedDRA Preferred Terms.   Empirical Bayes geometric means with corresponding 95% confidence intervals  (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined   as metrics with EB05 >/= 2.0. Overall, 1,018 IMR events were submitted for CPIs,   corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab.  The period of data collection precluded data on the most recently approved CPI  agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11%  hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs.  Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab,  respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for  pembrolizumab, for which nephritis and infusion-related reactions were not  reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and  individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and  pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for  CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest  signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for  nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8). CONCLUSION: Cancer  immunotherapy with CPIs is associated with a multitude of IMRs, especially  colitis and pneumonitis. Individual CPIs had variable IMR signals, and  pharmacoepidemiologic studies are required to evaluate the identified signals.CI  - (c) 2017 Pharmacotherapy Publications, Inc.
CANIT0001354	28950039	Clinical research	Melanoma, renal cell cancer, nonCsmall cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1018	N/A	A retrospective cohort study	Cancer immunotherapy with checkpoint inhibitors (CPIs) is associated with a multitude of immune-mediated reactions (IMRs), especially colitis and pneumonitis. Individual CPIs had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.	Adverse event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were identified by generic names, and IMRs were identified by MedDRA Preferred Terms. Empirical Bayes geometric means with corresponding 95% confidence intervals (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined as metrics with EB05  2.0. Overall, 1,018 IMR events were submitted for CPIs, corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab. The period of data collection precluded data on the most recently approved CPI agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs. Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for pembrolizumab, for which nephritis and infusion-related reactions were not reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8).	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint  Inhibitor Cancer Immunotherapies.	 Pharmacotherapy	 STUDY OBJECTIVE: Ipilimumab, pembrolizumab, and nivolumab are checkpoint  inhibitors (CPIs) that activate T-cell-mediated immune response. CPI can provide   durable benefits to some cancer patients with melanoma, renal cell cancer,  non-small cell lung cancer, or a growing list of other cancers. However, CPI  treatment is also associated with adverse immune-mediated reactions (IMRs) that  can be life-threatening. This pharmacovigilance analysis aims to characterize IMR  signals in relation to CPI treatment. DESIGN: Retrospective pharmacovigilance  disproportionality analysis. DATA SOURCE: U.S. Food and Drug Administration  Adverse Event Reporting System (FAERS). MEASUREMENTS AND MAIN RESULTS: Adverse  event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were  identified by generic names, and IMRs were identified by MedDRA Preferred Terms.   Empirical Bayes geometric means with corresponding 95% confidence intervals  (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined   as metrics with EB05 >/= 2.0. Overall, 1,018 IMR events were submitted for CPIs,   corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab.  The period of data collection precluded data on the most recently approved CPI  agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11%  hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs.  Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab,  respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for  pembrolizumab, for which nephritis and infusion-related reactions were not  reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and  individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and  pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for  CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest  signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for  nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8). CONCLUSION: Cancer  immunotherapy with CPIs is associated with a multitude of IMRs, especially  colitis and pneumonitis. Individual CPIs had variable IMR signals, and  pharmacoepidemiologic studies are required to evaluate the identified signals.CI  - (c) 2017 Pharmacotherapy Publications, Inc.
CANIT0001355	28950039	Clinical research	Melanoma, renal cell cancer, nonCsmall cell lung cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1018	N/A	A retrospective cohort study	Cancer immunotherapy with checkpoint inhibitors (CPIs) is associated with a multitude of immune-mediated reactions (IMRs), especially colitis and pneumonitis. Individual CPIs had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.	Adverse event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were identified by generic names, and IMRs were identified by MedDRA Preferred Terms. Empirical Bayes geometric means with corresponding 95% confidence intervals (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined as metrics with EB05  2.0. Overall, 1,018 IMR events were submitted for CPIs, corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab. The period of data collection precluded data on the most recently approved CPI agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs. Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for pembrolizumab, for which nephritis and infusion-related reactions were not reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8).	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint  Inhibitor Cancer Immunotherapies.	 Pharmacotherapy	 STUDY OBJECTIVE: Ipilimumab, pembrolizumab, and nivolumab are checkpoint  inhibitors (CPIs) that activate T-cell-mediated immune response. CPI can provide   durable benefits to some cancer patients with melanoma, renal cell cancer,  non-small cell lung cancer, or a growing list of other cancers. However, CPI  treatment is also associated with adverse immune-mediated reactions (IMRs) that  can be life-threatening. This pharmacovigilance analysis aims to characterize IMR  signals in relation to CPI treatment. DESIGN: Retrospective pharmacovigilance  disproportionality analysis. DATA SOURCE: U.S. Food and Drug Administration  Adverse Event Reporting System (FAERS). MEASUREMENTS AND MAIN RESULTS: Adverse  event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were  identified by generic names, and IMRs were identified by MedDRA Preferred Terms.   Empirical Bayes geometric means with corresponding 95% confidence intervals  (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined   as metrics with EB05 >/= 2.0. Overall, 1,018 IMR events were submitted for CPIs,   corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab.  The period of data collection precluded data on the most recently approved CPI  agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11%  hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs.  Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab,  respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for  pembrolizumab, for which nephritis and infusion-related reactions were not  reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and  individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and  pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for  CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest  signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for  nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8). CONCLUSION: Cancer  immunotherapy with CPIs is associated with a multitude of IMRs, especially  colitis and pneumonitis. Individual CPIs had variable IMR signals, and  pharmacoepidemiologic studies are required to evaluate the identified signals.CI  - (c) 2017 Pharmacotherapy Publications, Inc.
CANIT0001356	28950039	Clinical research	Melanoma, renal cell cancer, nonCsmall cell lung cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1018	N/A	A retrospective cohort study	Cancer immunotherapy with checkpoint inhibitors (CPIs) is associated with a multitude of immune-mediated reactions (IMRs), especially colitis and pneumonitis. Individual CPIs had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.	Adverse event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were identified by generic names, and IMRs were identified by MedDRA Preferred Terms. Empirical Bayes geometric means with corresponding 95% confidence intervals (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined as metrics with EB05  2.0. Overall, 1,018 IMR events were submitted for CPIs, corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab. The period of data collection precluded data on the most recently approved CPI agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11% hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs. Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab, respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for pembrolizumab, for which nephritis and infusion-related reactions were not reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8).	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Pharmacovigilance Assessment of Immune-Mediated Reactions Reported for Checkpoint  Inhibitor Cancer Immunotherapies.	 Pharmacotherapy	 STUDY OBJECTIVE: Ipilimumab, pembrolizumab, and nivolumab are checkpoint  inhibitors (CPIs) that activate T-cell-mediated immune response. CPI can provide   durable benefits to some cancer patients with melanoma, renal cell cancer,  non-small cell lung cancer, or a growing list of other cancers. However, CPI  treatment is also associated with adverse immune-mediated reactions (IMRs) that  can be life-threatening. This pharmacovigilance analysis aims to characterize IMR  signals in relation to CPI treatment. DESIGN: Retrospective pharmacovigilance  disproportionality analysis. DATA SOURCE: U.S. Food and Drug Administration  Adverse Event Reporting System (FAERS). MEASUREMENTS AND MAIN RESULTS: Adverse  event reports submitted to FAERS between 2011 and 2015 were analyzed. CPIs were  identified by generic names, and IMRs were identified by MedDRA Preferred Terms.   Empirical Bayes geometric means with corresponding 95% confidence intervals  (EB05-EB95) were calculated as CPI-IMR association metrics. Signals were defined   as metrics with EB05 >/= 2.0. Overall, 1,018 IMR events were submitted for CPIs,   corresponding to 76% for ipilimumab, 15% for nivolumab, and 9% for pembrolizumab.  The period of data collection precluded data on the most recently approved CPI  agents. IMRs consisted of 51% colitis, 16% endocrinopathies, 12% pneumonitis, 11%  hepatitis, 4% infusion-related reactions, 3% nephritis, and 3% other IMRs.  Colitis contributed to 63% and 41% of IMRs for ipilimumab and nivolumab,  respectively. Pneumonitis and hepatitis contributed to a majority of IMRs for  pembrolizumab, for which nephritis and infusion-related reactions were not  reported. Signals of IMRs were detected for CPIs as a class (EB05 = 12.4) and  individual agents: ipilimumab (EB05 = 13.2), nivolumab (EB05 = 15.0), and  pembrolizumab (EB05 = 7.3). Colitis and pneumonitis had the strongest signals for  CPIs (EB05 = 45.6 and EB05 = 17.6, respectively). Colitis was the strongest  signal for ipilimumab (EB05 = 54.2), and pneumonitis was the strongest signal for  nivolumab (EB05 = 48.0) and pembrolizumab (EB05 = 21.8). CONCLUSION: Cancer  immunotherapy with CPIs is associated with a multitude of IMRs, especially  colitis and pneumonitis. Individual CPIs had variable IMR signals, and  pharmacoepidemiologic studies are required to evaluate the identified signals.CI  - (c) 2017 Pharmacotherapy Publications, Inc.
CANIT0001357	28950298	Clinical research	Locally advanced or metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	220	N/A	A single-arm phase II IMvigor210 trial	In this single-arm study, patients who continued atezolizumab beyond RECIST v1.1 progression derived prolonged clinical benefit without additional safety signals. Identification of patients most likely to benefit from atezolizumab beyond progression remains an important challenge in the management of metastatic urothelial carcinoma.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Dec 1	 Atezolizumab in platinum-treated locally advanced or metastatic urothelial  carcinoma: post-progression outcomes from the phase II IMvigor210 study.	 Ann Oncol	 Background: Conventional criteria for tumor progression may not fully reflect the  clinical benefit of immunotherapy or appropriately guide treatment decisions. The  phase II IMvigor210 study demonstrated the efficacy and safety of atezolizumab, a  programmed death-ligand 1-directed antibody, in patients with platinum-treated  locally advanced or metastatic urothelial carcinoma. Patients could continue  atezolizumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1  progression at the investigator's discretion: this analysis assessed  post-progression outcomes in these patients. Patients and methods: Patients were   treated with atezolizumab 1200 mg i.v. every 3 weeks until loss of clinical  benefit. Efficacy and safety outcomes in patients who experienced RECIST v1.1  progression and did, or did not, continue atezolizumab were analyzed  descriptively. Results: In total, 220 patients who experienced progression from  the overall cohort (n = 310) were analyzed: 137 continued atezolizumab for >/= 1   dose after progression, 19 received other systemic therapy, and 64 received no  further systemic therapy. Compared with those who discontinued, patients  continuing atezolizumab beyond progression were more likely to have had a  baseline Eastern Cooperative Oncology Group performance status of 0 (43.1% versus  31.3%), less likely to have had baseline liver metastases (27.0% versus 41.0%),  and more likely to have had an initial response to atezolizumab (responses in  11.7% versus 1.2%). Five patients (3.6%) continuing atezolizumab after  progression had subsequent responses compared with baseline measurements. Median   post-progression overall survival was 8.6 months in patients continuing  atezolizumab, 6.8 months in those receiving another treatment, and 1.2 months in   those receiving no further treatment. Atezolizumab exposure-adjusted adverse  event frequencies were generally similar before and following progression.  Conclusion: In this single-arm study, patients who continued atezolizumab beyond   RECIST v1.1 progression derived prolonged clinical benefit without additional  safety signals. Identification of patients most likely to benefit from  atezolizumab beyond progression remains an important challenge in the management   of metastatic urothelial carcinoma. ClinicalTrials.gov ID: NCT02108652.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001358	28951518	Clinical research	Early-stage non-small cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus neoadjuvant chemotherapy 	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); neoadjuvant chemotherapy (NCIT:C15665); 	24	N/A	A single-arm phase II study	These results highlight the immune activating properties of ipilimumab in early-stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunologic data from combined immune checkpoint blockade immunotherapies.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	TAAs (NCIT:C154155); T-Lymphocyte (NCIT:C12476); 	Blood-based tumor-associated antigens T-cell responses	Gene expression signature on/in immune cell	 2017 Dec 15	 Immune Activation in Early-Stage Non-Small Cell Lung Cancer Patients Receiving  Neoadjuvant Chemotherapy Plus Ipilimumab.	 Clin Cancer Res	 Purpose: To determine the immunologic effects of neoadjuvant chemotherapy plus  ipilimumab in early-stage non-small cell lung cancer (NSCLC)  patients.Experimental Design: This is a single-arm chemotherapy plus phased  ipilimumab phase II study of 24 treatment-naive patients with stage IB-IIIA  NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel  with either cisplatin or carboplatin and ipilimumab included in the last 2  cycles.Results: Chemotherapy alone had little effect on immune parameters in  PBMCs. Profound CD28-dependent activation of both CD4 and CD8 cells was observed   following ipilimumab. Significant increases in the frequencies of CD4(+) cells  expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent.  Likewise, increased frequencies of CD8(+) cells expressing the same activation  markers, with the exception of PD-1, were observed. We also examined 7 resected  tumors and found higher frequencies of activated tumor-infiltrating lymphocytes  than those observed in PBMCs. Surprisingly, we found 4 cases of preexisting  tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3  present in PBMC at baseline, but neither increased frequencies nor the appearance  of newly detectable responses following ipilimumab therapy. Ipilimumab had little  effect on the frequencies of circulating regulatory T cells and  MDSCs.Conclusions: This study did not meet the primary endpoint of detecting an  increase in blood-based TAA T-cell responses after ipilimumab. Collectively,  these results highlight the immune activating properties of ipilimumab in  early-stage NSCLC. The immune profiling data for ipilimumab alone can contribute   to the interpretation of immunologic data from combined immune checkpoint  blockade immunotherapies. Clin Cancer Res; 23(24); 7474-82. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001359	28961608	Case report	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Nephrotic syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Nov/Dec	 Nivolumab-associated Nephrotic Syndrome in a Patient With Renal Cell Carcinoma: A  Case Report.	 J Immunother	 INTRODUCTION: Immune checkpoint inhibitors have taken an important place in the  treatment of different types of malignancies. These drugs are known to have  specific immune-mediated adverse events. We describe a case of severe nephrotic  syndrome secondary to treatment with nivolumab in a patient with renal cell  carcinoma. CASE PRESENTATION: A 62-year-old man was treated with nivolumab for  papillary renal cell carcinoma type 2 for 8 weeks when he was admitted to the  hospital with a severe nephrotic syndrome and acute kidney injury. Renal biopsy  showed focal segmental glomerulosclerosis. Treatment with high-dose  corticosteroids had insufficient effect, but the addition of mycophenolate  mofetil resulted in remission of the nephrotic syndrome and recovery of renal  function. Proteinuria subsequently relapsed during corticosteroid tapering.  CONCLUSIONS: The time course in this patient strongly suggests that the nephrotic  syndrome occurred as an adverse drug reaction to nivolumab treatment. If during  nivolumab treatment renal insufficiency, hypoalbuminemia, or proteinuria  develops, further analysis for a possible nephrotic syndrome is warranted for  early detection and treatment of this life-threatening complication.
CANIT0001360	28967485	Clinical research	Locally advanced and unresectable or metastatic urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	370	N/A	A multicentre, single-arm, phase II	First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities. In view of this result, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy.	The most common grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370 patients), alkaline phosphatase increase (five [1%]), colitis, and muscle weakness (both four [1%]). 36 (10%) of 370 patients had a serious treatment-related adverse event. 17 (5%) of 370 patients died from non-treatment-related adverse events associated with death, and one patient died from treatment-related adverse events (myositis in addition to grade 3 thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2017 Nov	 First-line pembrolizumab in cisplatin-ineligible patients with locally advanced  and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre,  single-arm, phase 2 study.	 Lancet Oncol	 BACKGROUND: More than half of all patients with advanced urothelial cancer cannot  receive standard, first-line cisplatin-based chemotherapy because of renal  dysfunction, poor performance status, or other comorbidities. We assessed the  activity and safety of first-line pembrolizumab in cisplatin-ineligible patients   with locally advanced and unresectable or metastatic urothelial cancer. METHODS:   In this multicentre, single-arm, phase 2 study (KEYNOTE-052),  cisplatin-ineligible patients with advanced urothelial cancer who had not been  previously treated with systemic chemotherapy were recruited from 91 academic  medical centres in 20 countries. Enrolled patients received intravenous  pembrolizumab 200 mg every 3 weeks. The primary endpoint was objective response  (the proportion of patients who achieved complete or partial response) in all  patients and by PD-L1 expression status according to the Response Evaluation  Criteria in Solid Tumors, version 1.1, as assessed by independent central review.  PD-L1 expression was assessed in tumour and inflammatory cells from tumour  biopsies provided at study entry. Activity and safety were analysed in all  patients who received at least one dose of pembrolizumab (all-patients-treated  population). This study is registered with ClinicalTrials.gov, number  NCT02335424, and follow-up is ongoing. FINDINGS: Between Feb 24, 2015, and Aug 8,  2016, 374 patients were enrolled and 370 patients received at least one dose of  pembrolizumab. 89 (24%, 95% CI 20-29) of 370 patients had a centrally assessed  objective response, and as of Sept 1, 2016 (data cutoff), 74 (83%) of 89  responses were ongoing. Median follow-up was 5 months (IQR 3.0-8.6). A  PD-L1-expression cutoff of 10% was associated with a higher frequency of response  to pembrolizumab; 42 (38%, 95% CI 29-48) of 110 patients with a combined positive  score of 10% or more had a centrally assessed objective response. The most common  grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370  patients), alkaline phosphatase increase (five [1%]), colitis, and muscle  weakness (both four [1%]). 36 (10%) of 370 patients had a serious  treatment-related adverse event. 17 (5%) of 370 patients died from  non-treatment-related adverse events associated with death, and one patient died   from treatment-related adverse events (myositis in addition to grade 3  thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis).  INTERPRETATION: First-line pembrolizumab has antitumour activity and acceptable  tolerability in cisplatin-ineligible patients with urothelial cancer, most of  whom were elderly, had poor prognostic factors, or had serious comorbidities. In   view of this result, pembrolizumab has become a new treatment option for patients  who are cisplatin-ineligible or not suitable candidates for chemotherapy.  Pembrolizumab in the first-line setting is being further assessed in the phase 3   KEYNOTE-361 trial (ClinicalTrials.gov, NCT02335424). FUNDING: Merck & Co.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001361	28967485	Clinical research	Locally advanced and unresectable or metastatic urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	370	N/A	A multicentre, single-arm, phase II	First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities. In view of this result, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy.	The most common grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370 patients), alkaline phosphatase increase (five [1%]), colitis, and muscle weakness (both four [1%]). 36 (10%) of 370 patients had a serious treatment-related adverse event. 17 (5%) of 370 patients died from non-treatment-related adverse events associated with death, and one patient died from treatment-related adverse events (myositis in addition to grade 3 thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2017 Nov	 First-line pembrolizumab in cisplatin-ineligible patients with locally advanced  and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre,  single-arm, phase 2 study.	 Lancet Oncol	 BACKGROUND: More than half of all patients with advanced urothelial cancer cannot  receive standard, first-line cisplatin-based chemotherapy because of renal  dysfunction, poor performance status, or other comorbidities. We assessed the  activity and safety of first-line pembrolizumab in cisplatin-ineligible patients   with locally advanced and unresectable or metastatic urothelial cancer. METHODS:   In this multicentre, single-arm, phase 2 study (KEYNOTE-052),  cisplatin-ineligible patients with advanced urothelial cancer who had not been  previously treated with systemic chemotherapy were recruited from 91 academic  medical centres in 20 countries. Enrolled patients received intravenous  pembrolizumab 200 mg every 3 weeks. The primary endpoint was objective response  (the proportion of patients who achieved complete or partial response) in all  patients and by PD-L1 expression status according to the Response Evaluation  Criteria in Solid Tumors, version 1.1, as assessed by independent central review.  PD-L1 expression was assessed in tumour and inflammatory cells from tumour  biopsies provided at study entry. Activity and safety were analysed in all  patients who received at least one dose of pembrolizumab (all-patients-treated  population). This study is registered with ClinicalTrials.gov, number  NCT02335424, and follow-up is ongoing. FINDINGS: Between Feb 24, 2015, and Aug 8,  2016, 374 patients were enrolled and 370 patients received at least one dose of  pembrolizumab. 89 (24%, 95% CI 20-29) of 370 patients had a centrally assessed  objective response, and as of Sept 1, 2016 (data cutoff), 74 (83%) of 89  responses were ongoing. Median follow-up was 5 months (IQR 3.0-8.6). A  PD-L1-expression cutoff of 10% was associated with a higher frequency of response  to pembrolizumab; 42 (38%, 95% CI 29-48) of 110 patients with a combined positive  score of 10% or more had a centrally assessed objective response. The most common  grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370  patients), alkaline phosphatase increase (five [1%]), colitis, and muscle  weakness (both four [1%]). 36 (10%) of 370 patients had a serious  treatment-related adverse event. 17 (5%) of 370 patients died from  non-treatment-related adverse events associated with death, and one patient died   from treatment-related adverse events (myositis in addition to grade 3  thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis).  INTERPRETATION: First-line pembrolizumab has antitumour activity and acceptable  tolerability in cisplatin-ineligible patients with urothelial cancer, most of  whom were elderly, had poor prognostic factors, or had serious comorbidities. In   view of this result, pembrolizumab has become a new treatment option for patients  who are cisplatin-ineligible or not suitable candidates for chemotherapy.  Pembrolizumab in the first-line setting is being further assessed in the phase 3   KEYNOTE-361 trial (ClinicalTrials.gov, NCT02335424). FUNDING: Merck & Co.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001362	28972039	Clinical research	Malignant pleural mesothelioma	Pleural mesothelioma	EFO:1000485	Soft tissue	GM-CSF (P04141); WT1 (P19544); 	GM-CSF; WT1	Galinpepimut-S plus montanide plus GM-CSF	Montanide plus GM-CSF	Tumor vaccine	Montanide ISA 51 VG (NCIT:C84843); galinpepimut-S (NCIT:C161778); GM-CSF (DB05386); 	20	21	A double-blind, controlled, two center phase II trial	The favorable safety profile was confirmed. PFS and OS were greater in those who received vaccine, but the trial was neither designed nor powered for comparison between the arms.	Treatment-related adverse events were mild, self-limited, and not clinically significant.	N/A	N/A	N/A	N/A	N/A	 2017 Dec 15	 A Randomized Phase II Trial of Adjuvant Galinpepimut-S, WT-1 Analogue Peptide  Vaccine, After Multimodality Therapy for Patients with Malignant Pleural  Mesothelioma.	 Clin Cancer Res	 Purpose: Determine the 1-year progression-free survival (PFS) rate among patients  with malignant pleural mesothelioma (MPM) receiving the WT1 peptide vaccine  galinpepimut-S after multimodality therapy versus those receiving control  adjuvants.Experimental Design: This double-blind, controlled, two center phase II  trial randomized MPM patients after surgery and another treatment modality to  galinpepimut-S with GM-CSF and Montanide or GM-CSF and Montanide alone. An  improvement in 1-year PFS from 50% to 70% was the predefined efficacy threshold,   and 78 patients total were planned. The study was not powered for comparison  between the two arms.Results: Forty-one patients were randomized.  Treatment-related adverse events were mild, self-limited, and not clinically  significant. On the basis of a stringent prespecified futility analysis (futility  = >/=10 of 20 patients on one arm experiencing progression < 1 year), the control  arm closed early. The treatment arm was subsequently closed because of the  resultant unblinding. The PFS rate at 1 year from beginning study treatment was  33% and 45% in the control and vaccine arms, respectively. Median PFS was 7.4  months versus 10.1 months and median OS was 18.3 months versus 22.8 months in the  control and vaccine arms, respectively.Conclusions: The favorable safety profile   was confirmed. PFS and OS were greater in those who received vaccine, but the  trial was neither designed nor powered for comparison between the arms. On the  basis of these promising results, the investigators are planning a larger  randomized trial with greater statistical power to define the optimal use and  benefit of galinpepimut-S in the treatment of MPM. Clin Cancer Res; 23(24);  7483-9. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001363	28975824	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Steroid responsive nivolumab-induced encephalitis	N/A	N/A	N/A	N/A	N/A	 2017 Oct-Dec	 A Case Report of Steroid Responsive Nivolumab-Induced Encephalitis.	 Cancer Control	 Nivolumab (Opdivo) approval for the treatment of non-small cell lung cancer  (NSCLC) prompts recognition of its future use in various cancers. Although rare,   occurring in 1% to 3% of treated cases, nivolumab along with other immune  checkpoint inhibitors are associated with immune-related encephalitis. With its  prospective use, nivolumab-induced encephalitis illustrates the necessity of  early recognition and successful management to decrease morbidity and mortality.   We describe a treated case of nivolumab-induced encephalitis. A 74-year-old male   with a history of stage 4 squamous NSCLC presenting with insidious altered mental  status following his first dose of nivolumab. After an extensive workup that  proved negative, the patient received intravenous steroids with gradual  improvement of mental status. Patient subsequently returned to baseline and was  discharged with oral steroid taper. Nivolumab-induced encephalitis is a diagnosis  of exclusion with nonspecific signs and symptoms. Immediate recognition of  patients prescribed nivolumab chemotherapy could potentially prevent fatal  complications of neurotoxicity.
CANIT0001364	28978598	Case report	Metastatic adenocarcinoma	Adenocarcinoma	EFO:0000228	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Colitis	N/A	N/A	N/A	N/A	N/A	 2017 Oct 4	 Unusual case of immune-related colitis.	 BMJ Case Rep	 The cancer immunotherapy field has had many promising developments in recent  years. Checkpoint inhibitors are good examples of that. This new class of  medications comes with a new constellation of side effects that require early  recognition and management. Here we present a patient with metastatic  adenocarcinoma on pembrolizumab who was admitted to the hospital for colitis.  This was found to be an immune-related adverse event from pembrolizumab. We  discuss our work-up and approach to the diagnosis, then highlight important  treatment pearls for internal medicine physicians who are increasingly taking  care of such patients.CI  - (c) BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)  2017. All rights reserved. No commercial use is permitted unless otherwise  expressly granted.
CANIT0001365	28982912	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	Better outcome with high lactate dehydrogenase (LDH) level was predictive of poor PFS in  patients with NSCLC treated with nivolumab. Careful monitoring is recommended for  treating such patients with nivolumab	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2017 Oct	 Predictive Factors for Poor Progression-free Survival in Patients with Non-small   Cell Lung Cancer Treated with Nivolumab.	 Anticancer Res	 BACKGROUND: Nivolumab has shown promising effects in patients with non-small-cell  lung cancer (NSCLC) as a second- or later-line treatment. This study aimed to  identify patients who would not experience any benefit from nivolumab treatment.   MATERIALS AND METHODS: In this study, data for 201 patients treated with  nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical  centers in Japan were retrospectively reviewed. We collected clinical data at the  time of nivolumab treatment commencement. We investigated the relationship  between progression-free survival (PFS) and patient characteristics. RESULTS: In   both univariate and multivariate analysis, performance status (PS) score >/=2,  steroid use at baseline and lactate dehydrogenase (LDH) level >240 IU/l were  significantly associated with poor PFS (all p<0.05). CONCLUSION: PS score >/=2,  steroid use at baseline and a high LDH level were predictive of poor PFS in  patients with NSCLC treated with nivolumab. Careful monitoring is recommended for  treating such patients with nivolumab (UMIN-ID: UMIN000025908).CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001366	28982912	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	Better outcome with steroid use at baseline was predictive of poor PFS in  patients with NSCLC treated with nivolumab. Careful monitoring is recommended for  treating such patients with nivolumab.	N/A	N/A	N/A	Steroid use status (NCIT:C135483); 	Steroid use	Exposure factors/status	 2017 Oct	 Predictive Factors for Poor Progression-free Survival in Patients with Non-small   Cell Lung Cancer Treated with Nivolumab.	 Anticancer Res	 BACKGROUND: Nivolumab has shown promising effects in patients with non-small-cell  lung cancer (NSCLC) as a second- or later-line treatment. This study aimed to  identify patients who would not experience any benefit from nivolumab treatment.   MATERIALS AND METHODS: In this study, data for 201 patients treated with  nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical  centers in Japan were retrospectively reviewed. We collected clinical data at the  time of nivolumab treatment commencement. We investigated the relationship  between progression-free survival (PFS) and patient characteristics. RESULTS: In   both univariate and multivariate analysis, performance status (PS) score >/=2,  steroid use at baseline and lactate dehydrogenase (LDH) level >240 IU/l were  significantly associated with poor PFS (all p<0.05). CONCLUSION: PS score >/=2,  steroid use at baseline and a high LDH level were predictive of poor PFS in  patients with NSCLC treated with nivolumab. Careful monitoring is recommended for  treating such patients with nivolumab (UMIN-ID: UMIN000025908).CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001367	28982912	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	Better outcome with performance status (PS) score >/=2 was predictive of poor PFS in  patients with NSCLC treated with nivolumab. Careful monitoring is recommended for  treating such patients with nivolumab.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2017 Oct	 Predictive Factors for Poor Progression-free Survival in Patients with Non-small   Cell Lung Cancer Treated with Nivolumab.	 Anticancer Res	 BACKGROUND: Nivolumab has shown promising effects in patients with non-small-cell  lung cancer (NSCLC) as a second- or later-line treatment. This study aimed to  identify patients who would not experience any benefit from nivolumab treatment.   MATERIALS AND METHODS: In this study, data for 201 patients treated with  nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical  centers in Japan were retrospectively reviewed. We collected clinical data at the  time of nivolumab treatment commencement. We investigated the relationship  between progression-free survival (PFS) and patient characteristics. RESULTS: In   both univariate and multivariate analysis, performance status (PS) score >/=2,  steroid use at baseline and lactate dehydrogenase (LDH) level >240 IU/l were  significantly associated with poor PFS (all p<0.05). CONCLUSION: PS score >/=2,  steroid use at baseline and a high LDH level were predictive of poor PFS in  patients with NSCLC treated with nivolumab. Careful monitoring is recommended for  treating such patients with nivolumab (UMIN-ID: UMIN000025908).CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001368	28982916	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	199	N/A	A multicentre, retrospective cohort study	Achievement of a clinical response to chemotherapy immediately before nivolumab, particularly when combined with bevacizumab, increases the likelihood of disease control post-nivolumab.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Bevacizumab treatment before nivolumab	Exposure factors/status	 2017 Oct	 The Association Between Chemotherapy Immediately Before Nivolumab and Outcomes  Thereafter.	 Anticancer Res	 BACKGROUND/AIM: We investigated whether the efficacy and type of pre-nivolumab  chemotherapy influence outcomes in non-small cell lung cancer patients following   nivolumab treatment. PATIENTS AND METHODS: In this multicenter study, 199  patients treated with nivolumab were retrospectively reviewed. We analyzed the  relationships between the clinical response to nivolumab and to chemotherapy  administered immediately beforehand. RESULTS: Patients who achieved objective  responses to pretreatments showed higher disease control rates with nivolumab  than patients who did not (64% vs. 47%, p=0.03), as did those who achieved  disease control with pretreatments (62% vs. 35%, p<0.001). Bevacizumab-pretreated  patients tended to show better objective response rates with nivolumab (27% vs.  13%, p=0.06); the objective response rate to nivolumab was significantly higher  in bevacizumab-pretreated patients who showed clinical responses (42% vs. 9.1%,  p=0.02). CONCLUSION: Achievement of a clinical response to chemotherapy  immediately before nivolumab, particularly when combined with bevacizumab,  increases the likelihood of disease control post-nivolumab.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001369	28983773	Clinical research	Metastastic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	71	N/A	N/A	CO-diffusion capacity (DLCO) decline maybe an early indicator of subclinical pulmonary drug toxicity. Therefore, routine pulmonary function testing including DLCO measurement during treatment might help for risk stratification to screen for ipilimumab-related pneumonitis.	Of 71 patients included in this study, a clinically meaningful lung function decline was registered in 6/65 (9%), 5/44 (11%), and 9/38 (24%) patients after 3, 6, and 9 weeks of treatment initiation, respectively. Even after adjusting for age, concomitant melanoma treatment, progressive pulmonary metastases, and baseline pulmonary function values, mean  SD DLCO decreased significantly during follow-up (-4.3%  13.6% from baseline, p = 0.033). Only 7% of patients reported respiratory symptoms. Clinically manifest ipilimumab-related pneumonitis was diagnosed only in one patient (1.4%).  DLCO decline maybe an early indicator  of subclinical pulmonary drug toxicity. Therefore, routine pulmonary function  testing including DLCO measurement during treatment might help for risk  stratification to screen for ipilimumab-related pneumonitis.	N/A	N/A	CO-diffusion capacity (NCIT:C58026); 	CO-diffusion capacity	Disease status	 2018 Jan	 Ipilimumab and early signs of pulmonary toxicity in patients with metastastic  melanoma: a prospective observational study.	 Cancer Immunol Immunother	 Ipilimumab, an immune checkpoint inhibitor, is approved for treatment metastastic  melanoma and is a promising agent against other malignancies. There is some  preliminary evidence from case reports that ipilimumab treatment may be  associated with pulmonary side effects. However, data from prospective studies on  ipilimumab-related pulmonary toxicity are still scarce. Serial spirometries and  measurements of CO-diffusion capacity (DLCO) in patients with metastatic melanoma  before and during treatment with ipilimumab were performed. A reduction from  baseline of forced vital capacity (FVC) of >/= 10%, or >/= 15% of DLCO was  defined as clinically meaningful and indicative for pulmonary toxicity. Of 71  patients included in this study, a clinically meaningful lung function decline  was registered in 6/65 (9%), 5/44 (11%), and 9/38 (24%) patients after 3, 6, and   9 weeks of treatment initiation, respectively. Even after adjusting for age,  concomitant melanoma treatment, progressive pulmonary metastases, and baseline  pulmonary function values, mean +/- SD DLCO decreased significantly during  follow-up (-4.3% +/- 13.6% from baseline, p = 0.033). Only 7% of patients  reported respiratory symptoms. Clinically manifest ipilimumab-related pneumonitis  was diagnosed only in one patient (1.4%). DLCO decline maybe an early indicator  of subclinical pulmonary drug toxicity. Therefore, routine pulmonary function  testing including DLCO measurement during treatment might help for risk  stratification to screen for ipilimumab-related pneumonitis.
CANIT0001370	28984691	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Erythematous scaly plaques and pustules of the forehead, legs and arms	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Intracorneal pustular drug eruption, a novel cutaneous adverse event in  anti-programmed cell death-1 patients that highlights the effect of  anti-programmed cell death-1 in neutrophils.	 Melanoma Res	 The introduction of anti-programmed cell death-1 (anti-PD1) monoclonal antibodies  has revolutionized the treatment of various advanced malignancies. Despite its  efficacy, anti-PD1 therapy is accompanied by a variety of cutaneous adverse  events. A 79-year-old man developed erythematous scaly plaques and pustules of  the forehead, legs and arms after four cycles of nivolumab infusions every 2  weeks. Histology showed intracorneal pustules with dermal neutrophils and  eosinophils. He was treated successfully with topical corticosteroids without  discontinuation of nivolumab. We report subcorneal pustular eruption as a novel  cutaneous adverse event in patients on anti-PD1 therapy. Other neutrophilic  eruptions (psoriasis, Sweet's syndrome, acute generalized pustulosis) have been  reported in patients on anti-PD1 treatments, suggesting the neutrophil as another  cell type modulated by anti-PD1 antibodies.
CANIT0001371	28986666	Case report	Leptomeningeal melanomatosis	Leptomeningeal melanomatosis	MONDO:0016745	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Case	This was also unsuccessful, and he died 5 months after treatment initiation. Further studies are needed to improve treatment and prognosis of this rare but serious disease.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2018 Jan	 Primary central nervous system malignant melanoma with leptomeningeal  melanomatosis: a case report and review of the literature.	 Neurosurg Rev	 Leptomeningeal melanomatosis is an extremely rare variant of primary central  nervous system (CNS) melanoma and has a poor prognosis and no standard treatment.  Primary CNS melanoma is derived from the melanocytes of the leptomeninges. Here,   we describe a case of a 37-year-old male who visited our hospital due to  worsening headaches. Characteristic imaging findings of this tumor type include  hyper-dense lesions that are enhanced by contrast medium on computed tomography  and hyper-intensity on T1-weighted magnetic resonance images and iso- to  hypo-intensity on T2-weighted magnetic resonance images. Imaging of the CNS in  our patient showed several lesions of this type. Pathological diagnosis and  exclusion of systemic melanoma are required to confirm primary CNS malignant  melanoma. Partial resection of the mass in the left temporal lobe of this patient  was performed, and histological analysis showed pigmentation, melanin black-45  positivity, and BRAF mutation. Because no lesions were found outside the CNS  following a thorough whole-body search, he was diagnosed with primary CNS  malignant melanoma with leptomeningeal melanomatosis. He was treated with  whole-brain radiation and the BRAF kinase inhibitor vemurafenib. His condition  worsened, and he was given the anti-programmed cell death-1 antibody nivolumab as  second-line therapy. This was also unsuccessful, and he died 5 months after  treatment initiation. Further studies are needed to improve treatment and  prognosis of this rare but serious disease.
CANIT0001372	28988363	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	46	N/A	N/A	Shortened infusion times for combined ipilimumab and nivolumab treatment are safe, thereby facilitating a more efficient use of outpatient facilities and enhancing patient's convenience.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 Safety of shortened infusion times for combined ipilimumab and nivolumab.	 Cancer Immunol Immunother	 BACKGROUND: Combined ipilimumab and nivolumab induces encouraging response rates   in patients with unresectable or metastatic melanoma. However, the approved  protocol for dual checkpoint inhibition (3 mg/kg ipilimumab over 90 min and 1  mg/kg nivolumab over 60 min) is time-intensive and several trials have shown that  both single agents can be safely administered at faster infusion rates. AIM: To  investigate whether combined checkpoint inhibition with 3 mg/kg ipilimumab and 1   mg/kg nivolumab can be safely administered over 30 min per agent. PATIENTS AND  METHODS: We reviewed the rate of infusion-related reactions (IRRs) in the first  12 months of our single-institution experience using shortened infusion times for  combined checkpoint inhibition with ipilimumab and nivolumab. RESULTS: Between  May 24, 2016 and June 10, 2017, a total of 46 melanoma patients received 100  shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab. One  patient (2.2%; 1/46) had a questionable reaction after administration of 1 mg/kg   nivolumab over 30 min, but none of the other patients had a bona fide IRR.  CONCLUSIONS: Shortened infusion times for combined ipilimumab and nivolumab  treatment are safe, thereby facilitating a more efficient use of outpatient  facilities and enhancing patient's convenience.
CANIT0001373	28988380	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	30	N/A	A retrospective cohort study	Our results corroborate the previous findings suggesting an association between an immunologically active tumor microenvironment and response to ipilimumab treatment, and propose new potential biomarkers for predicting treatment efficacy and disease outcome.	N/A	N/A	N/A	Tumor infiltrate (NCIT:C12546); Immune responses (NCIT:C17930); 	Tumor-infiltrating immune cells	Tumor-infiltrating immune cell	 2018 Jan	 Tumor-infiltrating immune cells as potential biomarkers predicting response to  treatment and survival in patients with metastatic melanoma receiving ipilimumab   therapy.	 Cancer Immunol Immunother	 Monoclonal antibodies targeting immune checkpoints are gaining ground in the  treatment of melanoma and other cancers, and considerable effort is made to  identify biomarkers predicting the efficacy of these therapies. Our retrospective  study was performed on surgical tissue samples (52 lymph nodes and 34  cutaneous/subcutaneous metastases) from 30 patients with metastatic melanoma  treated with ipilimumab. Using a panel of 11 antibodies against different immune   cell types, intratumoral immune cell densities were determined and evaluated in  relation to response to ipilimumab treatment and disease outcome. For most  markers studied, median immune cell densities were at least two times higher in  lymph node metastases compared to skin/subcutaneous ones; therefore, the  prognostic and predictive associations of immune cell infiltration were evaluated  separately in the two groups of metastases as well as in all samples as a whole.   Higher prevalence of several immune cell types was seen in lymph node metastases   of the responders compared to non-responders, particularly FOXP3(+) cells and  CD8(+) T lymphocytes. In subcutaneous or cutaneous metastases, on the other hand,  significant difference could be observed only in the case of CD16 and CD68.  Associations of labeled cell densities with survival were also found for most  cell types studied in nodal metastases, and for CD16(+) and CD68(+) cells in  skin/s.c. metastatic cases. Our results corroborate the previous findings  suggesting an association between an immunologically active tumor  microenvironment and response to ipilimumab treatment, and propose new potential   biomarkers for predicting treatment efficacy and disease outcome.
CANIT0001374	28993052	Clinical research	Advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	Placebo	Immune checkpoint therapy	Nivolumab (DB09035); 	330	163	A randomised, double-blind, placebo-controlled, phase III	In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer.	Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed.	N/A	N/A	N/A	N/A	N/A	 2017 Dec 2	 Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer  refractory to, or intolerant of, at least two previous chemotherapy regimens  (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled,  phase 3 trial.	 Lancet	 BACKGROUND: Patients with advanced gastric or gastro-oesophageal junction cancer   refractory to, or intolerant of, two or more previous regimens of chemotherapy  have a poor prognosis, and current guidelines do not recommend any specific  treatments for these patients. We assessed the efficacy and safety of nivolumab,   a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in  patients with advanced gastric or gastro-oesophageal junction cancer who had been  previously been treated with two or more chemotherapy regimens. METHODS: In this   randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical  sites in Japan, South Korea, and Taiwan, eligible patients (aged >/=20 years with  unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer   refractory to, or intolerant of, standard therapy [including two or more previous  chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG]  performance status of 0-1, and naive to anti-PD-1 therapy or other therapeutic  antibodies and pharmacotherapies for the regulation of T cells) were recruited.  Patients were randomly assigned (2:1) using an interactive web response system to  receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by  country, ECOG performance status, and number of organs with metastases. Study  treatment was continued until progressive disease per investigator assessment or   onset of toxicities requiring permanent discontinuation. Patients and  investigators were masked to group assignment. The primary endpoint was overall  survival in the intention-to-treat population. Safety was analysed in all  patients who received at least one dose of study treatment. This study is ongoing  but not recruiting new patients, and is registered with ClinicalTrials.gov,  number NCT02267343. FINDINGS: Between Nov 4, 2014, and Feb 26, 2016, we randomly   assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the  data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8.87  months (IQR 6.57-12.37) in the nivolumab group and 8.59 months (5.65-11.37) in  the placebo group. Median overall survival was 5.26 months (95% CI 4.60-6.37) in   the nivolumab group and 4.14 months (3.42-4.86) in the placebo group (hazard  ratio 0.63, 95% CI 0.51-0.78; p<0.0001). 12-month overall survival rates were  26.2% (95% CI 20.7-32.0) with nivolumab and 10.9% (6.2-17.0) with placebo. Grade   3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who   received nivolumab and seven (4%) of 161 patients who received placebo;  treatment-related adverse events led to death in five (2%) of 330 patients in the  nivolumab group and two (1%) of 161 patients in the placebo group. No new safety   signals were observed. INTERPRETATION: In this phase 3 study, the survival  benefits indicate that nivolumab might be a new treatment option for heavily  pretreated patients with advanced gastric or gastro-oesophageal junction cancer.   Ongoing trials that include non-Asian patients are investigating nivolumab for  advanced gastric or gastro-oesophageal junction cancer in various settings and  earlier treatment lines. FUNDING: Ono Pharmaceutical and Bristol-Myers Squibb.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001375	29016387	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	133	N/A	A retrospective cohort study	The baseline LMR is associated with PFS and OS in metastatic melanoma patients treated with pembrolizumab, and could represent a convenient and cost-effective prognostic biomarker.	N/A	N/A	N/A	Lymphocyte-to-monocyte ratios (EFO:0004587); 	Lymphocyte-to-monocyte ratios	Cell percentage/counts in blood	 2017 Dec	 Lymphocyte-to-monocyte ratio is associated with survival in pembrolizumab-treated  metastatic melanoma patients.	 Melanoma Res	 The peripheral blood lymphocyte-to-monocyte ratio (LMR) has been associated with   prognosis in many malignancies including metastatic melanoma. However, it has not  been studied in patients treated with immune checkpoint inhibitors. In this  study, we analyzed the baseline LMR with progression-free survival (PFS) and  overall survival (OS) in metastatic melanoma patients treated with pembrolizumab.  A total of 133 patients with metastatic melanoma treated with pembrolizumab were   included in this retrospective study. LMR was calculated from pretherapy  peripheral blood counts and the optimal cutoff value was determined by a receiver  operator characteristic curve. PFS and OS were evaluated using the Kaplan-Meier  method and multivariate Cox proportional hazard modeling. Patients with an LMR of  at least 1.7 showed improved PFS (hazard ratio=0.55; 95% confidence interval:  0.34-0.92; P=0.024) and OS (hazard ratio=0.29; 95% confidence interval:  0.15-0.59; P=0.0007). The baseline LMR is associated with PFS and OS in  metastatic melanoma patients treated with pembrolizumab, and could represent a  convenient and cost-effective prognostic biomarker. Validation of these findings   in an independent cohort is needed.
CANIT0001376	29018908	Clinical research	Metastasized cutaneous malignancies	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	26	N/A	A retrospective cohort study	Arthralgia is frequent during PD1ab treatment. The clinical picture varies between synovitis of predominantly large joints, progressive osteoarthritis and arthralgia without evident joint damage. Vast majority of cases can be satisfactorily managed by NSAID and/or low-dose corticosteroids.	26 of 195 patients (13.3%) developed arthralgia. The median onset of symptoms was 100 days (7-780 days). Most frequently, arthralgia involved large joints (shoulders, knees) in a predominantly symmetrical pattern. Only two patients were seropositive for rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients developed the clinical picture of arthritis, with seven of them showing synovitis in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by osteoarthritis. In 11 patients arthralgia could not be specified. The majority of patients was satisfactorily treated with non-steroidal anti-inflammatory drugs (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our patients received further immunosuppressive treatment.	N/A	N/A	N/A	N/A	N/A	 2018 Feb	 Characterization of arthralgia induced by PD-1 antibody treatment in patients  with metastasized cutaneous malignancies.	 Cancer Immunol Immunother	 BACKGROUND: PD-1 antibodies (PD1ab) are increasingly used in metastatic melanoma   and other malignancies. Arthralgia is an underestimated side effect of PD-1  antibody treatment with unknown cause. Our aim was to characterize PD1ab-induced   arthralgia. PATIENTS AND METHODS: We retrospectively included patients with  metastatic cutaneous malignancies treated with pembrolizumab or nivolumab +/-  ipilimumab at the National Center for Tumor Diseases (Heidelberg) between 01/2013  and 09/2016. Arthralgia was characterized by laboratory diagnostics, imaging, and  if indicated, rheumatologic consultation. RESULTS: 26 of 195 patients (13.3%)  developed arthralgia. The median onset of symptoms was 100 days (7-780 days).  Most frequently, arthralgia involved large joints (shoulders, knees) in a  predominantly symmetrical pattern. Only two patients were seropositive for  rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients  developed the clinical picture of arthritis, with seven of them showing synovitis  in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by  osteoarthritis. In 11 patients arthralgia could not be specified. The majority of  patients was satisfactorily treated with non-steroidal anti-inflammatory drugs  (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our  patients received further immunosuppressive treatment. Patients with arthralgia  showed a better treatment response and improved PFS and OS. CONCLUSION:  Arthralgia is frequent during PD1ab treatment. The clinical picture varies  between synovitis of predominantly large joints, progressive osteoarthritis and  arthralgia without evident joint damage. Vast majority of cases can be  satisfactorily managed by NSAID and/or low-dose corticosteroids.
CANIT0001377	29018908	Clinical research	Metastasized cutaneous malignancies	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); 	26	N/A	A retrospective cohort study	Arthralgia is frequent during PD1ab treatment. The clinical picture varies between synovitis of predominantly large joints, progressive osteoarthritis and arthralgia without evident joint damage. Vast majority of cases can be satisfactorily managed by NSAID and/or low-dose corticosteroids.	26 of 195 patients (13.3%) developed arthralgia. The median onset of symptoms was 100 days (7-780 days). Most frequently, arthralgia involved large joints (shoulders, knees) in a predominantly symmetrical pattern. Only two patients were seropositive for rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients developed the clinical picture of arthritis, with seven of them showing synovitis in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by osteoarthritis. In 11 patients arthralgia could not be specified. The majority of patients was satisfactorily treated with non-steroidal anti-inflammatory drugs (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our patients received further immunosuppressive treatment.	N/A	N/A	N/A	N/A	N/A	 2018 Feb	 Characterization of arthralgia induced by PD-1 antibody treatment in patients  with metastasized cutaneous malignancies.	 Cancer Immunol Immunother	 BACKGROUND: PD-1 antibodies (PD1ab) are increasingly used in metastatic melanoma   and other malignancies. Arthralgia is an underestimated side effect of PD-1  antibody treatment with unknown cause. Our aim was to characterize PD1ab-induced   arthralgia. PATIENTS AND METHODS: We retrospectively included patients with  metastatic cutaneous malignancies treated with pembrolizumab or nivolumab +/-  ipilimumab at the National Center for Tumor Diseases (Heidelberg) between 01/2013  and 09/2016. Arthralgia was characterized by laboratory diagnostics, imaging, and  if indicated, rheumatologic consultation. RESULTS: 26 of 195 patients (13.3%)  developed arthralgia. The median onset of symptoms was 100 days (7-780 days).  Most frequently, arthralgia involved large joints (shoulders, knees) in a  predominantly symmetrical pattern. Only two patients were seropositive for  rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients  developed the clinical picture of arthritis, with seven of them showing synovitis  in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by  osteoarthritis. In 11 patients arthralgia could not be specified. The majority of  patients was satisfactorily treated with non-steroidal anti-inflammatory drugs  (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our  patients received further immunosuppressive treatment. Patients with arthralgia  showed a better treatment response and improved PFS and OS. CONCLUSION:  Arthralgia is frequent during PD1ab treatment. The clinical picture varies  between synovitis of predominantly large joints, progressive osteoarthritis and  arthralgia without evident joint damage. Vast majority of cases can be  satisfactorily managed by NSAID and/or low-dose corticosteroids.
CANIT0001378	29018908	Clinical research	Metastasized cutaneous malignancies	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	26	N/A	A retrospective cohort study	Patients with arthralgia showed a better treatment response and improved PFS and OS.	26 of 195 patients (13.3%) developed arthralgia. The median onset of symptoms was 100 days (7-780 days). Most frequently, arthralgia involved large joints (shoulders, knees) in a predominantly symmetrical pattern. Only two patients were seropositive for rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients developed the clinical picture of arthritis, with seven of them showing synovitis in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by osteoarthritis. In 11 patients arthralgia could not be specified. The majority of patients was satisfactorily treated with non-steroidal anti-inflammatory drugs (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our patients received further immunosuppressive treatment.	N/A	N/A	Arthralgia (NCIT:C50464); 	Arthralgia	Adverse events	 2018 Feb	 Characterization of arthralgia induced by PD-1 antibody treatment in patients  with metastasized cutaneous malignancies.	 Cancer Immunol Immunother	 BACKGROUND: PD-1 antibodies (PD1ab) are increasingly used in metastatic melanoma   and other malignancies. Arthralgia is an underestimated side effect of PD-1  antibody treatment with unknown cause. Our aim was to characterize PD1ab-induced   arthralgia. PATIENTS AND METHODS: We retrospectively included patients with  metastatic cutaneous malignancies treated with pembrolizumab or nivolumab +/-  ipilimumab at the National Center for Tumor Diseases (Heidelberg) between 01/2013  and 09/2016. Arthralgia was characterized by laboratory diagnostics, imaging, and  if indicated, rheumatologic consultation. RESULTS: 26 of 195 patients (13.3%)  developed arthralgia. The median onset of symptoms was 100 days (7-780 days).  Most frequently, arthralgia involved large joints (shoulders, knees) in a  predominantly symmetrical pattern. Only two patients were seropositive for  rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients  developed the clinical picture of arthritis, with seven of them showing synovitis  in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by  osteoarthritis. In 11 patients arthralgia could not be specified. The majority of  patients was satisfactorily treated with non-steroidal anti-inflammatory drugs  (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our  patients received further immunosuppressive treatment. Patients with arthralgia  showed a better treatment response and improved PFS and OS. CONCLUSION:  Arthralgia is frequent during PD1ab treatment. The clinical picture varies  between synovitis of predominantly large joints, progressive osteoarthritis and  arthralgia without evident joint damage. Vast majority of cases can be  satisfactorily managed by NSAID and/or low-dose corticosteroids.
CANIT0001379	29018908	Clinical research	Metastasized cutaneous malignancies	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); 	26	N/A	A retrospective cohort study	Patients with arthralgia showed a better treatment response and improved PFS and OS.	26 of 195 patients (13.3%) developed arthralgia. The median onset of symptoms was 100 days (7-780 days). Most frequently, arthralgia involved large joints (shoulders, knees) in a predominantly symmetrical pattern. Only two patients were seropositive for rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients developed the clinical picture of arthritis, with seven of them showing synovitis in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by osteoarthritis. In 11 patients arthralgia could not be specified. The majority of patients was satisfactorily treated with non-steroidal anti-inflammatory drugs (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our patients received further immunosuppressive treatment.	N/A	N/A	Arthralgia (NCIT:C50464); 	Arthralgia	Adverse events	 2018 Feb	 Characterization of arthralgia induced by PD-1 antibody treatment in patients  with metastasized cutaneous malignancies.	 Cancer Immunol Immunother	 BACKGROUND: PD-1 antibodies (PD1ab) are increasingly used in metastatic melanoma   and other malignancies. Arthralgia is an underestimated side effect of PD-1  antibody treatment with unknown cause. Our aim was to characterize PD1ab-induced   arthralgia. PATIENTS AND METHODS: We retrospectively included patients with  metastatic cutaneous malignancies treated with pembrolizumab or nivolumab +/-  ipilimumab at the National Center for Tumor Diseases (Heidelberg) between 01/2013  and 09/2016. Arthralgia was characterized by laboratory diagnostics, imaging, and  if indicated, rheumatologic consultation. RESULTS: 26 of 195 patients (13.3%)  developed arthralgia. The median onset of symptoms was 100 days (7-780 days).  Most frequently, arthralgia involved large joints (shoulders, knees) in a  predominantly symmetrical pattern. Only two patients were seropositive for  rheumatoid factor and/or anti-citrullinated protein antibodies. Ten patients  developed the clinical picture of arthritis, with seven of them showing synovitis  in MRI or PET/CT. Five patients showed inflammation in joints pre-damaged by  osteoarthritis. In 11 patients arthralgia could not be specified. The majority of  patients was satisfactorily treated with non-steroidal anti-inflammatory drugs  (NSAIDs), 23.1% required additional low-dose corticosteroids and only 7.6% of our  patients received further immunosuppressive treatment. Patients with arthralgia  showed a better treatment response and improved PFS and OS. CONCLUSION:  Arthralgia is frequent during PD1ab treatment. The clinical picture varies  between synovitis of predominantly large joints, progressive osteoarthritis and  arthralgia without evident joint damage. Vast majority of cases can be  satisfactorily managed by NSAID and/or low-dose corticosteroids.
CANIT0001380	29023213	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Docetaxel	Immune checkpoint therapy	Nivolumab (DB09035); docetaxel (DB01248); 	418	397	A phase III clinical trial	Nivolumab provides long-term clinical benefit and a favorable tolerability profile compared with docetaxel in previously treated patients with advanced NSCLC.	Rates of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%).	N/A	N/A	N/A	N/A	N/A	 2017 Dec 10	 Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced  Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label,  Phase III Trials (CheckMate 017 and CheckMate 057).	 J Clin Oncol	 Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival  compared with docetaxel in two independent phase III studies in previously  treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov  identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov  identifier: NCT01673867) non-small-cell lung cancer (NSCLC). We report updated  results, including a pooled analysis of the two studies. Methods Patients with  stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease  progression during or after prior platinum-based chemotherapy were randomly  assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m(2) every   3 weeks). Minimum follow-up for survival was 24.2 months. Results Two-year  overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to  30%) versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%)  versus 16% (95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the   risk of death with nivolumab versus docetaxel remained similar to those reported   in the primary analyses. Durable responses were observed with nivolumab; 10 (37%)  of 27 confirmed responders with squamous NSCLC and 19 (34%) of 56 with  nonsquamous NSCLC had ongoing responses after 2 years' minimum follow-up. No  patient in either docetaxel group had an ongoing response. In the pooled  analysis, the relative reduction in the risk of death with nivolumab versus  docetaxel was 28% (hazard ratio, 0.72; 95% CI, 0.62 to 0.84), and rates of  treatment-related adverse events were lower with nivolumab than with docetaxel  (any grade, 68% v 88%; grade 3 to 4, 10% v 55%). Conclusion Nivolumab provides  long-term clinical benefit and a favorable tolerability profile compared with  docetaxel in previously treated patients with advanced NSCLC.
CANIT0001381	29023959	Case report	Metastatic hepatocellular carcinoma following live donor liver transplantation	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Complete radiological remission of metastatic lesions	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Pembrolizumab for metastatic hepatocellular carcinoma following live donor liver   transplantation: The silver bullet 	 Hepatology	Unable to provide
CANIT0001382	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Anti-PD-1 treatment before or after ipilimumab were significant independent predictors for improved melanoma-specific survival (MSS).	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Anti-PD-1 treatment before or after ipilimumab	Exposure factors/status	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001383	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Baseline eosinophil/lymphocyte ratio was not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS).	N/A	N/A	N/A	Eosinophil-to-lymphocyte ratios (NCIT:C64604); 	Eosinophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001384	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Baseline eosinophils was not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS).	N/A	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Eosinophil counts	Cell percentage/counts in blood	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001385	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Baseline leucocytes was not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS).	N/A	N/A	N/A	Leucocyte counts (EFO:0004308); 	Leucocyte counts	Cell percentage/counts in blood	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001386	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Baseline lymphocytes was not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS).	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001387	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Baseline neutrophil/lymphocyte ratio was not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS).	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001388	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Baseline serum vitamin D levels was not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS).	N/A	N/A	N/A	Vitamin D (EFO:0004631); 	Serum vitamin D levels	Gene expression signature in serum	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001389	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Baseline thrombocytes/lymphocyte ratio was not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS).	N/A	N/A	N/A	Thrombocytes-to-lymphocyte ratios (CL:0000762); 	Thrombocytes-to-lymphocyte ratios	Cell percentage/counts in blood	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001390	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Baseline thrombocytes was not significantly associated with ORR, progression-free survival (PFS) and melanoma-specific survival (MSS).	N/A	N/A	N/A	Thrombocyte counts (CL:0000762); 	Absolute thrombocyte counts	Cell percentage/counts in blood	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001391	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Low-LDH levels turned out to be significant independent predictors for prolonged progression-free survival (PFS).	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001392	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Low-S100B levels before or after ipilimumab were significant independent predictors for improved melanoma-specific survival (MSS).	N/A	N/A	N/A	S100B (P04271); 	Serum S100B levels	Gene expression signature in serum	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001393	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	More than two ipilimumab cycles turned out to be significant independent predictors for prolonged progression-free survival (PFS).	N/A	N/A	N/A	Therapy cycles (); 	Ipilimumab cycles	Exposure factors/status	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001394	29024038	Clinical research	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	N/A	Multivariate analysis confirmed anti-PD-1 pretreatment as significant predictor for ORR following ipilimumab therapy.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Anti-PD-1 before ipilimumab	Exposure factors/status	 2018 Jun	 Baseline laboratory parameters predicting clinical outcome in melanoma patients  treated with ipilimumab: a single-centre analysis.	 J Eur Acad Dermatol Venereol	 BACKGROUND: Overall response rates (ORRs) for ipilimumab in advanced melanoma are  only about 10%. Hence, it is important to explore biomarkers predicting  ipilimumab responders. OBJECTIVE: We aimed to explore biomarkers to predict  therapy outcome in melanoma patients who have undergone standard ipilimumab  therapy in a real-world setting. METHODS: Databases of cutaneous melanoma  patients (n = 52) who had received ipilimumab were reviewed and data collected on  patient characteristics and diverse laboratory parameters. We performed  univariate and multivariate statistics including logistic regression analysis and  Cox proportional-hazards regression. RESULTS: Baseline leucocytes, lymphocytes,  eosinophils, thrombocytes, neutrophil/lymphocyte ratio, thrombocytes/lymphocyte  ratio, eosinophil/lymphocyte ratio and serum vitamin D levels were not  significantly associated with ORR, progression-free survival (PFS) and  melanoma-specific survival (MSS). Multivariate analysis confirmed anti-PD-1  pretreatment as significant predictor for ORR following ipilimumab therapy.  Low-LDH levels and more than two ipilimumab cycles turned out to be significant  independent predictors for prolonged PFS. Low-S100B levels and anti-PD-1  treatment before or after ipilimumab were significant independent predictors for   improved MSS. All aforementioned parameters and faecal calprotectin did not turn   out to be predictors for ipilimumab-induced autoimmune-related adverse events and  autoimmune colitis, respectively. CONCLUSIONS: Low serum LDH before ipilimumab  treatment is an independent predictor for improved PFS. Furthermore, low serum  S100B is an independent predictor for MSS. The number of ipilimumab cycles (>2)  is significantly associated with prolonged PFS. Pretreatment calprotectin does  not predict the occurrence of autoimmune colitis under ipilimumab therapy.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001395	29028121	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	In this report, we describe a patient who developed a lupus-like cutaneous reaction in the setting of pembrolizumab therapy for metastatic melanoma, adding to the spectrum of reactions which may be observed in association with PD-1 inhibitor therapy.	Lupus-like cutaneous reaction following pembrolizumab	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 Lupus-like cutaneous reaction following pembrolizumab: An immune-related adverse   event associated with anti-PD-1 therapy.	 J Cutan Pathol	 PD-1 (programmed cell death-1) inhibitors, used to treat metastatic melanoma and   other malignancies, are associated with development of immune-related adverse  events in the skin. Such reactions include morbilliform eruptions, vitiligo,  alopecia areata and bullous pemphigoid. In this report, we describe a patient who  developed a lupus-like cutaneous reaction in the setting of pembrolizumab therapy  for metastatic melanoma, adding to the spectrum of reactions which may be  observed in association with PD-1 inhibitor therapy.CI  - (c) 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001396	29028788	Clinical research	Unresectable stage III/IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	947	N/A	N/A	The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.	One hundred eighty-one (19.1%) patients experienced 1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced 1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths.	N/A	N/A	N/A	N/A	N/A	 2017 Nov/Dec	 Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the  United States: An Expanded Access Program.	 J Immunother	 KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access  program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody,  for patients with advanced melanoma before its regulatory approval. Patients with  unresectable stage III/IV melanoma that progressed after standard-of-care  therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were  eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by  immune-related response criteria by investigator review. Adverse events (AEs)  were graded according to the National Cancer Institute Common Terminology  Criteria for Adverse Events, version 4.0. In the United States, 979 patients  enrolled between April and September 2014. Of the 947 evaluable patients, 621  (65.6%) remained on treatment and transitioned to receive commercial  pembrolizumab following approval by the Food and Drug Administration, whereas 326  (34.4%) discontinued, most commonly for disease progression (39.6%) or death  (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%-16.8%)  in the treated population (n=947) and 22.1% (95% confidence interval,  18.8%-25.5%) in patients who had >/=1 response assessment reported (n=619).  Twelve patients achieved complete response. One hundred eighty-one (19.1%)  patients experienced >/=1 treatment-related AE, most commonly general disorders  (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders  (6.4%); 29 (3.1%) patients experienced >/=1 grade 3/4 treatment-related AE.  Immune-mediated AEs were also reported. There were no treatment-related deaths.  The safety and efficacy observed in this expanded access program were consistent   with those previously reported for similar populations and support the use of  pembrolizumab for patients with advanced melanoma.
CANIT0001397	29034739	Case report	Non-small-cell carcinoma intramedullary spinal cord metastasis	Non-small cell carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Potential treatment option	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Regression of an intramedullary spinal cord metastasis with a checkpoint  inhibitor: a case report.	 CNS Oncol	 Intramedullary spinal cord metastasis is an increasingly common diagnosis in  patients with cancer largely owing to new imaging techniques and the increase  lifespan of patients with malignant tumors. The diagnosis confers significant  morbidity and a poor prognosis. Mainstay palliative treatment options include  corticosteroids, fractionated radiotherapy and surgery in select cases. In the  modern era of immunotherapy for the treatment of several tumor types, the  efficacy of these agents against parenchymal CNS tumors remains unanswered. Here,  we report a case of regression of an intramedullary spinal cord metastasis with a  checkpoint inhibitor.
CANIT0001398	29036015	Case report	Stage IV M1C (distant metastases) BRAF wild-type melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Transient pituitary ACTH-dependent Cushing syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Transient pituitary ACTH-dependent Cushing syndrome caused by an immune  checkpoint inhibitor combination.	 Melanoma Res	 Immune checkpoint inhibitors have improved survival in numerous advanced  malignancies, but are associated with a number of immune-related adverse events,   including endocrinopathies. Endogenous Cushing's syndrome (CS) is a rare disorder  resulting from exposure to high levels of circulating cortisol. CS can be caused   either by adrenal cortex tumors or hyperplasia or by pituitary or extra-pituitary  tumors over-secreting ACTH (known as ACTH-dependent CS). We report the first case  of transient ACTH-dependent CS, which appeared after combined ipilimumab and  nivolumab therapy. Our patient presented typical clinical features of CS after  three infusions of combined therapy, high serum and daily urinary free cortisol,   and high serum ACTH levels. Pituitary MRI showed an enlargement of the pituitary   gland suggesting ACTH secretion of pituitary origin, which was confirmed by  inferior petrosal sinus sampling. The pituitary findings were preceded by  thyroiditis. The evolution was characterized by spontaneous CS regression and  subsequent appearance of severe corticotroph deficiency consistent with  destructive hypophysitis. Immunotherapy is a novel cause of CS.
CANIT0001399	29036261	Case report	Non-small cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	1	N/A	Case	N/A	Halo Nevi	N/A	N/A	N/A	N/A	N/A	 2017 Oct 1	 Development of Halo Nevi in a Lung Cancer Patient: A Novel Immune-Related  Cutaneous Event from Atezolizumab.	 J Drugs Dermatol	 Immunotherapy-induced vitiligo is an immune-related adverse event (irAE) observed  in metastatic melanoma patients treated with immune checkpoint inhibitors that  target the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed  cell death-1 (PD-1) pathways. To date, the development of leukoderma, poliosis,  and halo nevi during immunotherapy has largely been reported in metastatic  melanoma patients. We report a case of immunotherapy-induced leukoderma  presenting as halo nevi in a patient with non-small cell lung cancer (NSCLC)  treated with atezolizumab, a programmed cell death ligand (PD-L1) antibody.  Immunotherapy-induced vitiligo in metastatic melanoma patients may be associated   with improved survival, but it remains to be determined whether its occurrence in  non-melanoma cancers has the same prognostic significance. <p><em>J Drugs  Dermatol. 2017;16(10):1047-1049.</em></p>.
CANIT0001400	29037215	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Radiotherapy (NCIT:C15313); pembrolizumab (DB09037); 	21	N/A	A retrospective cohort study	Concurrent pembrolizumab with brain RT appears safe in patients with metastatic melanoma, and SRS in particular is effective in markedly reducing the size of brain metastases at the time of first follow-up MRI. These results compare favorably to SRS in combination with ipilimumab and SRS without concurrent immunotherapy.	All treatments were well tolerated with no observed Grade 4 or 5 toxicities; Grade 3 edema and confusion occurred in 1 patient treated with WBRT after prior SRS.	N/A	N/A	N/A	N/A	N/A	 2017 Oct 17	 Melanoma brain metastases treated with stereotactic radiosurgery and concurrent  pembrolizumab display marked regression; efficacy and safety of combined  treatment.	 J Immunother Cancer	 BACKGROUND: Brain metastases are common in patients with metastatic melanoma.  With increasing numbers of melanoma patients on anti-PD-1 therapy, we sought to  evaluate the safety and initial response of brain metastases treated with  concurrent pembrolizumab and radiation therapy. METHODS: From an institutional  database, we retrospectively identified patients with melanoma brain metastases  treated with radiation therapy (RT) who received concurrent pembrolizumab.  Concurrent treatment was defined as RT during pembrolizumab administration period  and up to 4 months after most recent pembrolizumab treatment. Response was  categorized by change in maximum diameter on first scheduled follow-up MRI.  Lesion and patient specific outcomes including response, lesion control, brain  control and overall survival were recorded and descriptively compared to  contemporary treatments with RT and concurrent ipilimumab or RT without  immunotherapy. RESULTS: From January 2014 through December 2015, we identified 21  patients who received concurrent radiation therapy and pembrolizumab for brain  metastases or resection cavities that had at least one scheduled follow-up MRI.  Eleven underwent stereotactic radiosurgery (SRS), 7 received hypofractionated  radiation and 3 had whole brain treatment (WBRT). All treatments were well  tolerated with no observed Grade 4 or 5 toxicities; Grade 3 edema and confusion  occurred in 1 patient treated with WBRT after prior SRS. For metastases treated  with SRS, at first scheduled follow-up MRI (median 57 days post SRS), 70% (16/23)  exhibited complete (CR, n = 8) or partial response (PR, n = 8). The intracranial   response rates (CR/PR) for patients treated with SRS and concurrent ipilimumab  and SRS without concurrent immunotherapy was 32% and 22%, respectively.  CONCLUSIONS: Concurrent pembrolizumab with brain RT appears safe in patients with  metastatic melanoma, and SRS in particular is effective in markedly reducing the   size of brain metastases at the time of first follow-up MRI. These results  compare favorably to SRS in combination with ipilimumab and SRS without  concurrent immunotherapy.
CANIT0001401	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	42	N/A	A retrospective cohort study	Duration of prior anti-VEGF therapy of <6 months is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Treatment duration (NCIT:C83280); 	Duration of prior anti-VEGF therapy	Exposure factors/status	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001402	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	42	N/A	A retrospective cohort study	Duration of prior anti-VEGF therapy of <6 months is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Treatment duration (NCIT:C83280); 	Duration of prior anti-VEGF therapy	Exposure factors/status	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001403	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	42	N/A	A retrospective cohort study	Duration of prior anti-VEGF therapy of <6 months is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Treatment duration (NCIT:C83280); 	Duration of prior anti-VEGF therapy	Exposure factors/status	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001404	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	42	N/A	A retrospective cohort study	Duration of prior anti-VEGF therapy of <6 months is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Treatment duration (NCIT:C83280); 	Duration of prior anti-VEGF therapy	Exposure factors/status	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001405	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	42	N/A	A retrospective cohort study	Duration of prior anti-VEGF therapy of <6 months is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Treatment duration (NCIT:C83280); 	Duration of prior anti-VEGF therapy	Exposure factors/status	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001406	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	42	N/A	A retrospective cohort study	Pretherapy neutrophil lymphocyte ratio (NLR) <3 is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001407	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	42	N/A	A retrospective cohort study	Pretherapy neutrophil lymphocyte ratio (NLR) <3 is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001408	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	42	N/A	A retrospective cohort study	Pretherapy neutrophil lymphocyte ratio (NLR) <3 is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001409	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	42	N/A	A retrospective cohort study	Pretherapy neutrophil lymphocyte ratio (NLR) <3 is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001410	29041991	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	42	N/A	A retrospective cohort study	Pretherapy neutrophil lymphocyte ratio (NLR) <3 is independent statistically significant predictor of longer PFS and OS with ICI therapy in mRCC.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2017 Oct 17	 Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as  biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy.	 J Immunother Cancer	 BACKGROUND: There is an unmet need to determine factors predictive of clinical  benefit, to guide therapeutic sequencing and selection in metastatic RCC (mRCC).   We evaluated clinical factors such as the neutrophil lymphocyte ratio (NLR) and  duration of prior anti-vascular endothelial growth factor (VEGF) inhibitors, as  predictors of response rate, progression free survival (PFS) and overall survival  (OS) in mRCC patients treated with immune checkpoint inhibitor (ICI). METHODS:  Regulatory approval was obtained. A single center retrospective chart review of  mRCC patients at Karmanos Cancer Institute, treated with ICI based therapy  (PD-1/PD-L1 inhibitors) was conducted. Data were collected on demographics,  smoking status, prognostic scoring (Memorial Sloan Kettering and Heng criteria),   NLR pretherapy, post 1 and 4 doses of ICI, and duration of prior anti-VEGF  therapy >/=6 months or <6. RESULTS: 42 patients were evaluated with median age of  61 years (range, 24-85). Pretherapy NLR < 3 and >/=3 was seen in 19 (45%) and 23   (55%) patients, respectively. 24 (57%) and 18 (43%) patients had prior anti-VEGF   inhibitors for a duration of >/=6 months and <6 months, respectively. 12 (29%),  22 (52%) and 8 (19%) patients had favorable, intermediate and poor risk disease  based on Heng criteria, respectively. Multivariable analysis showed pretherapy  NLR >/=3 was predictive of shorter PFS and OS when treated with ICI with median  3.08 months and 13.50 months, respectively, versus 15.57 months and not reached  for NLR < 3 (adjusted p-values =0.003 and 0.025, respectively). Prior anti-VEGF  therapy <6 months was predictive of increased likelihood of benefit from ICI  therapies (adjusted p = 0.028). The median PFS was 3.72 months and 14.33 months,   respectively, in cases with prior anti-VEGF therapy for >/=6 months and <6  months. CONCLUSION: Pretherapy NLR <3 and duration of prior anti-VEGF therapy of   <6 months, are independent statistically significant predictors of longer PFS and  OS with ICI therapy in mRCC. Validation is required in a larger sample size with   multi-institutional collaboration.
CANIT0001411	29043574	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	A long-term prospective study from a referral institution	Autoimmune disorders were associated with a better clinical response to CTLA4 followed by PD1 treatment. Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome.	During ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1 associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7 patients (3 F) developed hypothyroidism with severe manifestations in 6 of them; 3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean follow-up after anti-CTLA4 inhibitors treatment was 36  28 months. Thyroid disorders occurred 45.1  20.8 and 151  67 days after the initiation of CTLA4 and PD1 inhibitors, respectively.	N/A	N/A	Autoimmune side effects (EFO:0005140); 	Autoimmune thyroid dysfunction	Disease status	 2018 May	 Characterization and implications of thyroid dysfunction induced by immune  checkpoint inhibitors in real-life clinical practice: a long-term prospective  study from a referral institution.	 J Endocrinol Invest	 PURPOSE: Autoimmune diseases are typically associated with immune checkpoints  blockade. This study aims at assessing, in real-life clinical practice, the  prevalence and impact of thyroid disorders induced by immune checkpoint  inhibitors. METHODS: 52 patients (30 F; age 61 +/- 13 years) with advanced  melanoma treated with ipilimumab (3 mg/kg i.v./3 weeks; 4 doses) were included.  For disease progression, 29 (16 F) of them received nivolumab (3 mg/kg i.v./2  weeks) or pembrolizumab (2 mg/kg i.v./3 weeks). Thyroid function and autoimmunity  were assessed before, after 6 weeks, at the end of ipilimumab, as well as before   and every 3 months during nivolumab/pembrolizumab treatment. RESULTS: During  ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1  associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid  multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7  patients (3 F) developed hypothyroidism with severe manifestations in 6 of them;   3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one  after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean  follow-up after anti-CTLA4 inhibitors treatment was 36 +/- 28 months. Thyroid  disorders occurred 45.1 +/- 20.8 and 151 +/- 67 days after the initiation of  CTLA4 and PD1 inhibitors, respectively. Autoimmune disorders and BRAF mutation  were associated with a better clinical response to CTLA4 followed by PD1  treatment. CONCLUSIONS: Immune checkpoint blockade is burdened by a high  incidence of autoimmune thyroid dysfunction, which is often severe. Therefore,  early and careful monitoring and, eventually, treatment are crucial to prevent  the negative impact of thyroid dysfunction on the clinical outcome.
CANIT0001412	29043574	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	52	N/A	A long-term prospective study from a referral institution	BRAF mutation were associated with a better clinical response to CTLA4 followed by PD1 treatment. Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome.	During ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1 associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7 patients (3 F) developed hypothyroidism with severe manifestations in 6 of them; 3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean follow-up after anti-CTLA4 inhibitors treatment was 36  28 months. Thyroid disorders occurred 45.1  20.8 and 151  67 days after the initiation of CTLA4 and PD1 inhibitors, respectively.	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2018 May	 Characterization and implications of thyroid dysfunction induced by immune  checkpoint inhibitors in real-life clinical practice: a long-term prospective  study from a referral institution.	 J Endocrinol Invest	 PURPOSE: Autoimmune diseases are typically associated with immune checkpoints  blockade. This study aims at assessing, in real-life clinical practice, the  prevalence and impact of thyroid disorders induced by immune checkpoint  inhibitors. METHODS: 52 patients (30 F; age 61 +/- 13 years) with advanced  melanoma treated with ipilimumab (3 mg/kg i.v./3 weeks; 4 doses) were included.  For disease progression, 29 (16 F) of them received nivolumab (3 mg/kg i.v./2  weeks) or pembrolizumab (2 mg/kg i.v./3 weeks). Thyroid function and autoimmunity  were assessed before, after 6 weeks, at the end of ipilimumab, as well as before   and every 3 months during nivolumab/pembrolizumab treatment. RESULTS: During  ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1  associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid  multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7  patients (3 F) developed hypothyroidism with severe manifestations in 6 of them;   3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one  after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean  follow-up after anti-CTLA4 inhibitors treatment was 36 +/- 28 months. Thyroid  disorders occurred 45.1 +/- 20.8 and 151 +/- 67 days after the initiation of  CTLA4 and PD1 inhibitors, respectively. Autoimmune disorders and BRAF mutation  were associated with a better clinical response to CTLA4 followed by PD1  treatment. CONCLUSIONS: Immune checkpoint blockade is burdened by a high  incidence of autoimmune thyroid dysfunction, which is often severe. Therefore,  early and careful monitoring and, eventually, treatment are crucial to prevent  the negative impact of thyroid dysfunction on the clinical outcome.
CANIT0001413	29044660	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	371	N/A	A multicentre, retrospective cohort study	During the time observed, ipilimumab was mainly used as second-line or later therapy. A significant proportion of patients received postipilimumab therapy, most of which was chemotherapy. Nevertheless, overall survival following progression on ipilimumab treatment remained poor, highlighting the need for research to develop more effective end-of-life treatment options.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Real-world treatment patterns and outcomes among metastatic cutaneous melanoma  patients treated with ipilimumab.	 J Eur Acad Dermatol Venereol	 BACKGROUND: There is a scarcity of real-world data on treatment patterns and  outcomes among advanced melanoma patients treated with immunotherapies including   ipilimumab, an anti-CTLA-4 antibody approved since 2011. OBJECTIVE: To evaluate  ipilimumab and postipilimumab treatment patterns and outcomes among patients with  advanced melanoma in Australia, Germany, Italy and Spain, following regulatory  approval. METHODS: Retrospective multicentre, multinational, observational chart   review study. Data were extracted from the start of ipilimumab therapy until the   end of at least 40 weeks of follow-up, or death. RESULTS: Data from 371 patients   (Australia, 103; Germany, 152; Italy, 76; Spain, 40) were analysed. Mean age was   65 years; 62% were male. Eastern Cooperative Oncology Group performance status  (ECOG PS) was 0 or 1 for 94%. In 67%, ipilimumab was initially received as  second-line or later therapy. Patients received on average 3.4 ipilimumab doses.   The ipilimumab-refractory cohort comprised of 226 patients. Of these, 17% in  Australia, 47% in Germany, 29% in Italy and 14% in Spain received another  antimelanoma treatment after ipilimumab including chemotherapy in 26% and  BRAF/other kinase inhibitors in 11%. Ipilimumab-refractory patients who received   postipilimumab treatment showed a 40% reduced hazard of dying than those not  receiving treatment after ipilimumab (HR 0.60; 95% CI 0.43-0.83), after  adjustment for potential confounders. CONCLUSION: During the time observed,  ipilimumab was mainly used as second-line or later therapy. A significant  proportion of patients received postipilimumab therapy, most of which was  chemotherapy. Nevertheless, overall survival following progression on ipilimumab   treatment remained poor, highlighting the need for research to develop more  effective end-of-life treatment options.CI  - (c) 2017 European Academy of Dermatology and Venereology.
CANIT0001414	29045188	Clinical research	Endocrine cancer	Endocrine cancer	MONDO:0021069	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	9	N/A	N/A	As the use of immune checkpoint inhibitor therapy increases, the need for prompt diagnosis and treatment of drug-induced thyroid disease will become more important. As illustrated in this case series, in  contrast to other causes of auto-immune thyroiditis, hypothyroidism can develop  rapidly within 3 months of treatment. Close monitoring is necessary to detect the development of thyroid dysfunction and avoid preventable morbidity.	Seven patients ultimately developed hypothyroidism. Five of the 7 patients developed abnormal thyroid function tests within the first 90 days of starting therapy (range 21-84 days), 3 of whom had transient hyperthyroidism. Transient hyperthyroidism evolved rapidly to hypothyroidism; elevated thyroid-stimulating hormone (TSH) levels were detected within 16 to 32 days of the last documented low TSH. In the 2 patients without a hyperthyroid phase, TSH levels >50 were found 18 to 28 days after the last normal TSH value.	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 RAPID EVOLUTION OF THYROID DYSFUNCTION IN PATIENTS TREATED WITH NIVOLUMAB.	 Endocr Pract	 OBJECTIVE: To describe the evolution of thyroid dysfunction in a series of  patients with cancer treated with the immune checkpoint inhibitor anti-programmed  cell death protein-1 (PD-1) monoclonal antibody, nivolumab. METHODS: Cases of  thyroid dysfunction after initiation of checkpoint inhibitor treatment were  identified from the Division of Endocrinology clinical practice at Mount Sinai  Hospital, New York from April 2016 to February 2017. Charts were reviewed to  identify patients treated with nivolumab with new onset of thyroid dysfunction.  RESULTS: Nine cases of thyroid function in patients who were treated with  nivolumab were identified. There were 4 male and 5 female patients, with a mean  age of 66 years (range 50-76 years). Seven patients ultimately developed  hypothyroidism. Five of the 7 patients developed abnormal thyroid function tests   within the first 90 days of starting therapy (range 21-84 days), 3 of whom had  transient hyperthyroidism. Transient hyperthyroidism evolved rapidly to  hypothyroidism; elevated thyroid-stimulating hormone (TSH) levels were detected  within 16 to 32 days of the last documented low TSH. In the 2 patients without a   hyperthyroid phase, TSH levels >50 were found 18 to 28 days after the last normal  TSH value. CONCLUSION: As the use of immune checkpoint inhibitor therapy  increases, the need for prompt diagnosis and treatment of drug-induced thyroid  disease will become more important. As illustrated in this case series, in  contrast to other causes of auto-immune thyroiditis, hypothyroidism can develop  rapidly within 3 months of treatment. Close monitoring is necessary to detect the  development of thyroid dysfunction and avoid preventable morbidity.  ABBREVIATIONS: Anti-TPO Abs = anti-thyroglobulin antibodies; CT = computed  tomography; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; FDA = U.S. Food  & Drug Administration; FDG-PET = fluorodeoxyglucose-positron emission tomography;  PD-1 = programmed cell death protein-1; PD-L1 = programmed death-ligand 1; T3 =  triiodothyronine; T4 = thyroxine; TG = thyroglobulin; TPO = thyroperoxidase; TSH   = thyroid-stimulating hormone.
CANIT0001415	29045540	Clinical research	Platinum refractory germ-cell tumors	Germ cell tumor	EFO:0000514	Testis	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	12	N/A	A single arm phase II trial	Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory germ-cell tumors	There were six grade 3 adverse events. No immune-related adverse events were reported.	N/A	N/A	N/A	N/A	N/A	 2018 Jan 1	 Phase II trial of pembrolizumab in patients with platinum refractory germ-cell  tumors: a Hoosier Cancer Research Network Study GU14-206.	 Ann Oncol	 Background: Despite remarkable results with salvage standard-dose or high-dose  chemotherapy approximately 15% of patients with relapsed germ-cell tumors (GCT)  are incurable. Immune checkpoint inhibitors have produced significant remission  in multiple tumor types. We report the first study of immunotherapy in patients  with GCT. Patients and methods: Single arm phase II trial investigating  pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with  relapsed GCT and no curable options. Patients age >/=18 with GCT who progressed  after first-line cisplatin-based chemotherapy and after at least one salvage  regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally  assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells  was scored. Primary end point was overall response rate using immune-related  response criteria. Simon two-stage design with type I error 20% and power 80% was  utilized. Results: Twelve male patients were enrolled. Median age was 38 years.  All patients had nonseminoma. Primary site was testis (11) or mediastinum (1).  Median AFP 615 (range 1-32, 760) and hCG 4 (range 0.6-37, 096). Six patients had   late relapse (>2 years). Median number of previous chemotherapy regimens was 3.  Six patients received prior high-dose chemotherapy. Two patients had positive  PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2  (range 1-8). There were six grade 3 adverse events. No immune-related adverse  events were reported. No partial or complete responses were observed. Two  patients achieved radiographic stable disease for 28 and 19 weeks, respectively;   both had continued rising AFP level despite radiographic stability and had  negative PD-L1 staining. Conclusion: This is the first reported trial evaluating   immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not  appear to have clinically meaningful single-agent activity in refractory GCT.  Clinical trial information: NCT02499952.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001416	29045547	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	80	N/A	N/A	Patients who discontinued CTLA-4/PD-1 blockade for severe immune-related adverse events had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.	Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03).	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2018 Jan 1	 Safety of resuming anti-PD-1 in patients with immune-related adverse events  (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.	 Ann Oncol	 Background: Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed  death 1 (PD-1) blockade induces high rates of immune-related adverse events  (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination  therapy due to irAEs is not known. Patients and methods: We assessed patients who  experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade  leading to treatment discontinuation at four academic centers. We assessed the  safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results:  Eighty patients discontinued combination therapy due to irAEs, including colitis   (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received  corticosteroids and 21% received additional immunosuppression (e.g. infliximab).   All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a  median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and  one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other  irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities  occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4).  Duration of steroid taper, severity of initial irAEs and use of additional  immunosuppressants did not predict for toxicity on rechallenge, although patients  remaining on steroid therapy at anti-PD-1 resumption had higher rates of  toxicities (55% versus 31%, P = 0.03). Conclusions: Patients who discontinued  CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or  distinct toxicities with anti-PD-1 resumption. However, many patients,  particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge  well, and this approach can be considered in selected patients.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001417	29045547	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	80	N/A	N/A	Patients who discontinued CTLA-4/PD-1 blockade for severe immune-related adverse events had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.	Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03).	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2018 Jan 1	 Safety of resuming anti-PD-1 in patients with immune-related adverse events  (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.	 Ann Oncol	 Background: Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed  death 1 (PD-1) blockade induces high rates of immune-related adverse events  (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination  therapy due to irAEs is not known. Patients and methods: We assessed patients who  experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade  leading to treatment discontinuation at four academic centers. We assessed the  safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results:  Eighty patients discontinued combination therapy due to irAEs, including colitis   (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received  corticosteroids and 21% received additional immunosuppression (e.g. infliximab).   All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a  median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and  one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other  irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities  occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4).  Duration of steroid taper, severity of initial irAEs and use of additional  immunosuppressants did not predict for toxicity on rechallenge, although patients  remaining on steroid therapy at anti-PD-1 resumption had higher rates of  toxicities (55% versus 31%, P = 0.03). Conclusions: Patients who discontinued  CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or  distinct toxicities with anti-PD-1 resumption. However, many patients,  particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge  well, and this approach can be considered in selected patients.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001418	29045547	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	80	N/A	N/A	Patients who discontinued CTLA-4/PD-1 blockade for severe immune-related adverse events had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.	Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03).	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2018 Jan 1	 Safety of resuming anti-PD-1 in patients with immune-related adverse events  (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.	 Ann Oncol	 Background: Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed  death 1 (PD-1) blockade induces high rates of immune-related adverse events  (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination  therapy due to irAEs is not known. Patients and methods: We assessed patients who  experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade  leading to treatment discontinuation at four academic centers. We assessed the  safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results:  Eighty patients discontinued combination therapy due to irAEs, including colitis   (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received  corticosteroids and 21% received additional immunosuppression (e.g. infliximab).   All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a  median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and  one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other  irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities  occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4).  Duration of steroid taper, severity of initial irAEs and use of additional  immunosuppressants did not predict for toxicity on rechallenge, although patients  remaining on steroid therapy at anti-PD-1 resumption had higher rates of  toxicities (55% versus 31%, P = 0.03). Conclusions: Patients who discontinued  CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or  distinct toxicities with anti-PD-1 resumption. However, many patients,  particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge  well, and this approach can be considered in selected patients.CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the  European Society for Medical Oncology. All rights reserved. For permissions,  please email: journals.permissions@oup.com.
CANIT0001419	29045938	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Docetaxel	Immune checkpoint therapy	Nivolumab (DB09035); docetaxel (DB01248); 	14	19	A retrospective cohort study	NSCLC patients treated with nivolumab as second-line therapy had a longer PFS compared to patients treated with docetaxel in a health care environment.	N/A	N/A	N/A	N/A	N/A	N/A	2017	 Effectiveness of Nivolumab versus Docetaxel as Second-Line Treatment in Non-Small  Cell Lung Cancer Patients in Clinical Practice.	 Chemotherapy	 AIMS: To evaluate the effectiveness of nivolumab as second-line treatment  compared to standard therapy with docetaxel in adult patients with non-small cell  lung cancer (NSCLC) in clinical practice. METHODS: This is an observational,  retrospective cohort study of adult patients diagnosed with NSCLC, stage III-IV,   treated with docetaxel or nivolumab as second-line treatment. The end points  evaluated were overall survival (OS) and progression-free survival (PFS). PFS and  OS were described using the Kaplan-Meier method. The Cox proportional hazards  model was applied to identify independent prognostic and predictive factors  related to disease progression or death. RESULTS: Thirty-three patients were  included in this study (i.e., 14 in the nivolumab group and 19 in the docetaxel  group). Nonsquamous NSCLC was the most frequent histological subtype. Cohorts  were homogeneous. The follow-up time was 116 +/- 87.3 days. The median PFS was 84  days (95% CI 39-300) for patients treated with nivolumab and 61 days (95% CI  48-76) for patients treated with docetaxel. The risk of progression was 60% lower  for patients treated with nivolumab (HR 0.40; 95% CI 0.16-0.97; p = 0.043)  compared to patients receiving docetaxel. Among the patients treated with  docetaxel, the median OS was 129 days (95% CI 106-300). More than 50% of the  patients treated with nivolumab were alive at the end of the follow-up period;  nevertheless, the risk difference was not statistically significant (HR 0.55; 95%  CI 0.20-1.51; p = 0.244). CONCLUSION: NSCLC patients treated with nivolumab as  second-line therapy had a longer PFS compared to patients treated with docetaxel   in a health care environment.CI  - (c) 2017 S. Karger AG, Basel.
CANIT0001420	29055840	Clinical research	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	41	N/A	N/A	CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases. Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis.	Immune-related diarrhea and colitis (irColitis)	N/A	N/A	Cytomegalovirus (NCIT:C14196); 	Cytomegalovirus-DNA in colonic biopsies	Microbiota	 2017 Nov	 Cytomegalovirus reactivation in patients with refractory checkpoint  inhibitor-induced colitis.	 Eur J Cancer	 OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse   events, with immune-related diarrhea and colitis (irColitis) being among the most  frequent ones. While the majority of patients with irColitis respond well to  corticosteroid treatment +/- other immunomodulatory drugs such as infliximab,  some patients do not show resolution of their symptoms. In the present study, we   analysed the frequency of therapy-refractory irColitis, the underlying cause, and  useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with  metastatic malignant melanoma were treated with checkpoint inhibitors at the  Department of Dermatology at the University Hospital Essen. All patients were  identified for whom diarrhea and/or colitis was documented in the digital patient  records. Patients who did not respond to standard immunosuppressive therapy  within 2 weeks were classified as refractory. Demographic and clinical data of  all patients were collected. RESULTS: We identified 41 patients with irColitis,  the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%)  were refractory to standard immunomodulatory treatment with corticosteroids and  infliximab. Therapy-refractory cases tended to show more severe inflammation in  colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus  (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly  more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005,  in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical  stainings of colon biopsies for CMV were also associated with refractory colitis   (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during  management of checkpoint inhibitor-induced colitis emphasises the need for  repetitive diagnostic measures in treatment-refractory irColitis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001421	29055840	Clinical research	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	41	N/A	N/A	CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases. Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis.	Immune-related diarrhea and colitis (irColitis)	N/A	N/A	Cytomegalovirus (NCIT:C14196); 	Serum cytomegalovirus-DNA levels	Microbiota	 2017 Nov	 Cytomegalovirus reactivation in patients with refractory checkpoint  inhibitor-induced colitis.	 Eur J Cancer	 OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse   events, with immune-related diarrhea and colitis (irColitis) being among the most  frequent ones. While the majority of patients with irColitis respond well to  corticosteroid treatment +/- other immunomodulatory drugs such as infliximab,  some patients do not show resolution of their symptoms. In the present study, we   analysed the frequency of therapy-refractory irColitis, the underlying cause, and  useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with  metastatic malignant melanoma were treated with checkpoint inhibitors at the  Department of Dermatology at the University Hospital Essen. All patients were  identified for whom diarrhea and/or colitis was documented in the digital patient  records. Patients who did not respond to standard immunosuppressive therapy  within 2 weeks were classified as refractory. Demographic and clinical data of  all patients were collected. RESULTS: We identified 41 patients with irColitis,  the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%)  were refractory to standard immunomodulatory treatment with corticosteroids and  infliximab. Therapy-refractory cases tended to show more severe inflammation in  colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus  (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly  more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005,  in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical  stainings of colon biopsies for CMV were also associated with refractory colitis   (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during  management of checkpoint inhibitor-induced colitis emphasises the need for  repetitive diagnostic measures in treatment-refractory irColitis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001422	29055840	Clinical research	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	41	N/A	N/A	CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases. Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis.	Immune-related diarrhea and colitis (irColitis)	N/A	N/A	Cytomegalovirus (NCIT:C14196); 	Cytomegalovirus-DNA in colonic biopsies	Microbiota	 2017 Nov	 Cytomegalovirus reactivation in patients with refractory checkpoint  inhibitor-induced colitis.	 Eur J Cancer	 OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse   events, with immune-related diarrhea and colitis (irColitis) being among the most  frequent ones. While the majority of patients with irColitis respond well to  corticosteroid treatment +/- other immunomodulatory drugs such as infliximab,  some patients do not show resolution of their symptoms. In the present study, we   analysed the frequency of therapy-refractory irColitis, the underlying cause, and  useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with  metastatic malignant melanoma were treated with checkpoint inhibitors at the  Department of Dermatology at the University Hospital Essen. All patients were  identified for whom diarrhea and/or colitis was documented in the digital patient  records. Patients who did not respond to standard immunosuppressive therapy  within 2 weeks were classified as refractory. Demographic and clinical data of  all patients were collected. RESULTS: We identified 41 patients with irColitis,  the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%)  were refractory to standard immunomodulatory treatment with corticosteroids and  infliximab. Therapy-refractory cases tended to show more severe inflammation in  colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus  (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly  more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005,  in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical  stainings of colon biopsies for CMV were also associated with refractory colitis   (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during  management of checkpoint inhibitor-induced colitis emphasises the need for  repetitive diagnostic measures in treatment-refractory irColitis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001423	29055840	Clinical research	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	41	N/A	N/A	CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases. Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis.	Immune-related diarrhea and colitis (irColitis)	N/A	N/A	Cytomegalovirus (NCIT:C14196); 	Serum cytomegalovirus-DNA levels	Microbiota	 2017 Nov	 Cytomegalovirus reactivation in patients with refractory checkpoint  inhibitor-induced colitis.	 Eur J Cancer	 OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse   events, with immune-related diarrhea and colitis (irColitis) being among the most  frequent ones. While the majority of patients with irColitis respond well to  corticosteroid treatment +/- other immunomodulatory drugs such as infliximab,  some patients do not show resolution of their symptoms. In the present study, we   analysed the frequency of therapy-refractory irColitis, the underlying cause, and  useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with  metastatic malignant melanoma were treated with checkpoint inhibitors at the  Department of Dermatology at the University Hospital Essen. All patients were  identified for whom diarrhea and/or colitis was documented in the digital patient  records. Patients who did not respond to standard immunosuppressive therapy  within 2 weeks were classified as refractory. Demographic and clinical data of  all patients were collected. RESULTS: We identified 41 patients with irColitis,  the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%)  were refractory to standard immunomodulatory treatment with corticosteroids and  infliximab. Therapy-refractory cases tended to show more severe inflammation in  colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus  (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly  more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005,  in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical  stainings of colon biopsies for CMV were also associated with refractory colitis   (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during  management of checkpoint inhibitor-induced colitis emphasises the need for  repetitive diagnostic measures in treatment-refractory irColitis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001424	29055840	Clinical research	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	41	N/A	N/A	CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases. Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis.	Immune-related diarrhea and colitis (irColitis)	N/A	N/A	Cytomegalovirus (NCIT:C14196); 	Cytomegalovirus-DNA in colonic biopsies	Microbiota	 2017 Nov	 Cytomegalovirus reactivation in patients with refractory checkpoint  inhibitor-induced colitis.	 Eur J Cancer	 OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse   events, with immune-related diarrhea and colitis (irColitis) being among the most  frequent ones. While the majority of patients with irColitis respond well to  corticosteroid treatment +/- other immunomodulatory drugs such as infliximab,  some patients do not show resolution of their symptoms. In the present study, we   analysed the frequency of therapy-refractory irColitis, the underlying cause, and  useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with  metastatic malignant melanoma were treated with checkpoint inhibitors at the  Department of Dermatology at the University Hospital Essen. All patients were  identified for whom diarrhea and/or colitis was documented in the digital patient  records. Patients who did not respond to standard immunosuppressive therapy  within 2 weeks were classified as refractory. Demographic and clinical data of  all patients were collected. RESULTS: We identified 41 patients with irColitis,  the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%)  were refractory to standard immunomodulatory treatment with corticosteroids and  infliximab. Therapy-refractory cases tended to show more severe inflammation in  colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus  (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly  more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005,  in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical  stainings of colon biopsies for CMV were also associated with refractory colitis   (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during  management of checkpoint inhibitor-induced colitis emphasises the need for  repetitive diagnostic measures in treatment-refractory irColitis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001425	29055840	Clinical research	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	41	N/A	N/A	CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases. Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis.	Immune-related diarrhea and colitis (irColitis)	N/A	N/A	Cytomegalovirus (NCIT:C14196); 	Serum cytomegalovirus-DNA levels	Microbiota	 2017 Nov	 Cytomegalovirus reactivation in patients with refractory checkpoint  inhibitor-induced colitis.	 Eur J Cancer	 OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse   events, with immune-related diarrhea and colitis (irColitis) being among the most  frequent ones. While the majority of patients with irColitis respond well to  corticosteroid treatment +/- other immunomodulatory drugs such as infliximab,  some patients do not show resolution of their symptoms. In the present study, we   analysed the frequency of therapy-refractory irColitis, the underlying cause, and  useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with  metastatic malignant melanoma were treated with checkpoint inhibitors at the  Department of Dermatology at the University Hospital Essen. All patients were  identified for whom diarrhea and/or colitis was documented in the digital patient  records. Patients who did not respond to standard immunosuppressive therapy  within 2 weeks were classified as refractory. Demographic and clinical data of  all patients were collected. RESULTS: We identified 41 patients with irColitis,  the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%)  were refractory to standard immunomodulatory treatment with corticosteroids and  infliximab. Therapy-refractory cases tended to show more severe inflammation in  colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus  (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly  more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005,  in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical  stainings of colon biopsies for CMV were also associated with refractory colitis   (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during  management of checkpoint inhibitor-induced colitis emphasises the need for  repetitive diagnostic measures in treatment-refractory irColitis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001426	29055840	Clinical research	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	41	N/A	N/A	Therapy-refractory cases tended to show more severe inflammation in colonic biopsies.	Immune-related diarrhea and colitis (irColitis)	N/A	N/A	Therapy-refractory (NCIT:C38014); 	Therapy-refractory	Disease status	 2017 Nov	 Cytomegalovirus reactivation in patients with refractory checkpoint  inhibitor-induced colitis.	 Eur J Cancer	 OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse   events, with immune-related diarrhea and colitis (irColitis) being among the most  frequent ones. While the majority of patients with irColitis respond well to  corticosteroid treatment +/- other immunomodulatory drugs such as infliximab,  some patients do not show resolution of their symptoms. In the present study, we   analysed the frequency of therapy-refractory irColitis, the underlying cause, and  useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with  metastatic malignant melanoma were treated with checkpoint inhibitors at the  Department of Dermatology at the University Hospital Essen. All patients were  identified for whom diarrhea and/or colitis was documented in the digital patient  records. Patients who did not respond to standard immunosuppressive therapy  within 2 weeks were classified as refractory. Demographic and clinical data of  all patients were collected. RESULTS: We identified 41 patients with irColitis,  the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%)  were refractory to standard immunomodulatory treatment with corticosteroids and  infliximab. Therapy-refractory cases tended to show more severe inflammation in  colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus  (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly  more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005,  in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical  stainings of colon biopsies for CMV were also associated with refractory colitis   (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during  management of checkpoint inhibitor-induced colitis emphasises the need for  repetitive diagnostic measures in treatment-refractory irColitis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001427	29055840	Clinical research	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	41	N/A	N/A	Therapy-refractory cases tended to show more severe inflammation in colonic biopsies.	Immune-related diarrhea and colitis (irColitis)	N/A	N/A	Therapy-refractory (NCIT:C38014); 	Therapy-refractory	Disease status	 2017 Nov	 Cytomegalovirus reactivation in patients with refractory checkpoint  inhibitor-induced colitis.	 Eur J Cancer	 OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse   events, with immune-related diarrhea and colitis (irColitis) being among the most  frequent ones. While the majority of patients with irColitis respond well to  corticosteroid treatment +/- other immunomodulatory drugs such as infliximab,  some patients do not show resolution of their symptoms. In the present study, we   analysed the frequency of therapy-refractory irColitis, the underlying cause, and  useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with  metastatic malignant melanoma were treated with checkpoint inhibitors at the  Department of Dermatology at the University Hospital Essen. All patients were  identified for whom diarrhea and/or colitis was documented in the digital patient  records. Patients who did not respond to standard immunosuppressive therapy  within 2 weeks were classified as refractory. Demographic and clinical data of  all patients were collected. RESULTS: We identified 41 patients with irColitis,  the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%)  were refractory to standard immunomodulatory treatment with corticosteroids and  infliximab. Therapy-refractory cases tended to show more severe inflammation in  colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus  (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly  more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005,  in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical  stainings of colon biopsies for CMV were also associated with refractory colitis   (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during  management of checkpoint inhibitor-induced colitis emphasises the need for  repetitive diagnostic measures in treatment-refractory irColitis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001428	29055840	Clinical research	Metastatic malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	41	N/A	N/A	Therapy-refractory cases tended to show more severe inflammation in colonic biopsies.	Immune-related diarrhea and colitis (irColitis)	N/A	N/A	Therapy-refractory (NCIT:C38014); 	Therapy-refractory	Disease status	 2017 Nov	 Cytomegalovirus reactivation in patients with refractory checkpoint  inhibitor-induced colitis.	 Eur J Cancer	 OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse   events, with immune-related diarrhea and colitis (irColitis) being among the most  frequent ones. While the majority of patients with irColitis respond well to  corticosteroid treatment +/- other immunomodulatory drugs such as infliximab,  some patients do not show resolution of their symptoms. In the present study, we   analysed the frequency of therapy-refractory irColitis, the underlying cause, and  useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with  metastatic malignant melanoma were treated with checkpoint inhibitors at the  Department of Dermatology at the University Hospital Essen. All patients were  identified for whom diarrhea and/or colitis was documented in the digital patient  records. Patients who did not respond to standard immunosuppressive therapy  within 2 weeks were classified as refractory. Demographic and clinical data of  all patients were collected. RESULTS: We identified 41 patients with irColitis,  the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%)  were refractory to standard immunomodulatory treatment with corticosteroids and  infliximab. Therapy-refractory cases tended to show more severe inflammation in  colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus  (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly  more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005,  in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical  stainings of colon biopsies for CMV were also associated with refractory colitis   (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during  management of checkpoint inhibitor-induced colitis emphasises the need for  repetitive diagnostic measures in treatment-refractory irColitis.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001429	29067858	Case report	Recurrent lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Immune-related intestinal pseudo-obstruction	N/A	N/A	N/A	N/A	N/A	 2019 Mar	 Immune-related intestinal pseudo-obstruction associated with nivolumab treatment   in a lung cancer patient.	 J Oncol Pharm Pract	 Immune checkpoint inhibition therapy using targeted monoclonal antibodies is a  new therapeutic approach with significant survival benefit for patients with  several cancer types. However, their use can be associated with unique  immune-related adverse effects as a consequence of impaired self-tolerance due to  loss of T-cell inhibition via a nonselective activation of the immune system.  Nivolumab is an anti-PD-1 immune checkpoint inhibitor that was recently developed  for cancer immunotherapy with remarkable responses in nonsmall cell lung cancer  patients. We present a 62-year-old Caucasian male with recurrent lung  adenocarcinoma and currently under third-line therapy with nivolumab, who was  admitted in our hospital with abdominal distension. Radiologic findings were  consistent with small bowel ileus. After four days of conservative treatment, the  patient underwent exploratory laparotomy where no cause of ileus was discovered.   Postoperative the ileus persisted and considering that an adverse effect of the  immune checkpoint inhibition therapy occurred, the patient received high-dose  prednisone resulting in gradual improvement of symptoms. Immune checkpoint  inhibitors may induce adverse effects to unaffected organ systems and tissues  including the skin, gastrointestinal, hepatic, pulmonary, and endocrine system.  The mainstay treatment consists of immunosuppression with corticosteroids in the   majority of cases. As the clinical use of immune checkpoint inhibitors is  expanding rapidly, there is an emergence of unique immune-related adverse effects  in a growing patient population. Gaining early awareness is essential in these  patients in order to ensure prompt diagnosis and management.
CANIT0001430	29074210	Case report	Advanced pulmonary pleomorphic carcinoma	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Prolonged tumor response	Acute diabetes mellitus and hypophysitis	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Nivolumab-Induced Acute Diabetes Mellitus and Hypophysitis in a Patient with  Advanced Pulmonary Pleomorphic Carcinoma with a Prolonged Tumor Response.	 J Thorac Oncol	Unable to provide
CANIT0001431	29077601	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	Awareness for potentially life-threatening irAE of checkpoint inhibitors like autoimmune cardiomyopathy and myocarditis is crucial to rapidly initiate adequate treatment.	Autoimmune cardiomyopathy (grade 3 CTCAE) and myocarditis	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 Life-threatening Autoimmune Cardiomyopathy Reproducibly Induced in a Patient by  Checkpoint Inhibitor Therapy.	 J Immunother	 Checkpoint inhibitors induce a plethora of immune-related adverse events (irAEs)   including autoimmune colitis, hepatitis, endocrinopathies, and rarer side effects  like neuritis. Here, a case of autoimmune cardiomyopathy (grade 3 CTCAE) and  myocarditis under combination therapy with nivolumab plus ipilimumab in a  72-year-old melanoma patient is reported. Treatment induced a partial response  for 14 months. However, after 10 infusions the patient developed dyspnea, edema  of the legs, ascites and a weight gain of 10 kg because of a decompensated heart   insufficiency with a reduced ejection fraction from formerly 48%-50% to 15%.  Ischemia and viral infections were ruled out. Histopathology showed hypertrophic   myocarditis with interstitial lymphocytes. Prednisolone improved the patient's  condition within 3 days, leading to a 25% and 30% ejection fraction after 2 and 8  weeks, respectively, and clinical symptoms subsided completely. Importantly,  reinduction of anti-PD1 therapy resulted in a flare of myocarditis. Awareness for  potentially life-threatening irAE of checkpoint inhibitors like autoimmune  cardiomyopathy and myocarditis is crucial to rapidly initiate adequate treatment.
CANIT0001432	29078173	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	14	N/A	N/A	In patients with high TV, plasma analysis of ctDNA, as validated by tumour tissue, suggested that a durable good response to nivolumab could be predicted within 2 weeks.	N/A	N/A	N/A	CtDNA (NCIT:C113243); 	CtDNA levels after starting nivolumab	Metabolite	 2017 Nov	 Very early response of circulating tumour-derived DNA in plasma predicts efficacy  of nivolumab treatment in patients with non-small cell lung cancer.	 Eur J Cancer	 INTRODUCTION: Immunotherapy has become a treatment option for lung cancer. The  utility of nivolumab as second-line treatment for non-small cell lung cancer has   been proven, but predictive biomarkers influencing its efficacy remain unknown.  METHODS: This study involved 14 patients who were treated with nivolumab from  February 1 to September 30, 2016. The early response of the level of circulating   tumour DNA (ctDNA) after starting nivolumab was evaluated to ascertain whether it  could predict treatment outcome. RESULTS: Of the 14 patients, six were responders  and eight were non-responders. DNA was analysed in both tumour tissue and plasma   samples. Only somatic mutations confirmed by analysis of tumour tissue were  defined as ctDNA. ctDNA was detected more often in the serial plasma samples of  patients with high tumour volume (TV) (p = 0.02). ctDNA was detected in seven  cases; basal and serial ctDNA analysis revealed that a decrease in allelic  frequency (AF) of ctDNA showed high-level correspondence with a good durable  response. When 2 weeks was set as a clinically significant time point, changes   in representative mutations of each case, defined as one of the highest baseline   AF, showed 100% concordance with the response. CONCLUSIONS: In patients with high  TV, plasma analysis of ctDNA, as validated by tumour tissue, suggested that a  durable good response to nivolumab could be predicted within 2 weeks.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001433	29088405	Case report	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Leptomeningeal carcinomatosis	Leptomeningeal carcinomatosis	N/A	N/A	N/A	N/A	N/A	 2018 Mar 1	 Development of leptomeningeal carcinomatosis during a marked response of brain  metastases to pembrolizumab in a patient with non-small-cell lung cancer.	 Ann Oncol	Unable to provide
CANIT0001434	29095678	Clinical research	Advanced cervical cancer	Cervical carcinoma	EFO:0001416	Cervix	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A phase Ib trial 	In patients with programmed death ligand 1-positive advanced cervical cancer, pembrolizumab demonstrated antitumor activity and exhibited a safety profile consistent with  that seen in other tumor types.	Treatment related adverse events (AEs) were experienced by 18 patients (75%); only rash (n = 5; 21%) and pyrexia (n = 4; 17%) and occurred in  10% of patients. Five patients experienced grade 3 treatment-related AEs. No grade 4 treatment-related AEs or deaths were observed.	N/A	N/A	N/A	N/A	N/A	 2017 Dec 20	 Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand  1-Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial.	 J Clin Oncol	 Purpose The KEYNOTE-028 trial ( ClinicalTrials.gov identifier: NCT02054806) was  designed to assess the safety and efficacy of pembrolizumab in 20 programmed  death ligand 1-positive, advanced solid tumor cohorts. Here, we present the  results from the cohort of patients with advanced cervical cancer. Methods  Patients were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24  months. Response was assessed every 8 weeks for the first 6 months and every 12  weeks thereafter. The primary end point was overall response rate per Response  Evaluation Criteria in Solid Tumors, version 1.1, by investigator review. Safety   was a secondary end point. Results Twenty-four patients were enrolled in the  cervical cancer cohort. The median age was 42 years (range, 26 to 62 years), 22  patients (92%) had received prior radiation therapy, and 15 patients (63%) had  received two or more lines of therapy, including bevacizumab (10 of 24 patients),  for advanced disease. At the data cutoff, median follow-up duration was 11.0  months (range, 1.3 to 32.2 months). Overall response rate was 17% (95% CI, 5% to   37%); four patients (17%) achieved a confirmed partial response, and three  patients (13%) had stable disease. Median duration of response for the four  patients who achieved a partial response was 5.4 months (4.1 to 7.5 months).  Treatment related adverse events (AEs) were experienced by 18 patients (75%);  only rash (n = 5; 21%) and pyrexia (n = 4; 17%) and occurred in >/= 10% of  patients. Five patients experienced grade 3 treatment-related AEs. No grade 4  treatment-related AEs or deaths were observed. Conclusion In patients with  programmed death ligand 1-positive advanced cervical cancer, pembrolizumab  demonstrated antitumor activity and exhibited a safety profile consistent with  that seen in other tumor types.
CANIT0001435	29096940	Case report	Nonsmall cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	N/A	Psoriasis	N/A	N/A	N/A	N/A	N/A	 2017 Nov - Dec	 Anti-PD1/PDL1 induced psoriasis.	 Curr Probl Cancer	 BACKGROUND: Immune checkpoint inhibitors are novel agents approved for the  treatment of late-stage malignancies. Despite its important clinical benefits,  checkpoint inhibition is associated with a unique spectrum of side effects known   as immune-related adverse events. Skin toxicities are the most frequent  immune-related adverse events during anti-PD1 blockade therapies. Among them,  rare cases of psoriasis exacerbation have been reported. METHODS: We present the   clinical characteristics of exacerbated psoriasis in 5 patients under  anti-PD1/PDL1 therapy. RESULTS: A total of 5 patients were overall included (4  males, 1 female mean age 65.8 years). Among them, 3 were diagnosed with nonsmall   cell lung cancer, 1 with papillary urothelial carcinoma, and 1 with squamous cell  carcinoma of the tonsil. Of all, 3 patients were treated with anti-PD1 (1 with  pembrolizumab, 2 with nivolumab), whereas the remaining 2 with anti-PDL1  (durvalumab). Only 1 out of 5 patients had active psoriatic lesions at the time  of treatment initiation, 2 shared a past history of psoriasis, and 1 reported a  strong related family history (3/5 siblings). Four out of 5 patients experienced   guttate lesions, though the most severe exacerbation was noted in the durvalumab   group. Four out of 5 patients managed to continue treatment after close  dermatologic monitoring, whereas 1 patient under durvalumab was forced to  treatment delays owing to the severity of the skin reactions. Skin rashes  appeared in all patients after the fourth cycle of immunotherapy. CONCLUSIONS:  Both anti-PD1 and anti-PDL1 therapies can lead to psoriasis exacerbation although  more severe flares were noted in patients treated with durvalumab. Not only  personal but also related family history of psoriasis are significant risk  factors and need to be outlined before treatment initiation. If such related  history exists, strict skin surveillance can lead to the early diagnosis and  treatment of any psoriatic exacerbations that could otherwise severely affect  quality of life or even compromise therapeutic protocols and final prognosis.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001436	29096940	Case report	Nonsmall cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1	N/A	Case	N/A	Psoriasis	N/A	N/A	N/A	N/A	N/A	 2017 Nov - Dec	 Anti-PD1/PDL1 induced psoriasis.	 Curr Probl Cancer	 BACKGROUND: Immune checkpoint inhibitors are novel agents approved for the  treatment of late-stage malignancies. Despite its important clinical benefits,  checkpoint inhibition is associated with a unique spectrum of side effects known   as immune-related adverse events. Skin toxicities are the most frequent  immune-related adverse events during anti-PD1 blockade therapies. Among them,  rare cases of psoriasis exacerbation have been reported. METHODS: We present the   clinical characteristics of exacerbated psoriasis in 5 patients under  anti-PD1/PDL1 therapy. RESULTS: A total of 5 patients were overall included (4  males, 1 female mean age 65.8 years). Among them, 3 were diagnosed with nonsmall   cell lung cancer, 1 with papillary urothelial carcinoma, and 1 with squamous cell  carcinoma of the tonsil. Of all, 3 patients were treated with anti-PD1 (1 with  pembrolizumab, 2 with nivolumab), whereas the remaining 2 with anti-PDL1  (durvalumab). Only 1 out of 5 patients had active psoriatic lesions at the time  of treatment initiation, 2 shared a past history of psoriasis, and 1 reported a  strong related family history (3/5 siblings). Four out of 5 patients experienced   guttate lesions, though the most severe exacerbation was noted in the durvalumab   group. Four out of 5 patients managed to continue treatment after close  dermatologic monitoring, whereas 1 patient under durvalumab was forced to  treatment delays owing to the severity of the skin reactions. Skin rashes  appeared in all patients after the fourth cycle of immunotherapy. CONCLUSIONS:  Both anti-PD1 and anti-PDL1 therapies can lead to psoriasis exacerbation although  more severe flares were noted in patients treated with durvalumab. Not only  personal but also related family history of psoriasis are significant risk  factors and need to be outlined before treatment initiation. If such related  history exists, strict skin surveillance can lead to the early diagnosis and  treatment of any psoriatic exacerbations that could otherwise severely affect  quality of life or even compromise therapeutic protocols and final prognosis.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001437	29096940	Case report	Papillary urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1	N/A	Case	N/A	Psoriasis	N/A	N/A	N/A	N/A	N/A	 2017 Nov - Dec	 Anti-PD1/PDL1 induced psoriasis.	 Curr Probl Cancer	 BACKGROUND: Immune checkpoint inhibitors are novel agents approved for the  treatment of late-stage malignancies. Despite its important clinical benefits,  checkpoint inhibition is associated with a unique spectrum of side effects known   as immune-related adverse events. Skin toxicities are the most frequent  immune-related adverse events during anti-PD1 blockade therapies. Among them,  rare cases of psoriasis exacerbation have been reported. METHODS: We present the   clinical characteristics of exacerbated psoriasis in 5 patients under  anti-PD1/PDL1 therapy. RESULTS: A total of 5 patients were overall included (4  males, 1 female mean age 65.8 years). Among them, 3 were diagnosed with nonsmall   cell lung cancer, 1 with papillary urothelial carcinoma, and 1 with squamous cell  carcinoma of the tonsil. Of all, 3 patients were treated with anti-PD1 (1 with  pembrolizumab, 2 with nivolumab), whereas the remaining 2 with anti-PDL1  (durvalumab). Only 1 out of 5 patients had active psoriatic lesions at the time  of treatment initiation, 2 shared a past history of psoriasis, and 1 reported a  strong related family history (3/5 siblings). Four out of 5 patients experienced   guttate lesions, though the most severe exacerbation was noted in the durvalumab   group. Four out of 5 patients managed to continue treatment after close  dermatologic monitoring, whereas 1 patient under durvalumab was forced to  treatment delays owing to the severity of the skin reactions. Skin rashes  appeared in all patients after the fourth cycle of immunotherapy. CONCLUSIONS:  Both anti-PD1 and anti-PDL1 therapies can lead to psoriasis exacerbation although  more severe flares were noted in patients treated with durvalumab. Not only  personal but also related family history of psoriasis are significant risk  factors and need to be outlined before treatment initiation. If such related  history exists, strict skin surveillance can lead to the early diagnosis and  treatment of any psoriatic exacerbations that could otherwise severely affect  quality of life or even compromise therapeutic protocols and final prognosis.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001438	29096940	Case report	Squamous cell carcinoma of the tonsil	Tonsillar squamous cell carcinoma	EFO:1000597	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Psoriasis	N/A	N/A	N/A	N/A	N/A	 2017 Nov - Dec	 Anti-PD1/PDL1 induced psoriasis.	 Curr Probl Cancer	 BACKGROUND: Immune checkpoint inhibitors are novel agents approved for the  treatment of late-stage malignancies. Despite its important clinical benefits,  checkpoint inhibition is associated with a unique spectrum of side effects known   as immune-related adverse events. Skin toxicities are the most frequent  immune-related adverse events during anti-PD1 blockade therapies. Among them,  rare cases of psoriasis exacerbation have been reported. METHODS: We present the   clinical characteristics of exacerbated psoriasis in 5 patients under  anti-PD1/PDL1 therapy. RESULTS: A total of 5 patients were overall included (4  males, 1 female mean age 65.8 years). Among them, 3 were diagnosed with nonsmall   cell lung cancer, 1 with papillary urothelial carcinoma, and 1 with squamous cell  carcinoma of the tonsil. Of all, 3 patients were treated with anti-PD1 (1 with  pembrolizumab, 2 with nivolumab), whereas the remaining 2 with anti-PDL1  (durvalumab). Only 1 out of 5 patients had active psoriatic lesions at the time  of treatment initiation, 2 shared a past history of psoriasis, and 1 reported a  strong related family history (3/5 siblings). Four out of 5 patients experienced   guttate lesions, though the most severe exacerbation was noted in the durvalumab   group. Four out of 5 patients managed to continue treatment after close  dermatologic monitoring, whereas 1 patient under durvalumab was forced to  treatment delays owing to the severity of the skin reactions. Skin rashes  appeared in all patients after the fourth cycle of immunotherapy. CONCLUSIONS:  Both anti-PD1 and anti-PDL1 therapies can lead to psoriasis exacerbation although  more severe flares were noted in patients treated with durvalumab. Not only  personal but also related family history of psoriasis are significant risk  factors and need to be outlined before treatment initiation. If such related  history exists, strict skin surveillance can lead to the early diagnosis and  treatment of any psoriatic exacerbations that could otherwise severely affect  quality of life or even compromise therapeutic protocols and final prognosis.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001439	29102951	Clinical research	Non-small lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	72	N/A	N/A	The total number of doses administered may be a risk factor for the development of thyroid dysfunction after nivolumab therapy.	Among the 72 patients with normal thyroid function prior to nivolumab treatment, the incidence of thyroid dysfunction was 19.5%. There were no significant differences between patients in whom thyroid dysfunction had occurred regarding sex, age, nivolumab dose, or thyroid function prior to nivolumab administration. However, the total number of doses of nivolumab was significantly greater in patients who developed thyroid dysfunction after nivolumab treatment (p=0.03).	N/A	N/A	Treatment doses (NCIT:C25488); 	Total number of doses of nivolumab	Exposure factors/status	 2017 Nov-Dec	 Potential Risk Factors for Nivolumab-induced Thyroid Dysfunction.	 In Vivo	 BACKGROUND: Thyroid dysfunction is occasionally reported after the administration  of nivolumab. We report on the incidence of and risk factors for  nivolumab-induced thyroid dysfunction in patients with non-small lung cancer.  PATIENTS AND METHODS: A total of 82 patients who received nivolumab between  January 2016 and December 2016 at the Kanagawa Cancer Center were included. Prior  to nivolumab treatment, 72 patients had normal thyroid function. RESULTS: Among  the 72 patients with normal thyroid function prior to nivolumab treatment, the  incidence of thyroid dysfunction was 19.5%. There were no significant differences  between patients in whom thyroid dysfunction had occurred regarding sex, age,  nivolumab dose, or thyroid function prior to nivolumab administration. However,  the total number of doses of nivolumab was significantly greater in patients who   developed thyroid dysfunction after nivolumab treatment (p=0.03). CONCLUSION: The  total number of doses administered may be a risk factor for the development of  thyroid dysfunction after nivolumab therapy.CI  - Copyright(c) 2017, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001440	29106665	Clinical research	Recurrent glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	30	10	A exploratory phase I cohorts of CheckMate 143.	Nivolumab monotherapy was better tolerated than nivolumab + ipilimumab; the tolerability of the combination was influenced by ipilimumab dose. These safety and exploratory findings merit further investigation of immunotherapies in glioblastoma.	The most common treatment-related adverse events (AEs) were fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%, 30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30% (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients.	N/A	N/A	N/A	N/A	N/A	 2018 Apr 9	 Nivolumab with or without ipilimumab in patients with recurrent glioblastoma:  results from exploratory phase I cohorts of CheckMate 143.	 Neuro Oncol	 Background: Immunotherapies have demonstrated efficacy across a diverse set of  tumors supporting further evaluation in glioblastoma. The objective of this study  was to evaluate the safety/tolerability and describe immune-mediated effects of  nivolumab +/- ipilimumab in patients with recurrent glioblastoma. Exploratory  efficacy outcomes are also reported. Methods: Patients were randomized to receive  nivolumab 3 mg/kg every 2 weeks (Q2W; NIVO3) or nivolumab 1 mg/kg + ipilimumab 3   mg/kg every 3 weeks (Q3W) for 4 doses, then nivolumab 3 mg/kg Q2W (NIVO1+IPI3).  An alternative regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses,  then nivolumab 3 mg/kg Q2W (NIVO3+IPI1) was investigated in a nonrandomized arm.   Results: Forty patients were enrolled (NIVO3, n = 10; NIVO1+IPI3, n = 10;  NIVO3+IPI1, n = 20). The most common treatment-related adverse events (AEs) were   fatigue (NIVO3, 30%; NIVO1+IPI3, 80%; NIVO3+IPI1, 55%) and diarrhea (10%, 70%,  30%, respectively). AEs leading to discontinuation occurred in 10% (NIVO3), 30%  (NIVO1+IPI3), and 20% (NIVO3+IPI1) of patients. Three patients achieved a partial  response (NIVO3, n = 1; NIVO3+IPI1, n = 2) and 8 had stable disease for >/=12  weeks (NIVO3, n = 2; NIVO1+IPI3, n = 2; NIVO3+IPI1, n = 4 [Response Assessment in  Neuro-Oncology criteria]). Most patients (68%) had tumor-cell programmed death  ligand-1 expression >/=1%. Immune-mediated effects mimicking radiographic  progression occurred in 2 patients. Conclusions: Nivolumab monotherapy was better  tolerated than nivolumab + ipilimumab; the tolerability of the combination was  influenced by ipilimumab dose. These safety and exploratory findings merit  further investigation of immunotherapies in glioblastoma.
CANIT0001441	29110847	Case report	Advanced adenocarcinoma of the lung	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Case	Symptomatic pseudo-progression followed by significant treatment response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 Symptomatic pseudo-progression followed by significant treatment response in two   lung cancer patients treated with immunotherapy.	 Lung Cancer	 In the setting of pseudo-progression in a cancer patient who receives  immunotherapeutic treatment, discontinuation of therapy is recommended if the  patient is symptomatic. Here, we present two patients with advanced  adenocarcinoma of the lung who developed massive tumor growth after initiation of  treatment with the anti-PD-1 antibody pembrolizumab. Even though clinical  deterioration occurred in the form of severe dyspnea and weight loss,  pembrolizumab therapy was continued, as the speed of tumor growth suggested  pseudo-progression and the tumors showed marked PD-L1 expression. This approach  was successful, and both patients experienced impressive treatment responses  within a few weeks.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001442	29119276	Clinical research	Metastatic pancreatic adenocarcinoma	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus gemcitabine plus nab-paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); nab-paclitaxel (DB01229); gemcitabine (DB00441); 	17	N/A	A single center phase Ib/II study	GNP can be safely given to chemotherapy naive PDAC patients. Efficacy appears to be slightly improved over previously reported results for standard weekly x 3 every 28 day gemcitabine and nab-paclitaxel dosing. CNI change may be prognostic for  OS.	Grade 3 events occurred in 53% of patients. 	N/A	N/A	CtDNA (NCIT:C113243); 	Tumor cfDNA copy number instability	Metabolite	 2018 Feb	 Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic  pancreatic adenocarcinoma.	 Invest New Drugs	 Background A single center phase Ib/II study of gemcitabine, nab-paclitaxel, and   pembrolizumab (GNP) to evaluate the safety and efficacy in metastatic pancreatic   adenocarcinoma (PDAC) was conducted (NCT02331251). Methods PDAC patients (pts)  with measurable disease, biopsy proven metastasis, adequate laboratory tests, and  KPS >/= 70% received GNP until progression or toxicity. Safety monitoring, RECIST  1.1, and irRECIST assessments were conducted. Response imaging was performed  prior to cycle 4, then every 3 months. Changes in tumor cell-free DNA copy number  instability (CNI) was retrospectively evaluated. Results 17 pts. with a median  age of 56 were treated. 11 were women and all had a KPS of at least 80%. Grade 3   events occurred in 53% of patients. The phase II portion was completed for  chemotherapy naive PDAC pts. Of the 11 evaluable chemotherapy naive PDAC, the  disease control rate (partial response [PR] + stable disease[SD]) was 100%. There  were 3 with PR on treatment for 8+, ~11, and 15 months; respectively. The primary  endpoint of >15% complete response was not met. The median progression-free  survival (PFS) and overall survival (OS) was 9.1 and 15.0 months for chemotherapy  naive treated patients. Of 9 patients evaluable for CNI change, a greater  reduction in CNI correlated with longer PFS and improved OS. Conclusions GNP can   be safely given to chemotherapy naive PDAC patients. Efficacy appears to be  slightly improved over previously reported results for standard weekly x 3 every   28 day gemcitabine and nab-paclitaxel dosing. CNI change may be prognostic for  OS.
CANIT0001443	29120964	Clinical research	Advanced skin melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Dabrafenib	Immune checkpoint therapy	Ipilimumab (DB06186); vemurafenib (DB08881); dabrafenib (DB08912); 	370	181	A retrospective cohort study	The probability of surviving 12 months in the group of patients treated  with vemurafenib was 40.5%, ipilimumab was 35.1% and dabrafenib was 60.7%. The  probability of surviving 24 and 36 months in the group of patients treated with  vemurafenib or ipilimumab amounted to, respectively, 20.1, 15.4 and 21, 18.8%. OS  of patients with advanced melanoma treated in daily clinical practice may be  comparable to the ones achieved in registration trials. The use of appropriate  treatment inclusion criteria may affect the obtained OS.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Feb	 Analysis of survival of patients treated with vemurafenib, ipilimumab and  dabrafenib for advanced skin melanoma in daily clinical practice (Real-World  Data): retrospective analysis of patients treated under drug/reimbursement  programmes in Poland in 2013-2016.	 Melanoma Res	 Vemurafenib, ipilimumab and dabrafenib were registered for the treatment of  advanced skin melanoma pursuant to the results of randomized phase III clinical  trials. Real-world data on survival time for patients treated with those drugs in  daily clinical practice are so far limited. Patients with advanced skin melanoma   treated under reimbursement programmes (drug programmes), for which they were  qualified pursuant to uniform inclusion criteria in force in all oncology centres  in Poland. Data were obtained from the electronic databases of the national payer  (NFZ) responsible for the implementation and monitoring of reimbursement (drug)  programmes. The analysis included all patients included for treatment with  vemurafenib (since March of 2013), ipilimumab (since March of 2014) and  dabrafenib (since July of 2015) until December 2016. The end date of the  observation was set to 31 December 2016. The total survival analysis was  performed using the Kaplan-Meier estimator. Until 31 December 2016, 759 patients   were treated with vemurafenib, 370 with ipilimumab and 181 with dabrafenib. The  overall survival (OS) median was 9.8 months for patients treated with vemurafenib  (95% confidence interval: 8.8-10.6) and 6.9 months for patients treated with  ipilimumab (95% confidence interval: 5.7-9.2). For patients treated with  dabrafenib, the OS median was not reached because of an overly short observation   period. The probability of surviving 12 months in the group of patients treated  with vemurafenib was 40.5%, ipilimumab was 35.1% and dabrafenib was 60.7%. The  probability of surviving 24 and 36 months in the group of patients treated with  vemurafenib or ipilimumab amounted to, respectively, 20.1, 15.4 and 21, 18.8%. OS  of patients with advanced melanoma treated in daily clinical practice may be  comparable to the ones achieved in registration trials. The use of appropriate  treatment inclusion criteria may affect the obtained OS.
CANIT0001444	29120964	Clinical research	Advanced skin melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Vemurafenib	Immune checkpoint therapy	Ipilimumab (DB06186); vemurafenib (DB08881); dabrafenib (DB08912); 	370	759	A retrospective cohort study	The probability of surviving 12 months in the group of patients treated  with vemurafenib was 40.5%, ipilimumab was 35.1% and dabrafenib was 60.7%. The  probability of surviving 24 and 36 months in the group of patients treated with  vemurafenib or ipilimumab amounted to, respectively, 20.1, 15.4 and 21, 18.8%. OS  of patients with advanced melanoma treated in daily clinical practice may be  comparable to the ones achieved in registration trials. The use of appropriate  treatment inclusion criteria may affect the obtained OS.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Feb	 Analysis of survival of patients treated with vemurafenib, ipilimumab and  dabrafenib for advanced skin melanoma in daily clinical practice (Real-World  Data): retrospective analysis of patients treated under drug/reimbursement  programmes in Poland in 2013-2016.	 Melanoma Res	 Vemurafenib, ipilimumab and dabrafenib were registered for the treatment of  advanced skin melanoma pursuant to the results of randomized phase III clinical  trials. Real-world data on survival time for patients treated with those drugs in  daily clinical practice are so far limited. Patients with advanced skin melanoma   treated under reimbursement programmes (drug programmes), for which they were  qualified pursuant to uniform inclusion criteria in force in all oncology centres  in Poland. Data were obtained from the electronic databases of the national payer  (NFZ) responsible for the implementation and monitoring of reimbursement (drug)  programmes. The analysis included all patients included for treatment with  vemurafenib (since March of 2013), ipilimumab (since March of 2014) and  dabrafenib (since July of 2015) until December 2016. The end date of the  observation was set to 31 December 2016. The total survival analysis was  performed using the Kaplan-Meier estimator. Until 31 December 2016, 759 patients   were treated with vemurafenib, 370 with ipilimumab and 181 with dabrafenib. The  overall survival (OS) median was 9.8 months for patients treated with vemurafenib  (95% confidence interval: 8.8-10.6) and 6.9 months for patients treated with  ipilimumab (95% confidence interval: 5.7-9.2). For patients treated with  dabrafenib, the OS median was not reached because of an overly short observation   period. The probability of surviving 12 months in the group of patients treated  with vemurafenib was 40.5%, ipilimumab was 35.1% and dabrafenib was 60.7%. The  probability of surviving 24 and 36 months in the group of patients treated with  vemurafenib or ipilimumab amounted to, respectively, 20.1, 15.4 and 21, 18.8%. OS  of patients with advanced melanoma treated in daily clinical practice may be  comparable to the ones achieved in registration trials. The use of appropriate  treatment inclusion criteria may affect the obtained OS.
CANIT0001445	29121363	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Oral dexamethasone is a safe and effective treatment for this side effect of the medication.	Vogt-Koyanagi-Harada Disease	N/A	N/A	N/A	N/A	N/A	 2017 Nov 1	 Treatment of Ipilimumab-Induced Vogt-Koyanagi-Harada Syndrome With Oral  Dexamethasone.	 Ophthalmic Surg Lasers Imaging Retina	 The author presents a retrospective case report of a 54-year-old male with  ipilimumab (Yervoy; Bristol-Myers Squibb, New York City, NY)-induced  Vogt-Koyanagi-Harada Disease (VKH), which consisted of uveitis, optic neuritis,  and choroiditis that was successfully treated with oral dexamethasone. The  patient demonstrated resolution of uveitis, optic neuritis, and choroiditis 1  month following initiation of oral dexamethasone. Ipilimumab is a recently  approved therapy for malignant melanoma. Reports have identified that VKH disease  is a potential side effect of the medication. Oral dexamethasone is a safe and  effective treatment for this side effect of the medication. [Ophthalmic Surg  Lasers Imaging Retina. 2017;48:928-931.].CI  - Copyright 2017, SLACK Incorporated.
CANIT0001446	29122555	Case report	Diffuse recurrent cutaneous melanoma of the scalp and neck	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); radiotherapy (NCIT:C15313); 	1	N/A	Case	Successfully treated	N/A	N/A	N/A	N/A	N/A	N/A	 2018 May - Jun	 Diffuse recurrent cutaneous melanoma of the scalp and neck successfully treated  with volumetric modulated arc therapy and concurrent ipilimumab.	 Pract Radiat Oncol	Unable to provide
CANIT0001447	29129441	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Chemotherapy	Immune checkpoint therapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	154	151	A multicentre, international, randomised, open-label, phase III	Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2017 Dec	 Health-related quality-of-life results for pembrolizumab versus chemotherapy in  advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international,  randomised, open-label phase 3 trial.	 Lancet Oncol	 BACKGROUND: In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab  conferred longer progression-free survival than did platinum-based therapy in  patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a  programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater   (PD-L1-positive). Here we report the prespecified exploratory endpoint of  pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). METHODS:  In this multicentre, international, randomised, open-label, phase 3 trial, we  recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16  countries. Eligible patients had measurable disease (per RECIST version 1.1) and   an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients   were randomly assigned (1:1) via an interactive voice response system and  integrated web response system to receive either pembrolizumab 200 mg every 3  weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6  cycles or until documented disease progression or unacceptable toxicity).  Randomisation was stratified according to geography, ECOG performance status, and  histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter,  at the treatment discontinuation visit, and at the 30-day safety assessment visit  using the European Organisation for the Research and Treatment of Cancer (EORTC)   Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life   Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5  Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints  (analysed for all patients who received at least one dose of study treatment and   completed at least one PRO instrument at at least one timepoint) were  baseline-to-week-15 change in the QLQ-C30 global health status  (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of  cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with  ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling  patients. FINDINGS: Between Sept 19, 2014, and Oct 29, 2015, 305 patients were  randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three  patients in each group did not complete any PRO instruments at any timepoints,  and so 299 patients were included in the full analysis set. Of these patients,  one in each group did not complete any PRO instruments before week 15, and so  were not included in analyses of change from baseline to week 15. PRO compliance   was greater than 90% at baseline and approximately 80% at week 15 for both  groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score  was 6.9 (95% CI 3.3 to 10.6) for pembrolizumab and -0.9 (-4.8 to 3.0) for  chemotherapy, for a difference of 7.8 (2.9 to 12.8; two-sided nominal p=0.0020).   Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite   endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58  [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than   with chemotherapy (median not reached [95% CI 8.5 to not reached] vs 5.0 months  [3.6 to not reached]; hazard ratio 0.66, 95% CI 0.44-0.97; two-sided nominal  p=0.029). INTERPRETATION: Pembrolizumab improves or maintains health-related QOL   compared with that for chemotherapy, and might represent a new first-line  standard of care for PD-L1-expressing, advanced NSCLC. FUNDING: Merck & Co.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001448	29129758	Clinical research	Advanced Squamous Non-Small Cell Lung Cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Docetaxel	Immune checkpoint therapy	Nivolumab (DB09035); docetaxel (DB01248); 	97	89	A retrospective cohort study	Nivolumab alleviates symptom burden and improves health status versus docetaxel as second-line squamous NSCLC treatment.	N/A	N/A	N/A	Health-related quality of life (NCIT:C142570); 	First health-related quality of life deterioration	Disease status	 2018 Feb	 Impact of Nivolumab versus Docetaxel on Health-Related Quality of Life and  Symptoms in Patients with Advanced Squamous Non-Small Cell Lung Cancer: Results  from the CheckMate 017 Study.	 J Thorac Oncol	 INTRODUCTION: In the phase III CheckMate 017 study, nivolumab prolonged overall  survival versus docetaxel in previously treated patients with advanced squamous  NSCLC. Study objectives included health-related quality of life (HRQoL) and  symptom assessments. METHODS: Patients serially completed the Lung Cancer Symptom  Scale (LCSS) and European Quality of Life Five Dimensions (EQ-5D) questionnaires.  The LCSS average symptom burden index (ASBI) (mean score for six lung  cancer-specific symptoms; range 0-100), LCSS three-item global index, EQ-5D  utility index, and EQ-5D visual analog scale scores were analyzed. The proportion  of patients exhibiting clinically meaningful improvement (a >/=10-point decrease)  in ASBI scores by week 12 was a secondary end point. Mixed-effect model repeated   measures analysis of HRQoL changes from baseline and analyses of time to HRQoL  deterioration were conducted. RESULTS: Baseline mean plus or minus SD LCSS ASBI  scores were similar in the nivolumab (29.6 +/- 16.4) and docetaxel (29.6 +/-  14.7) groups. By week 12, the proportions of patients (95% confidence interval)  with clinically meaningful improvement in ASBI scores were 20.0% (13.6-27.7) with  nivolumab and 21.9% (15.3-29.8) with docetaxel. At weeks 16 to 54, significant  improvements in ASBI scores from baseline were seen with nivolumab; clinically  meaningful improvements were observed at weeks 42 to 84. No significant changes  in ASBI scores from baseline were observed with docetaxel; at week 36, a  clinically meaningful deterioration was seen. Improvements in HRQoL with  nivolumab versus with docetaxel were supported by other measures, and time to  first HRQoL deterioration was longer. CONCLUSION: Nivolumab alleviates symptom  burden and improves health status versus docetaxel as second-line squamous NSCLC   treatment.CI  - Copyright (c) 2017 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0001449	29131510	Case report	Pulmonary pleomorphic carcinoma	Pulmonary pleomorphic carcinoma	NCIT:C45542	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 Pulmonary pleomorphic carcinoma with few PD-1-positive immune cells and  regulatory T cells that showed a complete response to nivolumab.	 Thorac Cancer	 Pulmonary pleomorphic carcinoma has been shown to respond remarkably to PD-1  inhibitors; however, the biomarkers for this therapy have not been fully proven.   We report a case of pulmonary pleomorphic carcinoma with overexpressed PD-L1, in   which a complete response to nivolumab was sustained for >14 months.  Immunohistochemical analysis revealed few PD-1(+) immune cells and regulatory T  cells in the tumor, in addition to predominant infiltration of CD8(+) cells and  macrophages. Our findings suggest that the presence of a small number of PD-1(+)   immune cells and regulatory T cells should be investigated as candidate  therapeutic biomarkers.CI  - (c) 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and   John Wiley & Sons Australia, Ltd.
CANIT0001450	29133121	Clinical research	Early Death in Advanced Non-small-cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	N/A	Disease progression and immune-related adverse events are 2 major causes of early death with nivolumab in patients with NSCLC. An Eastern Cooperative Oncology Group performance status score  2 to prior treatment were associated with early death.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2018 Mar	 Analysis of Early Death in Japanese Patients With Advanced Non-small-cell Lung  Cancer Treated With Nivolumab.	 Clin Lung Cancer	 BACKGROUND: The increased risk for early death owing to anti-programmed cell  death 1 inhibitors is a major disadvantage that requires special management. We  evaluated the frequency, causes, and risk factors of early death during nivolumab  treatment for non-small cell lung cancer (NSCLC) in a Japanese clinical setting.   PATIENTS AND METHODS: The medical records of patients with NSCLC who started  receiving nivolumab between December 17, 2015 and July 31, 2016 in 3 Japanese  institutes were collected. Early death was defined as any death within 3 months  from the start of nivolumab treatment, irrespective of its cause. Treatment  response was evaluated using the Response Evaluation Criteria In Solid Tumors  criteria, version 1.1. RESULTS: A total of 201 patients with NSCLC were enrolled,  and 38 (18.9%) died within the first 3 months. Thirty-one (81.6%) patients who  experienced early death developed progressive disease, whereas 14 (36.8%)  patients who experienced early death demonstrated nivolumab-induced  immune-related adverse events, which required corticosteroid intervention,  including interstitial lung disease in 7 (18.4%) patients. Multivariate logistic   regression demonstrated that an Eastern Cooperative Oncology Group performance  status score >/= 2 (odds ratio [OR], 5.66; 95% confidence interval [CI],  2.01-15.61; P < .001), C-reactive protein-to-albumin ratio > 0.3 (OR, 10.56; 95%   CI, 3.61-30.86; P < .001), and the response to prior treatment (OR, 2.07; 95% CI,  1.03-4.14; P = .041) were independent predictors for early death. CONCLUSION:  Disease progression and immune-related adverse events are 2 major causes of early  death with nivolumab in patients with NSCLC. An Eastern Cooperative Oncology  Group performance status score >/= 2, pretreatment C-reactive protein-to-albumin   ratio > 0.3, and poor response to prior treatment were associated with early  death.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001451	29133121	Clinical research	Early Death in Advanced Non-small-cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	N/A	Disease progression and immune-related adverse events are 2 major causes of early death with nivolumab in patients with NSCLC. A pretreatment C-reactive protein-to-albumin ratio > 0.3 to prior treatment were associated with early death.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein-to-albumin ratios	Gene expression signature in serum	 2018 Mar	 Analysis of Early Death in Japanese Patients With Advanced Non-small-cell Lung  Cancer Treated With Nivolumab.	 Clin Lung Cancer	 BACKGROUND: The increased risk for early death owing to anti-programmed cell  death 1 inhibitors is a major disadvantage that requires special management. We  evaluated the frequency, causes, and risk factors of early death during nivolumab  treatment for non-small cell lung cancer (NSCLC) in a Japanese clinical setting.   PATIENTS AND METHODS: The medical records of patients with NSCLC who started  receiving nivolumab between December 17, 2015 and July 31, 2016 in 3 Japanese  institutes were collected. Early death was defined as any death within 3 months  from the start of nivolumab treatment, irrespective of its cause. Treatment  response was evaluated using the Response Evaluation Criteria In Solid Tumors  criteria, version 1.1. RESULTS: A total of 201 patients with NSCLC were enrolled,  and 38 (18.9%) died within the first 3 months. Thirty-one (81.6%) patients who  experienced early death developed progressive disease, whereas 14 (36.8%)  patients who experienced early death demonstrated nivolumab-induced  immune-related adverse events, which required corticosteroid intervention,  including interstitial lung disease in 7 (18.4%) patients. Multivariate logistic   regression demonstrated that an Eastern Cooperative Oncology Group performance  status score >/= 2 (odds ratio [OR], 5.66; 95% confidence interval [CI],  2.01-15.61; P < .001), C-reactive protein-to-albumin ratio > 0.3 (OR, 10.56; 95%   CI, 3.61-30.86; P < .001), and the response to prior treatment (OR, 2.07; 95% CI,  1.03-4.14; P = .041) were independent predictors for early death. CONCLUSION:  Disease progression and immune-related adverse events are 2 major causes of early  death with nivolumab in patients with NSCLC. An Eastern Cooperative Oncology  Group performance status score >/= 2, pretreatment C-reactive protein-to-albumin   ratio > 0.3, and poor response to prior treatment were associated with early  death.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001452	29146617	Case report	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	3	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Cure in Advanced Renal Cell Cancer: Is It an Achievable Goal 	 Oncologist	 BACKGROUND: Immunotherapy has historically been of interest in the management of   metastatic renal cell cancer (mRCC) because of its relative chemoresistance and  the reproducible but low incidence of spontaneous remission in metastatic  disease. Recently, targeted immunotherapies in the form of checkpoint inhibitors   have shown durable responses in approximately 20%-30% of patients with solid  tumors, with a much more acceptable side-effect profile. Anti-programmed death  receptor 1 (PD-1)/programmed death receptor ligand 1 antibodies rely on the  presence of host T cells in the tumor microenvironment to be stimulated in order   to activate an antitumor response. The presence of tumor antigens augments this  stimulation. This has led to further research into combination therapy with  anti-PD-1 inhibitors and radiotherapy, chemotherapy, or targeted therapy with the  aim of increasing the response rate to these agents. MATERIALS AND METHODS: We  describe three cases of patients with mRCC treated with anti-PD-1 antibody  therapy in combination with targeted therapy (bevacizumab), anti-cytotoxic T  lymphocyte antigen 4 therapy (ipilimumab), or radiotherapy. We perform a  comprehensive literature review on combination immunotherapy and the scope for  the future. RESULTS: Two patients had a complete clinical response within 3  months of commencing treatment. The third patient had a further significant  response to radiotherapy outside the field of treatment after initial response to  anti-PD-1 therapy, which lasted for over 12 months. CONCLUSION: We are now in the  era of immunotherapy with promising results in select patients. However, the  number of complete remissions with single agents are low. This report  demonstrates the potential for combination therapy in mRCC to produce complete  responses and improved survival rates. Whether these results equate to cure in a   subset of patients requires longer follow-up. Further evaluation of dosing  regimens, sequencing methods, and biomarkers to select patient population is  required to advance this treatment strategy. IMPLICATIONS FOR PRACTICE: Multiple   phase I-III studies exploring the benefit of combination immunotherapy are  currently under way. Further research into predictive biomarkers to identify the   cohort of patients who gain this benefit is pertinent. This case series  demonstrates that the combination of immunotherapy with other treatments can lead  to complete responses, even in patients with initially bulky disease. Combination  therapy with immunotherapy seems to cause more durable responses in patients with  metastatic renal cell cancer compared with monotherapy. Significantly longer  follow-up is necessary to determine whether durable complete response confers a  cure in a select group of patients.CI  - (c) AlphaMed Press 2017.
CANIT0001453	29146617	Case report	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	Radiotherapy	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	3	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Cure in Advanced Renal Cell Cancer: Is It an Achievable Goal 	 Oncologist	 BACKGROUND: Immunotherapy has historically been of interest in the management of   metastatic renal cell cancer (mRCC) because of its relative chemoresistance and  the reproducible but low incidence of spontaneous remission in metastatic  disease. Recently, targeted immunotherapies in the form of checkpoint inhibitors   have shown durable responses in approximately 20%-30% of patients with solid  tumors, with a much more acceptable side-effect profile. Anti-programmed death  receptor 1 (PD-1)/programmed death receptor ligand 1 antibodies rely on the  presence of host T cells in the tumor microenvironment to be stimulated in order   to activate an antitumor response. The presence of tumor antigens augments this  stimulation. This has led to further research into combination therapy with  anti-PD-1 inhibitors and radiotherapy, chemotherapy, or targeted therapy with the  aim of increasing the response rate to these agents. MATERIALS AND METHODS: We  describe three cases of patients with mRCC treated with anti-PD-1 antibody  therapy in combination with targeted therapy (bevacizumab), anti-cytotoxic T  lymphocyte antigen 4 therapy (ipilimumab), or radiotherapy. We perform a  comprehensive literature review on combination immunotherapy and the scope for  the future. RESULTS: Two patients had a complete clinical response within 3  months of commencing treatment. The third patient had a further significant  response to radiotherapy outside the field of treatment after initial response to  anti-PD-1 therapy, which lasted for over 12 months. CONCLUSION: We are now in the  era of immunotherapy with promising results in select patients. However, the  number of complete remissions with single agents are low. This report  demonstrates the potential for combination therapy in mRCC to produce complete  responses and improved survival rates. Whether these results equate to cure in a   subset of patients requires longer follow-up. Further evaluation of dosing  regimens, sequencing methods, and biomarkers to select patient population is  required to advance this treatment strategy. IMPLICATIONS FOR PRACTICE: Multiple   phase I-III studies exploring the benefit of combination immunotherapy are  currently under way. Further research into predictive biomarkers to identify the   cohort of patients who gain this benefit is pertinent. This case series  demonstrates that the combination of immunotherapy with other treatments can lead  to complete responses, even in patients with initially bulky disease. Combination  therapy with immunotherapy seems to cause more durable responses in patients with  metastatic renal cell cancer compared with monotherapy. Significantly longer  follow-up is necessary to determine whether durable complete response confers a  cure in a select group of patients.CI  - (c) AlphaMed Press 2017.
CANIT0001454	29146617	Case report	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab	Bevacizumab	Immune checkpoint therapy followed by Target therapy	Atezolizumab (DB11595); bevacizumab (DB00112); 	3	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Cure in Advanced Renal Cell Cancer: Is It an Achievable Goal 	 Oncologist	 BACKGROUND: Immunotherapy has historically been of interest in the management of   metastatic renal cell cancer (mRCC) because of its relative chemoresistance and  the reproducible but low incidence of spontaneous remission in metastatic  disease. Recently, targeted immunotherapies in the form of checkpoint inhibitors   have shown durable responses in approximately 20%-30% of patients with solid  tumors, with a much more acceptable side-effect profile. Anti-programmed death  receptor 1 (PD-1)/programmed death receptor ligand 1 antibodies rely on the  presence of host T cells in the tumor microenvironment to be stimulated in order   to activate an antitumor response. The presence of tumor antigens augments this  stimulation. This has led to further research into combination therapy with  anti-PD-1 inhibitors and radiotherapy, chemotherapy, or targeted therapy with the  aim of increasing the response rate to these agents. MATERIALS AND METHODS: We  describe three cases of patients with mRCC treated with anti-PD-1 antibody  therapy in combination with targeted therapy (bevacizumab), anti-cytotoxic T  lymphocyte antigen 4 therapy (ipilimumab), or radiotherapy. We perform a  comprehensive literature review on combination immunotherapy and the scope for  the future. RESULTS: Two patients had a complete clinical response within 3  months of commencing treatment. The third patient had a further significant  response to radiotherapy outside the field of treatment after initial response to  anti-PD-1 therapy, which lasted for over 12 months. CONCLUSION: We are now in the  era of immunotherapy with promising results in select patients. However, the  number of complete remissions with single agents are low. This report  demonstrates the potential for combination therapy in mRCC to produce complete  responses and improved survival rates. Whether these results equate to cure in a   subset of patients requires longer follow-up. Further evaluation of dosing  regimens, sequencing methods, and biomarkers to select patient population is  required to advance this treatment strategy. IMPLICATIONS FOR PRACTICE: Multiple   phase I-III studies exploring the benefit of combination immunotherapy are  currently under way. Further research into predictive biomarkers to identify the   cohort of patients who gain this benefit is pertinent. This case series  demonstrates that the combination of immunotherapy with other treatments can lead  to complete responses, even in patients with initially bulky disease. Combination  therapy with immunotherapy seems to cause more durable responses in patients with  metastatic renal cell cancer compared with monotherapy. Significantly longer  follow-up is necessary to determine whether durable complete response confers a  cure in a select group of patients.CI  - (c) AlphaMed Press 2017.
CANIT0001455	29150430	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	20	N/A	N/A	Upregulation of an IFNG-response gene expression signature, including CTLA4 itself, which correlated significantly with durable response.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	IFNG (P01579); 	IFNG-response gene expression signature	Gene expression signature on/in tumor cell	 2018 Jan 15	 Interferon-gamma Signaling in Melanocytes and Melanoma Cells Regulates Expression  of CTLA-4.	 Cancer Res	 CTLA4 is a cell surface receptor on T cells that functions as an immune  checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA4  immunotherapy is highly effective at reactivating T-cell responses against  melanoma, which is postulated to be due to targeting CTLA4 on T cells. Here, we  report that CTLA4 is also highly expressed by most human melanoma cell lines, as   well as in normal human melanocytes. InterferonG (IFNG) signaling activated   the expression of the human CTLA4 gene in a melanocyte and melanoma cell-specific  manner. Mechanistically, IFNG activated CTLA4 expression through JAK1/2-dependent  phosphorylation of STAT1, which bound a specific gamma-activated sequence site on  the CTLA4 promoter, thereby licensing CBP/p300-mediated histone acetylation and  local chromatin opening. In melanoma cell lines, elevated baseline expression  relied upon constitutive activation of the MAPK pathway. Notably, RNA-seq  analyses of melanoma specimens obtained from patients who had received anti-CTLA4  immunotherapy (ipilimumab) showed upregulation of an IFNG-response gene  expression signature, including CTLA4 itself, which correlated significantly with  durable response. Taken together, our results raise the possibility that CTLA4  targeting on melanoma cells may contribute to the clinical immunobiology of  anti-CTLA4 responses.Significance: These findings show that human melanoma cells   express high levels of the immune checkpoint molecule CTLA4, with important  possible implications for understanding how anti-CTLA4 immunotherapy mediates its  therapeutic effects. Cancer Res; 78(2); 436-50. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001456	29153896	Clinical research	Non-small-cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	34	N/A	N/A	The radiographic pattern of treatment response to nivolumab therapy in advanced NSCLC is heterogeneous in the early posttreatment surveillance period. Radiographic improvement in the early surveillance period predicts a favorable and durable response, although stability or apparent disease progression during this time is of limited prognostic utility.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Sequential CT Findings in Patients With Non-small-cell Lung Cancer Receiving  Nivolumab.	 Clin Lung Cancer	 BACKGROUND: Nivolumab is a novel immunotherapy that was recently approved for  treatment of advanced non-small-cell lung cancer (NSCLC). Patients treated with  checkpoint inhibitors may show variable computed tomography (CT) features on  follow-up imaging, and it is unclear how reliable conventional response criteria   are to determine patient management and outcomes. We report the spectrum of  sequential CT findings in patients with advanced stage lung cancer who received  nivolumab in an effort to better inform appropriate imaging strategies. MATERIALS  AND METHODS: We identified all patients at our institution with advanced NSCLC  who received nivolumab. Pre- and posttreatment CT scans were reviewed and  categorized based on radiographic response to therapy. Demographic data as well  as survival data were recorded. RESULTS: There were 34 patients with advanced  NSCLC who received nivolumab with sufficient follow-up data. Nineteen patients  were classified as responders to treatment; 6 (32%) of 19 showed improvement on  their initial follow-up CT and had an average survival of 11.2 months, whereas 13  (68%) of 19 responders initially had stable or progressive disease on CT with an   average survival of 11.6 months. Fifteen patients were classified as  nonresponders to treatment with an average survival of 3.4 months. CONCLUSION:  Novel immunotherapies such as nivolumab mechanistically differ from conventional   chemotherapy. Some patients have improved survival despite initial radiographic  progression of disease. Our findings underscore the heterogeneous radiographic  appearance at follow-up CT in patients with lung cancer who ultimately respond to  nivolumab.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001457	29157297	Case report	Cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Smoldering myocarditis	N/A	N/A	N/A	N/A	N/A	 2017 Nov 21	 Smoldering myocarditis following immune checkpoint blockade.	 J Immunother Cancer	 BACKGROUND: Severe myocarditis associated with electrical conduction  abnormalities and occasionally heart failure has been well documented following  treatment with immune checkpoint blockade with an estimated incidence of less  than 1%. However, the incidence, early detection, and management of less severe  immune-related myocarditis are unknown since most immunotherapy trials have not  included routine cardiac monitoring. Herein, we provide the first description of   subclinical or smoldering myocarditis with minimal signs and symptoms following  immune checkpoint blockade with a single dose of ipilimumab and nivolumab. CASE  PRESENTATION: Our patient was diagnosed with immune checkpoint blockade-induced  myocarditis based upon an acute rise in serum cardiac troponin I beginning 2  weeks after the initial dose of ipilimumab/nivolumab consistent with the reported  median onset of clinical myocarditis at 17 days, as well as a lack of other  causes despite extensive cardiac evaluation. The patient initially presented with  intractable nausea with no known gastrointestinal etiology. High dose  glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease  in troponin I over 4 days. Serum troponin I spiked again following a steroid  taper to 13 times the upper limit of normal with endomyocardial biopsy revealing   collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T   cells consistent with chronic smoldering myocarditis. Serum anti-striated muscle   antibodies were also detected with no evidence of rhabdomyolysis. Serum cardiac  troponin I levels as an indicator of ongoing myocyte damage gradually improved  with chronic prednisone at 10 mg daily. Late addition of intravenous  immunoglobulin was associated with rapid normalization of creatine  kinase-myocardial band. CONCLUSIONS: This case demonstrates that subclinical,  smoldering myocarditis may occur following immune checkpoint blockade, with  evidence of both humoral and cell-mediated immunity responsive to corticosteroid   therapy. This experience supports early monitoring for myocarditis with serial  electrocardiograms and serum troponin I determinations in large, prospective  cohorts of patients receiving combination immune checkpoint blockade as early  detection and initiation of immunosuppression may forestall fulminant  presentation of this disease and limit myocardial damage.
CANIT0001458	29157298	Case report	Metastatic gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Almost complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Nov 21	 Impressive response to immunotherapy in a metastatic gastric cancer patient:  could somatic copy number alterations help patient selection 	 J Immunother Cancer	 BACKGROUND: Metastatic gastric cancer (GC) is an incurable and aggressive disease  with a poor prognosis. Immunotherapy is an attractive approach for treating  patients with cancer, and studies using immunotherapy have shown promising  results in melanoma, kidney and non-small cell lung cancers, among others. CASE  PRESENTATION: We present a case of a 50-year-old woman with metastatic GC whose  cancer had progressed after first-line chemotherapy and who received  pembrolizumab as an experimental treatment. Molecular analyses showed that her  tumor was negative for PD-L1 expression, contained microsatellite stability and  several focal somatic copy number alterations. The patient experienced an almost   complete response after eleven cycles of treatment. Her symptoms related to the  disease disappeared, and the medication was well tolerated. CONCLUSIONS: Despite   reports of promising responses in some patients, immunotherapy is not suitable  for all patients; therefore, we explored the molecular characteristics that could  explain the exceptional response and clinical benefits observed in our patient.
CANIT0001459	29157306	Clinical research	Breast cancer	Breast cancer	MONDO:0007254	Breast	CEA (P06731); HER2 (P04626); MAGEA1 (P43355); MAGEA3 (P43357); MAGEA10 (P43363); TLR3 (O15455); NY-ESO-1 (P78358); 	CEA ;  HER2 ;  MAGEA1 	9-peptide breast cancer vaccine plus poly-ICLC	N/A	Tumor vaccine	Poly-ICLC (NCIT:C1198); 9-peptide breast cancer vaccine plus poly-ICLC (NCIT:C121947); 	12	N/A	N/A	Peptide vaccine administered in the adjuvant breast cancer setting was safe and feasible. The TLR3 adjuvant, poly-ICLC, plus helper peptide mixture provided modest immune stimulation.	There were no dose-limiting toxicities. Toxicities were limited to Grade 1 and Grade 2 and included mild injection site reactions and flu-like symptoms, which occurred in most patients. The most common toxicities were injection site reaction/induration and fatigue, which were experienced by 100% and 92% of participants, respectively.	N/A	N/A	N/A	N/A	N/A	 2017 Nov 21	 A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus  poly-ICLC in early stage breast cancer.	 J Immunother Cancer	 BACKGROUND: Breast cancer remains a leading cause of cancer death worldwide.  There is evidence that immunotherapy may play a role in the eradication of  residual disease. Peptide vaccines for immunotherapy are capable of durable  immune memory, but vaccines alone have shown sparse clinical activity against  breast cancer to date. Toll-like receptor (TLR) agonists and helper peptides are   excellent adjuvants for vaccine immunotherapy and they are examined in this human  clinical trial. METHODS: A vaccine consisting of 9 MHC class I-restricted breast   cancer-associated peptides (from MAGE-A1, -A3, and -A10, CEA, NY-ESO-1, and HER2   proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper  peptide derived from tetanus toxoid. The vaccine was administered on days 1, 8,  15, 36, 57, 78. CD8(+) T cell responses to the vaccine were assessed by both  direct and stimulated interferon gamma ELIspot assays. RESULTS: Twelve patients  with breast cancer were treated: five had estrogen receptor positive disease and   five were HER2 amplified. There were no dose-limiting toxicities. Toxicities were  limited to Grade 1 and Grade 2 and included mild injection site reactions and  flu-like symptoms, which occurred in most patients. The most common toxicities  were injection site reaction/induration and fatigue, which were experienced by  100% and 92% of participants, respectively. In the stimulated ELIspot assays,  peptide-specific CD8(+) T cell responses were detected in 4 of 11 evaluable  patients. Two patients had borderline immune responses to the vaccine. The two  peptides derived from CEA were immunogenic. No difference in immune response was   evident between patients receiving endocrine therapy and those not receiving  endocrine therapy during the vaccine series. CONCLUSIONS: Peptide vaccine  administered in the adjuvant breast cancer setting was safe and feasible. The  TLR3 adjuvant, poly-ICLC, plus helper peptide mixture provided modest immune  stimulation. Further optimization is required for this multi-peptide  vaccine/adjuvant combination. TRIAL REGISTRATION: ClinicalTrials.gov (posted  2/15/2012): NCT01532960. Registered 2/8/2012.  https://clinicaltrials.gov/show/NCT01532960.
CANIT0001460	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	BRAF mutations were less frequent in patients who experienced clinical benefit. 	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001461	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	BRAF mutations were less frequent in patients who experienced clinical benefit. 	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001462	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	Elevated proportions of circulating CD8+/PD-1+ T cells during treatment were associated with worse survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Percentage of circulating CD8(+)/PD-1(+) T-cell 	Gene expression signature on/in immune cell	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001463	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	Elevated proportions of circulating CD8+/PD-1+ T cells during treatment were associated with worse survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Percentage of circulating CD8(+)/PD-1(+) T-cell 	Gene expression signature on/in immune cell	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001464	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	Non-responders had a higher proportion of circulating late differentiated B cells.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	B-Lymphocyte (NCIT:C12474); 	Percentage of circulating late differentiated B cells	Cell percentage/counts in blood	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001465	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	Non-responders had a higher proportion of circulating late differentiated B cells.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	B-Lymphocyte (NCIT:C12474); 	Percentage of circulating late differentiated B cells	Cell percentage/counts in blood	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001466	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	NRAS mutations were less frequent in patients who experienced clinical benefit. 	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001467	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	NRAS mutations were less frequent in patients who experienced clinical benefit. 	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001468	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	Pre-existing high levels of advanced B cell differentiation was strongly associated with worse patient overall survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	B-Lymphocyte (NCIT:C12474); 	Advanced B cell differentiation	Immune response	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001469	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	Pre-existing high levels of advanced B cell differentiation was strongly associated with worse patient overall survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	B-Lymphocyte (NCIT:C12474); 	Advanced B cell differentiation	Immune response	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001470	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	Pre-existing high levels of chemokines CCL3 was strongly associated with worse patient overall survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CCL3 (P10147); 	Serum CCL3 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001471	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	Pre-existing high levels of chemokines CCL3 was strongly associated with worse patient overall survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CCL3 (P10147); 	Serum CCL3 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001472	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	Pre-existing high levels of chemokines CCL4 was strongly associated with worse patient overall survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CCL4 (Q8NHW4); 	Serum CCL4 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001473	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	Pre-existing high levels of chemokines CCL4 was strongly associated with worse patient overall survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CCL4 (Q8NHW4); 	Serum CCL4 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001474	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	Pre-existing high levels of chemokines CXCL8 was strongly associated with worse patient overall survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	IL8 (P10145); 	Serum IL8 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001475	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	Pre-existing high levels of chemokines CXCL8 was strongly associated with worse patient overall survival.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	IL8 (P10145); 	Serum IL8 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001476	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	Response to treatment was positively correlated with a higher tumor CD3+ infiltrate (immune score) at baseline.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CD3 (P07766); Tumor infiltrate (NCIT:C12546); Immune responses (NCIT:C17930); 	Tumor-infiltrating CD3(+) T-cell 	Tumor-infiltrating immune cell	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001477	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	Response to treatment was positively correlated with a higher tumor CD3+ infiltrate (immune score) at baseline.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CD3 (P07766); Tumor infiltrate (NCIT:C12546); Immune responses (NCIT:C17930); 	Tumor-infiltrating CD3(+) T-cell 	Tumor-infiltrating immune cell	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001478	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CCL3 (P10147); 	Serum CCL3 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001479	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CCL3 (P10147); 	Serum CCL3 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001480	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CCL4 (Q8NHW4); 	Serum CCL4 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001481	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	CCL4 (Q8NHW4); 	Serum CCL4 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001482	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	IL8 (P10145); 	Serum CXCL8 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001483	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	IL8 (P10145); 	Serum CXCL8 expression levels	Gene expression signature in serum	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001484	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	B-Lymphocyte (NCIT:C12474); 	B cell differentiation	Microbiota	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001485	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	B-Lymphocyte (NCIT:C12474); 	B cell differentiation	Microbiota	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001486	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus carboplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Proportion of circulating CD8(+)/PD-1(+) T-cell 	Gene expression signature on/in immune cell	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001487	29157311	Clinical research	Untreated unresectable/metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); paclitaxel (DB01229); 	30	N/A	A phase II clinical trial	The combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment.	Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed.	N/A	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Proportion of circulating CD8(+)/PD-1(+) T-cell 	Gene expression signature on/in immune cell	 2017 Nov 21	 Peripheral and local predictive immune signatures identified in a phase II trial   of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV  melanoma.	 J Immunother Cancer	 BACKGROUND: Checkpoint blockade with ipilimumab provides long-term survival to a   significant proportion of patients with metastatic melanoma. New approaches to  increase survival and to predict which patients will benefit from treatment are  needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP)   to assess its safety, efficacy, and to search for peripheral and tumor-based  predictive biomarkers. METHODS: Thirty patients with untreated  unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse  events (AEs) were monitored and response to treatment was evaluated. Tumor tissue  and peripheral blood were collected at specified time points to characterize  tumor immune markers by immunohistochemistry and systemic immune activity by  multiplex assays and flow cytometry. RESULTS: Eighty three percent of patients  received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs  occurred in 13% of patients, and no treatment-related deaths were observed. Best   Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%,  respectively. Median overall survival was 16.2 months. Response to treatment was   positively correlated with a higher tumor CD3(+) infiltrate (immune score) at  baseline. NRAS and BRAF mutations were less frequent in patients who experienced   clinical benefit. Assessment of peripheral blood revealed that non-responders had  elevated baseline levels of CXCL8 and CCL4, and a higher proportion of  circulating late differentiated B cells. Pre-existing high levels of chemokines  (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly  associated with worse patient overall survival. Elevated proportions of  circulating CD8(+)/PD-1(+) T cells during treatment were associated with worse  survival. CONCLUSIONS: The combination of ipilimumab and CP was well tolerated  and revealed novel characteristics associated with patients likely to benefit  from treatment. A pre-existing systemic inflammatory state characterized by  elevation of selected chemokines and advanced B cell differentiation, was  strongly associated with poor patient outcomes, revealing potential predictive  circulating biomarkers. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01676649 ,  registered on August 29, 2012.
CANIT0001488	29161357	Case report	Non-small-cell lung cancer with EGFR mutation	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	Case	Better outcome may in patients with uncommon EGFR mutation.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Mar 1	 Nivolumab in non-small-cell lung cancer with EGFR mutation.	 Ann Oncol	Unable to provide
CANIT0001489	29169677	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	Unexpected adverse events	A 79-year-old patient with a large-cell carcinoma showed a muscle weakness after the second course, revealing myositis with a CPK grade IV elevation as well as symptoms of myasthenia. The diagnosis of myositis was confirmed by a muscle biopsy. An 82-year-old patient followed for bronchial adenocarcinoma with EGFR mutation, presented with nivolumab shoulder and hip pain with extreme fatigue. After further investigations, the diagnosis of systemic erythematosus lupus was retained. Investigations led to the diagnosis of systemic lupus erythematosus. For both patients treatment was interrupted and systemic corticosteroid therapy was initiated permitting resolution of symptoms.	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 [Unexpected adverse events of immunotherapies in non-small cell lung cancer:  About 2 cases].	 Rev Pneumol Clin	 Programmed death receptor 1 (PD1) checkpoint inhibitors are known for immune  mediated toxicities such as colitis, endocrinopathies and pneumonitis. However,  other rare adverse effects are reported in the literature. Nivolumab is an  anti-PD1 immunotherapy used in the second line of non-small cell lung cancer  (NSCLC). We report two cases of rare toxicities occurring under nivolumab in  patients without a history of dysimmunity. A 79-year-old patient with a  large-cell carcinoma showed a muscle weakness after the second course, revealing   myositis with a CPK grade IV elevation as well as symptoms of myasthenia. The  diagnosis of myositis was confirmed by a muscle biopsy. An 82-year-old patient  followed for bronchial adenocarcinoma with EGFR mutation, presented with  nivolumab shoulder and hip pain with extreme fatigue. After further  investigations, the diagnosis of systemic erythematosus lupus was retained.  Investigations led to the diagnosis of systemic lupus erythematosus. For both  patients treatment was interrupted and systemic corticosteroid therapy was  initiated permitting resolution of symptoms. The occurrence of symptoms of  dysimmunity should attract the attention of the clinician, leading to  discontinuation of anti-PD1 therapy and corticosteroid therapy. Retreatment after  symptoms resolution must be collegially discussed if no alternative therapeutic  is available.CI  - Copyright (c) 2017 Elsevier Masson SAS. All rights reserved.
CANIT0001490	29170120	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	134	N/A	A retrospective cohort study	A baseline signature of a high absolute eosinophil count was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.	N/A	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Eosinophil counts	Cell percentage/counts in blood	 2018 Jan	 Peripheral Blood Biomarkers Associated with Clinical Outcome in Non-Small Cell  Lung Cancer Patients Treated with Nivolumab.	 J Thorac Oncol	 OBJECTIVE: The aim of this study was to identify baseline peripheral blood  biomarkers associated with clinical outcome in patients with NSCLC treated with  nivolumab. METHODS: Univariable and multivariable analyses were performed  retrospectively for 134 patients with advanced or recurrent NSCLC treated with  nivolumab to evaluate the relationship between survival and peripheral blood  parameters measured before treatment initiation, including absolute neutrophil  count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and  absolute eosinophil count (AEC), as well as serum C-reactive protein and lactate   dehydrogenase levels. Progression-free survival, overall survival, and response  rate were determined. RESULTS: Among the variables selected by univariable  analysis, a low ANC, high ALC, and high AEC were significantly and independently   associated with both better progression-free survival (p = 0.001, p = 0.04, and p  = 0.02, respectively) and better overall survival (p = 0.03, p = 0.03, and p =  0.003, respectively) in multivariable analysis. Categorization of patients  according to the number of favorable factors revealed that those with only one  factor had a significantly worse outcome than those with two or three factors. A   similar trend was apparent for patients with a programmed death 1 ligand tumor  proportion score less than 50%, whereas all patients with a score of 50% or  higher had at least two favorable factors. CONCLUSIONS: A baseline signature of a  low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab  treatment, with the number of favorable factors identifying subgroups of patients  differing in survival and response rate.CI  - Copyright (c) 2017 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0001491	29170120	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	134	N/A	A retrospective cohort study	A baseline signature of a low absolute neutrophil count was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2018 Jan	 Peripheral Blood Biomarkers Associated with Clinical Outcome in Non-Small Cell  Lung Cancer Patients Treated with Nivolumab.	 J Thorac Oncol	 OBJECTIVE: The aim of this study was to identify baseline peripheral blood  biomarkers associated with clinical outcome in patients with NSCLC treated with  nivolumab. METHODS: Univariable and multivariable analyses were performed  retrospectively for 134 patients with advanced or recurrent NSCLC treated with  nivolumab to evaluate the relationship between survival and peripheral blood  parameters measured before treatment initiation, including absolute neutrophil  count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and  absolute eosinophil count (AEC), as well as serum C-reactive protein and lactate   dehydrogenase levels. Progression-free survival, overall survival, and response  rate were determined. RESULTS: Among the variables selected by univariable  analysis, a low ANC, high ALC, and high AEC were significantly and independently   associated with both better progression-free survival (p = 0.001, p = 0.04, and p  = 0.02, respectively) and better overall survival (p = 0.03, p = 0.03, and p =  0.003, respectively) in multivariable analysis. Categorization of patients  according to the number of favorable factors revealed that those with only one  factor had a significantly worse outcome than those with two or three factors. A   similar trend was apparent for patients with a programmed death 1 ligand tumor  proportion score less than 50%, whereas all patients with a score of 50% or  higher had at least two favorable factors. CONCLUSIONS: A baseline signature of a  low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab  treatment, with the number of favorable factors identifying subgroups of patients  differing in survival and response rate.CI  - Copyright (c) 2017 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0001492	29170120	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	134	N/A	A retrospective cohort study	A baseline signature of  high absolute lymphocyte count was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2018 Jan	 Peripheral Blood Biomarkers Associated with Clinical Outcome in Non-Small Cell  Lung Cancer Patients Treated with Nivolumab.	 J Thorac Oncol	 OBJECTIVE: The aim of this study was to identify baseline peripheral blood  biomarkers associated with clinical outcome in patients with NSCLC treated with  nivolumab. METHODS: Univariable and multivariable analyses were performed  retrospectively for 134 patients with advanced or recurrent NSCLC treated with  nivolumab to evaluate the relationship between survival and peripheral blood  parameters measured before treatment initiation, including absolute neutrophil  count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and  absolute eosinophil count (AEC), as well as serum C-reactive protein and lactate   dehydrogenase levels. Progression-free survival, overall survival, and response  rate were determined. RESULTS: Among the variables selected by univariable  analysis, a low ANC, high ALC, and high AEC were significantly and independently   associated with both better progression-free survival (p = 0.001, p = 0.04, and p  = 0.02, respectively) and better overall survival (p = 0.03, p = 0.03, and p =  0.003, respectively) in multivariable analysis. Categorization of patients  according to the number of favorable factors revealed that those with only one  factor had a significantly worse outcome than those with two or three factors. A   similar trend was apparent for patients with a programmed death 1 ligand tumor  proportion score less than 50%, whereas all patients with a score of 50% or  higher had at least two favorable factors. CONCLUSIONS: A baseline signature of a  low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab  treatment, with the number of favorable factors identifying subgroups of patients  differing in survival and response rate.CI  - Copyright (c) 2017 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0001493	29171176	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	N/A	CR of individual metastases is common and influenced by site and size. Most patients with OR demonstrate homogenous regression in all metastases at the first assessment. In contrast, patients with early  heterogeneity had a poor outcome.	N/A	N/A	N/A	Early heterogeneity (NCIT:C28359); 	Early heterogeneity	Disease status	 2018 May	 Metastasis-specific patterns of response and progression with anti-PD-1 treatment  in metastatic melanoma.	 Pigment Cell Melanoma Res	 This study evaluated patterns of response as discerned by comprehensive  metastasis-specific analysis in metastatic melanoma patients receiving anti-PD-1   antibodies. Bi-dimensional measurements of every metastasis in patients enrolled   in the KEYNOTE-001 trial at a single institution were obtained at baseline and  throughout treatment. Twenty-seven evaluable patients had 399 baseline metastases  measurable on CT imaging. Complete response (CR) which occurred in 52.6% of  metastases was smaller (mean 223 mm(2) versus 760 mm(2) , p < .01) and occurred  more frequently in the lungs (65% versus 39.4%, p < .01). Response was  heterogenous (new/progressing metastases alongside CR metastases) at first  assessment in 4/14 patients with objective response (OR) as opposed to 7/13  patients with non-OR. CR of individual metastases is common and influenced by  site and size. Most patients with OR demonstrate homogenous regression in all  metastases at the first assessment. In contrast, patients with early  heterogeneity had a poor outcome.CI  - (c) 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001494	29187509	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab plus  pembrolizumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); 	15	162	A prospective study conducted at Melanoma Institute Australia between April 2014 and October 2015.	Combination immunotherapy has a greater risk of development of endocrinopathy compared to anti-PD-1 monotherapy. Regular biochemical profiling of patients, particularly within the first twelve weeks, results in early detection of endocrinopathy to minimise morbidity.	Endocrinopathies	N/A	N/A	N/A	N/A	N/A	 2018 Feb	 The spectrum, incidence, kinetics and management of endocrinopathies with immune   checkpoint inhibitors for metastatic melanoma.	 Eur J Endocrinol	 OBJECTIVE: Endocrine immune-related adverse events (endocrinopathies) are  increasingly prevalent with the use of immune checkpoint inhibitors for the  treatment of metastatic melanoma and other malignancies. There are no  evidence-based guidelines for the screening or management of such patients. To  describe the spectrum, incidence, kinetics and management of endocrinopathies  with immune checkpoint inhibitors. DESIGN: A prospective study conducted at  Melanoma Institute Australia between April 2014 and October 2015. METHODS: A  total of 177 patients were treated with (a) ipilimumab (n = 15), (b) anti-PD-1  (nivolumab, pembrolizumab) (n = 103) or (c) combination ipilimumab and anti-PD-1   (n = 59) and were screened and managed for the subsequent endocrinopathies. The  main outcome measures were the incidence and kinetics of endocrinopathy by  immunotherapy drug class. RESULTS: Thirty-one patients (18%) developed an  endocrine immune-related adverse event (thyroid dysfunction: 14%, hypophysitis:  6% and autoimmune diabetes: 0.6%). Combination immunotherapy was more likely to  result in a single or multiple endocrinopathy compared to anti-PD-1 monotherapy  (27% vs 9% and 7% vs 0% respectively, P < 0.01). Endocrinopathies occurred after   a median of 8 weeks from treatment commencement (range: 12-225 days), with  combination immunotherapy resulting in significantly earlier onset compared to  ipilimumab (median: 30 vs 76 days, P = 0.046). The majority of endocrinopathies  were identified in asymptomatic patients with hormonal screening. There were no  baseline predictors for endocrinopathy. CONCLUSIONS: Combination immunotherapy  has a greater risk of development of endocrinopathy compared to anti-PD-1  monotherapy. Regular biochemical profiling of patients, particularly within the  first twelve weeks, results in early detection of endocrinopathy to minimise  morbidity.CI  - (c) 2018 European Society of Endocrinology.
CANIT0001495	29189265	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	104	N/A	N/A	These results demonstrate PD-L1 IHC 28-8 pharmDx is a precise, robust, and reproducible assay for determining PD-L1 expression in melanoma. This is the first PD-L1 IHC test to receive FDA approval as a complementary diagnostic in melanoma patients whereby positive PD-L1 expression is correlated with the magnitude of nivolumab treatment effect.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Jan	 Development of a Diagnostic Programmed Cell Death 1-Ligand 1 Immunohistochemistry  Assay for Nivolumab Therapy in Melanoma.	 Appl Immunohistochem Mol Morphol	 Nivolumab is a monoclonal antibody that blocks the interaction between programmed  cell death 1 (PD1) and programmed cell death 1-ligand 1 (PD-L1), resulting in  enhanced antitumor activity by the immune system. Nivolumab is currently approved  by the US Food and Drug Administration (FDA) for melanoma, non-small cell lung  cancer (NSCLC), renal cell carcinoma, classical Hodgkin lymphoma, squamous cell  carcinoma of the head and neck, and urothelial carcinoma. PD-L1 IHC 28-8 pharmDx   is FDA-approved as a complementary diagnostic for immunohistochemical (IHC)  detection of PD-L1 in non-squamous NSCLC and melanoma. We report validation of  PD-L1 IHC 28-8 pharmDx for PD-L1 detection on formalin-fixed, paraffin-embedded  human melanoma specimens using Autostainer Link 48. A prevalence assessment of  104 melanoma specimens indicated that PD-L1 was detected across the full  expression level range (0% to 100% of tumor cells). Assay robustness and  precision studies were conducted at Agilent Technologies, with additional  reproducibility studies performed at 3 external laboratories. Precision studies  evaluated at >/=1% and >/=5% expression levels revealed a range of average  negative agreement from 89.5%, 95% CI (83.2, 93.6) to 100%, 95% CI (97.3, 100),  and average positive agreement from 85.5%, 95% CI (77.6, 90.9) to 100%, 95% CI  (97.9, 100). For external reproducibility, precise results were obtained. These  results demonstrate PD-L1 IHC 28-8 pharmDx is a precise, robust, and reproducible  assay for determining PD-L1 expression in melanoma. This is the first PD-L1 IHC  test to receive FDA approval as a complementary diagnostic in melanoma patients  whereby positive PD-L1 expression is correlated with the magnitude of nivolumab  treatment effect.
CANIT0001496	29191606	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Durvalumab followed by single-agent chemotherapy	N/A	Immune checkpoint therapy followed by Chemotherapy	Durvalumab (DB11714); single-agent chemotherapy (NCIT:C15756); 	28	N/A	A retrospective cohort study	In NSCLC patients, the confirmed ORR to single-agent chemotherapy after immunotherapy exposure was higher as compared to historical data from the pre-anti-PD1 era, and approached ORR to first-line  platinum-based chemotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Response rates to single-agent chemotherapy after exposure to immune checkpoint  inhibitors in advanced non-small cell lung cancer.	 Lung Cancer	 INTRODUCTION: Exploratory analysis of clinical trials in various tumor types have  demonstrated potential improvements in overall response rate (ORR) to  chemotherapy after exposure to vaccine-based immunotherapy. The objective of this  retrospective study was to determine if single-agent chemotherapy (3rd-line or  beyond) would yield improved ORR when given after exposure to programmed  death-(ligand)1 inhibitors (anti-PD1) in metastatic non-small cell lung cancer  (NSCLC). MATERIALS AND METHODS: We queried the Thoracic GEMINI database of MD  Anderson Cancer Center for patients treated between 06/12 and 11/16 who received   at least one single-agent chemotherapy as 3rd-line or beyond, following  progression after platinum-based chemotherapy and anti-PD1. We evaluated efficacy  outcomes to each therapy, including ORR by RECIST version 1.1, progression-free  survival (PFS), and overall survival (OS). RESULTS: Out of 306 anti-PD1-treated  patients registered in the database, 28 met eligibility criteria - 54% were male,  median age was 66 years, 82% had adenocarcinoma, and 71% were former/current  smokers. The anti-PD1 and single-agent chemotherapy most commonly used were  nivolumab (86%) and docetaxel (50%), respectively. ORR to single-agent  chemotherapy after exposure to anti-PD1 was 39% (11/28 patients, 8 confirmed). In  contrast, ORR to first-line chemotherapy in this cohort was 37%. Liver metastasis  was the only factor associated with response to single-agent chemotherapy on  univariate analysis (p<0.05). CONCLUSION: In NSCLC patients, the confirmed ORR to  single-agent chemotherapy after immunotherapy exposure was higher as compared to   historical data from the pre-anti-PD1 era, and approached ORR to first-line  platinum-based chemotherapy. Further investigation of a possible  immunotherapy-induced chemosensitization effect is warranted.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001497	29191606	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by single-agent chemotherapy	N/A	Immune checkpoint therapy followed by Chemotherapy	Nivolumab (DB09035); single-agent chemotherapy (NCIT:C15756); 	28	N/A	A retrospective cohort study	In NSCLC patients, the confirmed ORR to single-agent chemotherapy after immunotherapy exposure was higher as compared to historical data from the pre-anti-PD1 era, and approached ORR to first-line  platinum-based chemotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Response rates to single-agent chemotherapy after exposure to immune checkpoint  inhibitors in advanced non-small cell lung cancer.	 Lung Cancer	 INTRODUCTION: Exploratory analysis of clinical trials in various tumor types have  demonstrated potential improvements in overall response rate (ORR) to  chemotherapy after exposure to vaccine-based immunotherapy. The objective of this  retrospective study was to determine if single-agent chemotherapy (3rd-line or  beyond) would yield improved ORR when given after exposure to programmed  death-(ligand)1 inhibitors (anti-PD1) in metastatic non-small cell lung cancer  (NSCLC). MATERIALS AND METHODS: We queried the Thoracic GEMINI database of MD  Anderson Cancer Center for patients treated between 06/12 and 11/16 who received   at least one single-agent chemotherapy as 3rd-line or beyond, following  progression after platinum-based chemotherapy and anti-PD1. We evaluated efficacy  outcomes to each therapy, including ORR by RECIST version 1.1, progression-free  survival (PFS), and overall survival (OS). RESULTS: Out of 306 anti-PD1-treated  patients registered in the database, 28 met eligibility criteria - 54% were male,  median age was 66 years, 82% had adenocarcinoma, and 71% were former/current  smokers. The anti-PD1 and single-agent chemotherapy most commonly used were  nivolumab (86%) and docetaxel (50%), respectively. ORR to single-agent  chemotherapy after exposure to anti-PD1 was 39% (11/28 patients, 8 confirmed). In  contrast, ORR to first-line chemotherapy in this cohort was 37%. Liver metastasis  was the only factor associated with response to single-agent chemotherapy on  univariate analysis (p<0.05). CONCLUSION: In NSCLC patients, the confirmed ORR to  single-agent chemotherapy after immunotherapy exposure was higher as compared to   historical data from the pre-anti-PD1 era, and approached ORR to first-line  platinum-based chemotherapy. Further investigation of a possible  immunotherapy-induced chemosensitization effect is warranted.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001498	29191606	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab followed by single-agent chemotherapy	N/A	Immune checkpoint therapy followed by Chemotherapy	Pembrolizumab (DB09037); single-agent chemotherapy (NCIT:C15756); 	28	N/A	A retrospective cohort study	In NSCLC patients, the confirmed ORR to single-agent chemotherapy after immunotherapy exposure was higher as compared to historical data from the pre-anti-PD1 era, and approached ORR to first-line  platinum-based chemotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Oct	 Response rates to single-agent chemotherapy after exposure to immune checkpoint  inhibitors in advanced non-small cell lung cancer.	 Lung Cancer	 INTRODUCTION: Exploratory analysis of clinical trials in various tumor types have  demonstrated potential improvements in overall response rate (ORR) to  chemotherapy after exposure to vaccine-based immunotherapy. The objective of this  retrospective study was to determine if single-agent chemotherapy (3rd-line or  beyond) would yield improved ORR when given after exposure to programmed  death-(ligand)1 inhibitors (anti-PD1) in metastatic non-small cell lung cancer  (NSCLC). MATERIALS AND METHODS: We queried the Thoracic GEMINI database of MD  Anderson Cancer Center for patients treated between 06/12 and 11/16 who received   at least one single-agent chemotherapy as 3rd-line or beyond, following  progression after platinum-based chemotherapy and anti-PD1. We evaluated efficacy  outcomes to each therapy, including ORR by RECIST version 1.1, progression-free  survival (PFS), and overall survival (OS). RESULTS: Out of 306 anti-PD1-treated  patients registered in the database, 28 met eligibility criteria - 54% were male,  median age was 66 years, 82% had adenocarcinoma, and 71% were former/current  smokers. The anti-PD1 and single-agent chemotherapy most commonly used were  nivolumab (86%) and docetaxel (50%), respectively. ORR to single-agent  chemotherapy after exposure to anti-PD1 was 39% (11/28 patients, 8 confirmed). In  contrast, ORR to first-line chemotherapy in this cohort was 37%. Liver metastasis  was the only factor associated with response to single-agent chemotherapy on  univariate analysis (p<0.05). CONCLUSION: In NSCLC patients, the confirmed ORR to  single-agent chemotherapy after immunotherapy exposure was higher as compared to   historical data from the pre-anti-PD1 era, and approached ORR to first-line  platinum-based chemotherapy. Further investigation of a possible  immunotherapy-induced chemosensitization effect is warranted.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001499	29193151	Case report	Metastatic melanoma with history of myasthenia gravis 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Refractory myasthenia gravis exacerbation triggered By pembrolizumab.	Refractory myasthenia gravis exacerbation	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Refractory myasthenia gravis exacerbation triggered By pembrolizumab.	 Muscle Nerve	Unable to provide
CANIT0001500	29193772	Case report	Systemic refractory ALK+ anaplastic large cell lymphoma	Anaplastic large cell lymphoma	EFO:0003032	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Altogether, these three cases along with the unique immunogenic properties of ALCL including intrinsic PD-L1 induction and the good tolerance profile of PD1 inhibitors10 advocate for the development of clinical trials evaluating the efficacy of PD-1 inhibitors in refractory/relapsed ALCL, either in case of progression after targeted therapies or as consolidative immunotherapy in patients in CR after ALK inhibitors or brentuximab vedotin.	N/A	N/A	N/A	N/A	N/A	N/A	2018 Apr	Efficacy of nivolumab in a patient with systemic refractory ALK+ anaplastic large cell lymphoma.	Pediatr Blood Cancer	Unable to provide
CANIT0001501	29194286	Case report	Desmoplastic Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus irradiation	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); radiotherapy (NCIT:C15313); 	1	N/A	Case	Complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Mar/Apr	 Desmoplastic Melanoma of the Periorbital Region.	 Ophthalmic Plast Reconstr Surg	 Desmoplastic melanoma (DM) is a rare subtype of melanoma and an even smaller  proportion of periocular melanomas. Here, the authors report 2 cases of DM in the  periocular region. Staged according to the American Joint Committee on Cancer  (AJCC) eighth edition classification, patient 1 presented with a stage IIIC  (pT4apN1cM0) DM in the left lateral canthus with upper and lower eyelid and  patient 2 presented with a stage IIIB (T4aN1bM0) DM in the left brow and  supraorbital region with a parotid lymph node metastasis. In both patients, the  lesions were amelanotic, with inflammatory appearance, and had been noted for  several years before the correct diagnosis was made. In both patients, wide  excision led to large surgical defects, and perineural invasion prompted adjuvant  radiation therapy postoperatively. Patient 2 was treated with an immune  checkpoint inhibitor for his parotid metastasis. Ophthalmologists should be aware  of DM, its neurotrophic nature, and potential to metastasize with locally  advanced lesions.
CANIT0001502	29195497	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Bilateral uveitis and macular edema	N/A	N/A	N/A	N/A	N/A	 2017 Dec 1	 Bilateral uveitis and macular edema induced by Nivolumab: a case report.	 BMC Ophthalmol	 BACKGROUND: Nivolumab is a fully human antibody which is routinely used at first   therapy for metastatic melanoma. Usually, side effects are immune-related adverse  events. We report a case of a man who developed bilateral anterior uveitis and  macular serous retinal detachment during nivolumab treatment for metastatic  melanoma. CASE PRESENTATION: A man on nivolumab treatment for a leg melanoma with  duodenal and lymph nodes metastases developed a sudden bilateral visual acuity  impairment and bilateral non-painfull redness eyes several days after the third  infusion. The clinical examination showed a significant decreased of the visual  acuity. Slit lamp examination revealed the presence of bilateral granulomatous  keratic precipitates, anterior chamber cells +++, bilateral synechiae, bilateral   papilledema and macular edema associated with serous retinal detachment in the  left eye. The anti-Programmed cells Death-1 was stopped and a topical  corticosteroid treatment was administrated. After 8 days of topical  corticosteroid treatment visual acuity was worsening with similar optical  coherence tomography examination. An oral corticosteroid treatment was started.  Evolution was favorable with a decrease of ocular inflammation and a complete  visual acuity recovery after 3 weeks. Nivolumab was re-initiated. CONCLUSIONS:  This is the second clinical report of bilateral anterior uveitis associated with   macular serous retinal detachment related to anti-PD-1 treatment, and the first  with nivolumab. Cases of uveitis were reported several times. Although rare,  ophthalmologic manifestations that are rapidly recognized and adequately managed   can be treated.
CANIT0001503	29206889	Case report	Stage IIIa non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Good outcome in lung caner patient with HIV infected	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Feb 1	 Drastic decrease of the HIV reservoir in a patient treated with nivolumab for  lung cancer.	 Ann Oncol	Unable to provide
CANIT0001504	29207939	Clinical research	Non-small cell lung carcinoma, small cell lung carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Tocilizumab	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); Tocilizumab (DB06273); 	62	N/A	N/A	Tocilizumab may be a therapeutic option for the management of steroid refractory immune-related adverse events secondary of patient with non-small cell lung carcinoma to immune checkpoint blockade. There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.	Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). Clinical improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a single dose, while 38.2% required two, 8.8% required three and 1 patient required four doses. Twenty-seven doses were given in the inpatient setting (49.1%). Median time to discharge was four days (range 1-27). Seventy-four percent of patients were discharged home. For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 (WAC) during the 18 month study period.	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Apr	 Tocilizumab for the management of immune mediated adverse events secondary to  PD-1 blockade.	 J Oncol Pharm Pract	 BACKGROUND: Immune checkpoint inhibitors are poised to revolutionize the  management of a growing number of malignancies. Unfortunately, the management of   steroid-refractory immune mediated adverse events is based on a paucity of  randomized data and limited to single center experiences. Our initial experience   with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a  wide variety of irAEs. As a result, we adopted the use of tocilizumab for the  management of steroid refractory irAEs. METHODS: The character and clinical  course of irAEs were abstracted from the medical record and analyzed. The dose of  tocilizumab was 4 mg/kg given IV over one hour. C-reactive protein was drawn at  first nivolumab infusion and at q two weeks (and with irAEs) thereafter. Clinical  improvement was defined as either: documentation of resolution of symptoms or  hospital discharge within seven days. RESULTS: Of the initial 87 patients that  were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were  on corticosteroids. The majority (88.2%) were lung cancer patients. The index  grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/SIRS in 35.3%, cerebritis  in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and   immune mediated coagulopathy. Median time between first nivolumab and initiation   of tocilizumab was 76 days (range 1-429). There was a statistically significant  increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at  baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a  decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). Clinical  improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a  single dose, while 38.2% required two, 8.8% required three and 1 patient required  four doses. Twenty-seven doses were given in the inpatient setting (49.1%).  Median time to discharge was four days (range 1-27). Seventy-four percent of  patients were discharged home. For the 53 doses of tocilizumab that were  delivered when infliximab was an option, there was a cost savings of $141,048.72   (WAC) during the 18 month study period. CONCLUSIONS: Tocilizumab may be a  therapeutic option for the management of steroid refractory irAEs secondary to  immune checkpoint blockade. However, randomized trials are needed to better  elucidate the relative efficacy and safety of these agents.
CANIT0001505	29207939	Clinical research	Non-small cell lung carcinoma, small cell lung carcinoma etc.	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Tocilizumab	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); Tocilizumab (DB06273); 	9	N/A	N/A	Tocilizumab may be a therapeutic option for the management of steroid refractory immune-related adverse events secondary of patient with small cell lung carcinoma to immune checkpoint blockade. There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.	Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). Clinical improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a single dose, while 38.2% required two, 8.8% required three and 1 patient required four doses. Twenty-seven doses were given in the inpatient setting (49.1%). Median time to discharge was four days (range 1-27). Seventy-four percent of patients were discharged home. For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 (WAC) during the 18 month study period.	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Apr	 Tocilizumab for the management of immune mediated adverse events secondary to  PD-1 blockade.	 J Oncol Pharm Pract	 BACKGROUND: Immune checkpoint inhibitors are poised to revolutionize the  management of a growing number of malignancies. Unfortunately, the management of   steroid-refractory immune mediated adverse events is based on a paucity of  randomized data and limited to single center experiences. Our initial experience   with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a  wide variety of irAEs. As a result, we adopted the use of tocilizumab for the  management of steroid refractory irAEs. METHODS: The character and clinical  course of irAEs were abstracted from the medical record and analyzed. The dose of  tocilizumab was 4 mg/kg given IV over one hour. C-reactive protein was drawn at  first nivolumab infusion and at q two weeks (and with irAEs) thereafter. Clinical  improvement was defined as either: documentation of resolution of symptoms or  hospital discharge within seven days. RESULTS: Of the initial 87 patients that  were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were  on corticosteroids. The majority (88.2%) were lung cancer patients. The index  grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/SIRS in 35.3%, cerebritis  in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and   immune mediated coagulopathy. Median time between first nivolumab and initiation   of tocilizumab was 76 days (range 1-429). There was a statistically significant  increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at  baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a  decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). Clinical  improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a  single dose, while 38.2% required two, 8.8% required three and 1 patient required  four doses. Twenty-seven doses were given in the inpatient setting (49.1%).  Median time to discharge was four days (range 1-27). Seventy-four percent of  patients were discharged home. For the 53 doses of tocilizumab that were  delivered when infliximab was an option, there was a cost savings of $141,048.72   (WAC) during the 18 month study period. CONCLUSIONS: Tocilizumab may be a  therapeutic option for the management of steroid refractory irAEs secondary to  immune checkpoint blockade. However, randomized trials are needed to better  elucidate the relative efficacy and safety of these agents.
CANIT0001506	29214290	Clinical research	Elderly Patients With Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	92	N/A	A retrospective cohort study	Age might be associated with a better clinical outcome after treatment with immunotherapy in the real-life setting. In our cohort, older patients did not have more immune-related adverse events. Further studies are warranted to confirm our results and describe the underlying mechanisms involved.	N/A	N/A	N/A	Age (NCIT:C25150); 	Older than 65 years	Personal feature	 2018 Jan 1	 Association of Immunotherapy With Overall Survival in Elderly Patients With  Melanoma.	 JAMA Dermatol	 Importance: Melanoma treatment has been revolutionized with the development of  immune-based therapies that offer durable clinical responses in a subset of  patients. Clinical outcomes after treatment by immunotherapy can be influenced by  the host's immune system. The immune system is modified with age by age-related  immune dysfunction. Objective: To evaluate if age influences clinical outcome and  immune adverse events in patients treated by immunotherapy for metastatic  melanoma. Design, Setting, and Participants: This was a single-center cohort  analysis in patients treated with immunotherapy for metastatic melanoma between  January 2007 and February 2016, in the Lyon Sud Hospital, France. A total of 92  patients with metastatic melanoma treated with ipilimumab, nivolumab, or  pembrolizumab were retrospectively analyzed. Main Outcomes and Measures: Overall   survival, progression-free survival, and immune-related adverse events were  evaluated for each treatment line according to the patients' age. Results: A  total of 92 patients were eligible and included in this study for a total of 120   lines of treatment. Fifty-four patients were included in the cohort that was 65  years or younger (24 [44%] were female; mean [SD] age, 48.1 [12.5] years), and 38  patients were included in the cohort that was older than 65 years (12 [34%] were   female; mean [SD] age, 74.8 [6.9] years). Mean follow-up duration starting at  treatment initiation was 12.5 months. Patients older than 65 years treated with  immunotherapy had a better mean progression-free survival (4.8 vs 3.4 months; P =  .04) and overall survival (not reached vs 10.1 months; P = .009) than younger  patients in univariate analysis, and after adjusting on prognosis covariates.  This was particularly true with patients treated with anti-programmed cell death   protein 1. Common immune-related adverse effects were similar in both cohorts.  Conclusions and Relevance: Age might be associated with a better clinical outcome  after treatment with immunotherapy in the real-life setting. In our cohort, older  patients did not have more immune-related adverse events. Further studies are  warranted to confirm our results and describe the underlying mechanisms involved.
CANIT0001507	29214290	Clinical research	Elderly Patients With Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	92	N/A	A retrospective cohort study	Age might be associated with a better clinical outcome after treatment with immunotherapy in the real-life setting. In our cohort, older patients did not have more immune-related adverse events. Further studies are warranted to confirm our results and describe the underlying mechanisms involved.	N/A	N/A	N/A	Age (NCIT:C25150); 	Older than 65 years	Personal feature	 2018 Jan 1	 Association of Immunotherapy With Overall Survival in Elderly Patients With  Melanoma.	 JAMA Dermatol	 Importance: Melanoma treatment has been revolutionized with the development of  immune-based therapies that offer durable clinical responses in a subset of  patients. Clinical outcomes after treatment by immunotherapy can be influenced by  the host's immune system. The immune system is modified with age by age-related  immune dysfunction. Objective: To evaluate if age influences clinical outcome and  immune adverse events in patients treated by immunotherapy for metastatic  melanoma. Design, Setting, and Participants: This was a single-center cohort  analysis in patients treated with immunotherapy for metastatic melanoma between  January 2007 and February 2016, in the Lyon Sud Hospital, France. A total of 92  patients with metastatic melanoma treated with ipilimumab, nivolumab, or  pembrolizumab were retrospectively analyzed. Main Outcomes and Measures: Overall   survival, progression-free survival, and immune-related adverse events were  evaluated for each treatment line according to the patients' age. Results: A  total of 92 patients were eligible and included in this study for a total of 120   lines of treatment. Fifty-four patients were included in the cohort that was 65  years or younger (24 [44%] were female; mean [SD] age, 48.1 [12.5] years), and 38  patients were included in the cohort that was older than 65 years (12 [34%] were   female; mean [SD] age, 74.8 [6.9] years). Mean follow-up duration starting at  treatment initiation was 12.5 months. Patients older than 65 years treated with  immunotherapy had a better mean progression-free survival (4.8 vs 3.4 months; P =  .04) and overall survival (not reached vs 10.1 months; P = .009) than younger  patients in univariate analysis, and after adjusting on prognosis covariates.  This was particularly true with patients treated with anti-programmed cell death   protein 1. Common immune-related adverse effects were similar in both cohorts.  Conclusions and Relevance: Age might be associated with a better clinical outcome  after treatment with immunotherapy in the real-life setting. In our cohort, older  patients did not have more immune-related adverse events. Further studies are  warranted to confirm our results and describe the underlying mechanisms involved.
CANIT0001508	29214290	Clinical research	Elderly Patients With Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	92	N/A	A retrospective cohort study	Age might be associated with a better clinical outcome after treatment with immunotherapy in the real-life setting. In our cohort, older patients did not have more immune-related adverse events. Further studies are warranted to confirm our results and describe the underlying mechanisms involved.	N/A	N/A	N/A	Age (NCIT:C25150); 	Older than 65 years	Personal feature	 2018 Jan 1	 Association of Immunotherapy With Overall Survival in Elderly Patients With  Melanoma.	 JAMA Dermatol	 Importance: Melanoma treatment has been revolutionized with the development of  immune-based therapies that offer durable clinical responses in a subset of  patients. Clinical outcomes after treatment by immunotherapy can be influenced by  the host's immune system. The immune system is modified with age by age-related  immune dysfunction. Objective: To evaluate if age influences clinical outcome and  immune adverse events in patients treated by immunotherapy for metastatic  melanoma. Design, Setting, and Participants: This was a single-center cohort  analysis in patients treated with immunotherapy for metastatic melanoma between  January 2007 and February 2016, in the Lyon Sud Hospital, France. A total of 92  patients with metastatic melanoma treated with ipilimumab, nivolumab, or  pembrolizumab were retrospectively analyzed. Main Outcomes and Measures: Overall   survival, progression-free survival, and immune-related adverse events were  evaluated for each treatment line according to the patients' age. Results: A  total of 92 patients were eligible and included in this study for a total of 120   lines of treatment. Fifty-four patients were included in the cohort that was 65  years or younger (24 [44%] were female; mean [SD] age, 48.1 [12.5] years), and 38  patients were included in the cohort that was older than 65 years (12 [34%] were   female; mean [SD] age, 74.8 [6.9] years). Mean follow-up duration starting at  treatment initiation was 12.5 months. Patients older than 65 years treated with  immunotherapy had a better mean progression-free survival (4.8 vs 3.4 months; P =  .04) and overall survival (not reached vs 10.1 months; P = .009) than younger  patients in univariate analysis, and after adjusting on prognosis covariates.  This was particularly true with patients treated with anti-programmed cell death   protein 1. Common immune-related adverse effects were similar in both cohorts.  Conclusions and Relevance: Age might be associated with a better clinical outcome  after treatment with immunotherapy in the real-life setting. In our cohort, older  patients did not have more immune-related adverse events. Further studies are  warranted to confirm our results and describe the underlying mechanisms involved.
CANIT0001509	29220526	Case report	Merkel cell carcinoma	Merkel cell skin cancer	EFO:1001471	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	1	N/A	Case	To our knowledge, this is the first report of central  DI associated with anti-PD-L1 immunotherapy.  The patients received the anti-PD-L1 monoclonal antibody avelumab and achieved partial response with central diabetes insipidus. The patient's endocrinopathy was successfully managed by holding treatment with the immune checkpoint inhibitor. 	Central diabetes insipidus	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Central diabetes insipidus	Disease status	 2018 Feb 1	 Anti-PD-L1 Treatment Induced Central Diabetes Insipidus.	 J Clin Endocrinol Metab	 Context: Immune checkpoint inhibitors, including anti-programmed cell death  protein 1 (PD-1), anti-programmed cell death protein ligand 1 (PD-L1), and  anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) monoclonal antibodies, have  been widely used in cancer treatment. They are known to cause immune-related  adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary  hypophysitis with secondary hypopituitarism is a frequently reported irAE,  especially in patients receiving anti-CTLA4 treatment. In contrast, posterior  pituitary involvement, such as central diabetes insipidus (DI), is relatively  rare and is unreported in patients undergoing PD-1/PD-L1 blockade. Case  Description: We describe a case of a 73-year-old man with Merkel cell carcinoma  who received the anti-PD-L1 monoclonal antibody avelumab and achieved partial  response. The patient developed nocturia, polydipsia, and polyuria 3 months after  starting avelumab. Further laboratory testing revealed central DI. Avelumab was  held and he received desmopressin for the management of central DI. Within 6  weeks after discontinuation of avelumab, the patient's symptoms resolved and he  was eventually taken off desmopressin. The patient remained off avelumab and  there were no signs or symptoms of DI 2 months after the discontinuation of  desmopressin. Conclusion: To our knowledge, this is the first report of central  DI associated with anti-PD-L1 immunotherapy. The patient's endocrinopathy was  successfully managed by holding treatment with the immune checkpoint inhibitor.  This case highlights the importance of early screening and appropriate management  of hormonal irAEs in subjects undergoing treatment with immune checkpoint  inhibitors to minimize morbidity and mortality.CI  - Copyright (c) 2017 Endocrine Society
CANIT0001510	29229594	Clinical research	Relapsed or refractory Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	CD30 (P28908); PD-1 (Q15116); 	CD30; PD-1	Nivolumab plus brentuximab vedotin	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); brentuximab vedotin (DB08870); 	32	N/A	A phase I/II study	The combination of BV plus Nivo was an active and well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy.	Before autologous stem cell transplantation (ASCT), adverse events (AEs) occurred in 98% of patients, mostly grades 1 and 2. Infusion-related reactions (IRRs) occurred in 44% of patients overall, with 41% of patients experiencing an IRR during at least 1 infusion of brentuximab vedotin (BV).  Five patients (8%) were treated with systemic steroids for immune-related AEs. 	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Interim results of brentuximab vedotin in combination with nivolumab in patients   with relapsed or refractory Hodgkin lymphoma.	 Blood	 In this phase 1/2 study, brentuximab vedotin (BV) and nivolumab (Nivo)  administered in combination were evaluated as initial salvage therapy in patients  with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). Patients  received up to 4 cycles of combination treatment, with BV administered on day 1  and Nivo on day 8 of the first cycle. For cycles 2 to 4, BV and Nivo were both  administered on day 1. After study treatment, responses were evaluated by  investigators per the 2014 Lugano classification, and patients could proceed to  autologous stem cell transplantation (ASCT). Sixty-two patients were enrolled;  the complete response rate among all treated patients (n = 61) was 61%, with an  objective response rate of 82%. Before ASCT, adverse events (AEs) occurred in 98%  of patients, mostly grades 1 and 2. Infusion-related reactions (IRRs) occurred in  44% of patients overall, with 41% of patients experiencing an IRR during at least  1 infusion of BV. Five patients (8%) were treated with systemic steroids for  immune-related AEs. A reduction of peripheral T-cell subsets including regulatory  T cells was observed after the first dose of BV, and reduced serum levels of  thymus- and activation-regulated chemokine concurrent with an increase in  proinflammatory cytokines and chemokines were seen after the first BV plus Nivo  infusions. The combination of BV plus Nivo was an active and well-tolerated first  salvage regimen, potentially providing patients with R/R HL an alternative to  traditional chemotherapy. This trial was registered at www.clinicaltrials.gov as   #NCT02572167.CI  - (c) 2018 by The American Society of Hematology.
CANIT0001511	29232184	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	101	N/A	A retrospective cohort study	Image-guided transthoracic core needle biopsy is an effective method for obtaining tissue for PD-L1 expression analysis.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Apr	 Feasibility and Safety of Intrathoracic Biopsy and Repeat Biopsy for Evaluation  of Programmed Cell Death Ligand-1 Expression for Immunotherapy in Non-Small Cell   Lung Cancer.	 Radiology	 Purpose To determine feasibility and safety of biopsy and repeat biopsy for  assessment of programmed cell death ligand-1 (PD-L1) status. Materials and  Methods This retrospective analysis reviewed 101 patients who underwent  transthoracic core needle biopsy for the KEYNOTE-001 (MK-3475) clinical trial of   pembrolizumab, an antiprogrammed cell death-1 therapy for non-small cell lung  cancer, from May 2012 to September 2014. Sixty-one male patients (mean age, 66.1   years; range 36-83 years) and 40 female patients (mean age, 66.8 years; age  range, 36-90 years) were included. Data collected included population  characteristics, treatment history, target location, size, and depth from pleura.  Adequacy of the tissue sample for diagnostic testing and rates of biopsy-related   complications were assessed. Statistical analysis was performed by using  univariate and multivariate generalized linear models to determine significant  risk factors for biopsy complications. Results A total of 110 intrathoracic  biopsies were performed, and 101 (91.8%) were performed as repeat biopsies  subsequent to a previous percutaneous or bronchoscopic biopsy or previous  surgical biopsy or resection. More than 84.5% (93 of 110) of biopsies were  performed in patients who had undergone previous local or systemic therapy.  Specimens were adequate for evaluation of PD-L1 expression in 96.4% of biopsies.   Procedure-related complications occurred in 28 biopsies (25.4%); pneumothorax was  most common (22.7%). Overall mean number of core needle biopsy samples obtained  was 7.9 samples. Conclusion Image-guided transthoracic core needle biopsy is an  effective method for obtaining tissue for PD-L1 expression analysis. ((c)) RSNA,   2017.
CANIT0001512	29233789	Clinical research	Nonsmall-cell lung cancers	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	40	N/A	A retrospective cohort study	The 28-8, 22C3, and SP263 PD-L1 IHC assays showed equivalent predictive performance, whereas the SP142 assay showed lower predictive performance.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Mar	 Predictive Performance of Four Programmed Cell Death Ligand 1 Assay Systems on  Nivolumab Response in Previously Treated Patients with Non-Small Cell Lung  Cancer.	 J Thorac Oncol	 INTRODUCTION: Nivolumab has demonstrated efficacy against metastatic NSCLC. Four   programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems  are available for identification of responders among patients with NSCLC, and  these assays show some differing characteristics. Accordingly, in this study, we   evaluated the ability of these assays to identify responders to nivolumab  therapy. METHODS: We retrospectively analyzed patients with previously treated  advanced NSCLC, who received nivolumab between January 2016 and September 2016.  Specimens were stained using four PD-L1 IHC assays (28-8, 22C3, SP142, and  SP263). We classified patients as having test results that were strongly positive  (tumor proportion score [TPS] >/=50%), weakly positive (TPS 1%-49%), or negative   (TPS <1%). RESULTS: A total of 40 patients with NSCLC and their specimens were  analyzed. Analytical comparisons demonstrated good concordance of PD-L1-stained  tumor cells among the 28-8, 22C3, and SP263 assays (weighted kappa coefficient  0.64-0.71), whereas the SP142 assay showed lower concordance with other assays  (weighted kappa coefficient 0.39-0.55). Progression-free survival in patients  showing strongly positive PD-L1 staining classified by 28-8, 22C3, and SP263  assays was significantly longer than that in patients with a negative result for   PD-L1 staining. Predictive performance of response to nivolumab, as assessed by  receiver operating characteristic analysis, was also equivalent among the 28-8,  22C3, and SP263 assays (area under the curve 0.75-0.82), whereas the SP142 assay   exhibited lower predictive performance (area under the curve 0.68). CONCLUSIONS:   The 28-8, 22C3, and SP263 PD-L1 IHC assays showed equivalent predictive  performance, whereas the SP142 assay showed lower predictive performance.CI  - Copyright (c) 2017 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0001513	29237435	Clinical research	11 Lung cancer, 4 Malignant melanoma, 1 Pleural mesothelioma	Pleural mesothelioma	EFO:1000485	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus viscum album L. therapy	Viscum album L. therapy	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); Viscum album (NCIT:C14379); 	9	7	A retrospective cohort study	The overall AE rate of the study cohort is comparable to AE rates of ICM treatment in the literature. Our data indicate a first impression that concomitant VA application may not alter ICM-induced AE rates. However, the  nature of this study does not allow excluding possible immunological interactions between ICM and VA.	Of the sixteen patients receiving ICM, nine patients received additional VA (56%; ICM/VA group) and seven did not (44%; ICM group). No statistically significant differences were seen between groups with respect to AE-rates (67% ICM/VA versus 71% ICM). Adjusted multivariate regression analysis revealed that concomitant application of VA did not alter the AE rate in ICM treated patients. 85% of AEs were expected ICM reactions. No AEs of grade 3 or greater were documented for the total study cohort.	N/A	N/A	N/A	N/A	N/A	 2017 Dec 13	 Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum  album L. therapy in patients with advanced or metastatic cancer.	 BMC Complement Altern Med	 BACKGROUND: Despite improvement of tumour response rates in patients with  progressive and metastatic cancer, immune checkpoint inhibitors (ICM) induce  toxicities in cancer patients. Viscum album L. (VA, mistletoe) extracts are  applied as add-on cancer therapy especially in German speaking countries and  within integrative and anthroposophical concepts with the goal to improve quality  of life. The primary objective of this pilot observational cohort study was to  determine the rate of adverse events (AE) related to ICM therapy with and without  VA in patients with advanced or metastatic cancer in a certified Cancer Center.  METHODS: ICM or combined ICM/VA therapies were applied in patients with  progressive or metastatic cancer. AE rates of both therapy groups were compared.   RESULTS: A total of sixteen cancer patients were treated with ICM: nivolumab  (75%), ipilimumab (19%) or pembrolizumab (6%). The median age of the study  population was 64 years (IQR 57.8; 69.3); 44% were male. Of the sixteen patients   receiving ICM, nine patients received additional VA (56%; ICM/VA group) and seven  did not (44%; ICM group). No statistically significant differences were seen  between groups with respect to AE-rates (67% ICM/VA versus 71% ICM). Adjusted  multivariate regression analysis revealed that concomitant application of VA did   not alter the AE rate in ICM treated patients. 85% of AEs were expected ICM  reactions. No AEs of grade 3 or greater were documented for the total study  cohort. CONCLUSIONS: This is the first study evaluating the clinical safety  profile of ICM in combination with VA in patients with advanced or metastatic  cancer. The overall AE rate of the study cohort is comparable to AE rates of ICM   treatment in the literature. Our data indicate a first impression that  concomitant VA application may not alter ICM-induced AE rates. However, the  nature of this study does not allow excluding possible immunological interactions  between ICM and VA. Further prospective trials in larger study cohorts should  focus on the assessment of safety aspects, clinical efficacy and health related  quality of life in patients with combined ICM/VA therapy. TRIAL REGISTRATION:  DRKS00013335 , retrospectively registered (November 27th, 2017) at the German  Clinical Trials Register ( www.drks.de ).
CANIT0001514	29237435	Clinical research	11 Lung cancer, 4 Malignant melanoma, 1 Pleural mesothelioma	Pleural mesothelioma	EFO:1000485	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab plus viscum album L. therapy	Viscum album L. therapy	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); Viscum album (NCIT:C14379); 	9	7	A retrospective cohort study	The overall AE rate of the study cohort is comparable to AE rates of ICM treatment in the literature. Our data indicate a first impression that concomitant VA application may not alter ICM-induced AE rates. However, the  nature of this study does not allow excluding possible immunological interactions between ICM and VA.	Of the sixteen patients receiving ICM, nine patients received additional VA (56%; ICM/VA group) and seven did not (44%; ICM group). No statistically significant differences were seen between groups with respect to AE-rates (67% ICM/VA versus 71% ICM). Adjusted multivariate regression analysis revealed that concomitant application of VA did not alter the AE rate in ICM treated patients. 85% of AEs were expected ICM reactions. No AEs of grade 3 or greater were documented for the total study cohort.	N/A	N/A	N/A	N/A	N/A	 2017 Dec 13	 Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum  album L. therapy in patients with advanced or metastatic cancer.	 BMC Complement Altern Med	 BACKGROUND: Despite improvement of tumour response rates in patients with  progressive and metastatic cancer, immune checkpoint inhibitors (ICM) induce  toxicities in cancer patients. Viscum album L. (VA, mistletoe) extracts are  applied as add-on cancer therapy especially in German speaking countries and  within integrative and anthroposophical concepts with the goal to improve quality  of life. The primary objective of this pilot observational cohort study was to  determine the rate of adverse events (AE) related to ICM therapy with and without  VA in patients with advanced or metastatic cancer in a certified Cancer Center.  METHODS: ICM or combined ICM/VA therapies were applied in patients with  progressive or metastatic cancer. AE rates of both therapy groups were compared.   RESULTS: A total of sixteen cancer patients were treated with ICM: nivolumab  (75%), ipilimumab (19%) or pembrolizumab (6%). The median age of the study  population was 64 years (IQR 57.8; 69.3); 44% were male. Of the sixteen patients   receiving ICM, nine patients received additional VA (56%; ICM/VA group) and seven  did not (44%; ICM group). No statistically significant differences were seen  between groups with respect to AE-rates (67% ICM/VA versus 71% ICM). Adjusted  multivariate regression analysis revealed that concomitant application of VA did   not alter the AE rate in ICM treated patients. 85% of AEs were expected ICM  reactions. No AEs of grade 3 or greater were documented for the total study  cohort. CONCLUSIONS: This is the first study evaluating the clinical safety  profile of ICM in combination with VA in patients with advanced or metastatic  cancer. The overall AE rate of the study cohort is comparable to AE rates of ICM   treatment in the literature. Our data indicate a first impression that  concomitant VA application may not alter ICM-induced AE rates. However, the  nature of this study does not allow excluding possible immunological interactions  between ICM and VA. Further prospective trials in larger study cohorts should  focus on the assessment of safety aspects, clinical efficacy and health related  quality of life in patients with combined ICM/VA therapy. TRIAL REGISTRATION:  DRKS00013335 , retrospectively registered (November 27th, 2017) at the German  Clinical Trials Register ( www.drks.de ).
CANIT0001515	29237435	Clinical research	11 Lung cancer, 4 Malignant melanoma, 1 Pleural mesothelioma	Pleural mesothelioma	EFO:1000485	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus viscum album L. therapy	Viscum album L. therapy	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); Viscum album (NCIT:C14379); 	9	7	A retrospective cohort study	The overall AE rate of the study cohort is comparable to AE rates of ICM treatment in the literature. Our data indicate a first impression that concomitant VA application may not alter ICM-induced AE rates. However, the  nature of this study does not allow excluding possible immunological interactions between ICM and VA.	Of the sixteen patients receiving ICM, nine patients received additional VA (56%; ICM/VA group) and seven did not (44%; ICM group). No statistically significant differences were seen between groups with respect to AE-rates (67% ICM/VA versus 71% ICM). Adjusted multivariate regression analysis revealed that concomitant application of VA did not alter the AE rate in ICM treated patients. 85% of AEs were expected ICM reactions. No AEs of grade 3 or greater were documented for the total study cohort.	N/A	N/A	N/A	N/A	N/A	 2017 Dec 13	 Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum  album L. therapy in patients with advanced or metastatic cancer.	 BMC Complement Altern Med	 BACKGROUND: Despite improvement of tumour response rates in patients with  progressive and metastatic cancer, immune checkpoint inhibitors (ICM) induce  toxicities in cancer patients. Viscum album L. (VA, mistletoe) extracts are  applied as add-on cancer therapy especially in German speaking countries and  within integrative and anthroposophical concepts with the goal to improve quality  of life. The primary objective of this pilot observational cohort study was to  determine the rate of adverse events (AE) related to ICM therapy with and without  VA in patients with advanced or metastatic cancer in a certified Cancer Center.  METHODS: ICM or combined ICM/VA therapies were applied in patients with  progressive or metastatic cancer. AE rates of both therapy groups were compared.   RESULTS: A total of sixteen cancer patients were treated with ICM: nivolumab  (75%), ipilimumab (19%) or pembrolizumab (6%). The median age of the study  population was 64 years (IQR 57.8; 69.3); 44% were male. Of the sixteen patients   receiving ICM, nine patients received additional VA (56%; ICM/VA group) and seven  did not (44%; ICM group). No statistically significant differences were seen  between groups with respect to AE-rates (67% ICM/VA versus 71% ICM). Adjusted  multivariate regression analysis revealed that concomitant application of VA did   not alter the AE rate in ICM treated patients. 85% of AEs were expected ICM  reactions. No AEs of grade 3 or greater were documented for the total study  cohort. CONCLUSIONS: This is the first study evaluating the clinical safety  profile of ICM in combination with VA in patients with advanced or metastatic  cancer. The overall AE rate of the study cohort is comparable to AE rates of ICM   treatment in the literature. Our data indicate a first impression that  concomitant VA application may not alter ICM-induced AE rates. However, the  nature of this study does not allow excluding possible immunological interactions  between ICM and VA. Further prospective trials in larger study cohorts should  focus on the assessment of safety aspects, clinical efficacy and health related  quality of life in patients with combined ICM/VA therapy. TRIAL REGISTRATION:  DRKS00013335 , retrospectively registered (November 27th, 2017) at the German  Clinical Trials Register ( www.drks.de ).
CANIT0001516	29237657	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	N/A	Guillain-Barr syndrome	N/A	N/A	N/A	N/A	N/A	 2017 Dec 13	 Rare side effect of adjuvant ipilimumab after surgical resection of melanoma:  Guillain-Barre syndrome.	 BMJ Case Rep	 Guillain-Barre syndrome is a life-threatening neurological disorder that presents  with rapid ascending paralysis and areflexia. Guillain-Barre syndrome is  traditionally associated with infections from a gastrointestinal or respiratory  tract source. We report the case of a 71-year-old man with melanoma who was  treated with ipilimumab as adjuvant immunotherapy and subsequently developed  Guillain-Barre syndrome. The diagnosis was made clinically through physical exam   findings. He was successfully treated with a combination of intravenous  immunoglobulin therapy and corticosteroids.CI  - (c) BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)  2017. All rights reserved. No commercial use is permitted unless otherwise  expressly granted.
CANIT0001517	29237802	Clinical research	5 Melanoma, 3 Thyroid cancer, 2 Adrenocortical cancer, 2 Adenoid cystic cancer, 4 Leiomyosarcoma, 7 Hodgkin Lymphoma, 3 Renal cell carcinoma	Adenoid cystic carcinoma	EFO:0000231	Head and neck	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus lenalidomide	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); lenalidomide (DB00480); 	36	N/A	A phase I Dose-Escalation Study	Combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers.	DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). 	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Phase I Dose-Escalation Study of Anti-CTLA-4 Antibody Ipilimumab and Lenalidomide  in Patients with Advanced Cancers.	 Mol Cancer Ther	 Preclinical data suggest that combining a checkpoint inhibition with  immunomodulatory derivative can increase anticancer response. We designed a  dose-escalation study using a 3 + 3 design to determine the safety, maximum  tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting  toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3 mg/kg  intravenously every 28 days x 4) and lenalidomide (10-25 mg orally daily for 21  of 28 days until disease progression or unacceptable toxicity) in advanced  cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma,   4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior  therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and  lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3  patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other  than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3  thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis,   and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per  immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+  months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling,   a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of   the patients achieving a PR demonstrated intermediate mutation burden. In  conclusion, combination of ipilimumab and lenalidomide is well tolerated and  demonstrated preliminary signals of activity in patients with refractory Hodgkin   lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671-6. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001518	29237802	Clinical research	5 Melanoma, 3 Thyroid cancer, 2 Adrenocortical cancer, 2 Adenoid cystic cancer, 4 Leiomyosarcoma, 7 Hodgkin Lymphoma, 3 Renal cell carcinoma	Adrenal cortex carcinoma	EFO:1000796	Adrenal gland	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus lenalidomide	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); lenalidomide (DB00480); 	36	N/A	A phase I Dose-Escalation Study	Combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers.	DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). 	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Phase I Dose-Escalation Study of Anti-CTLA-4 Antibody Ipilimumab and Lenalidomide  in Patients with Advanced Cancers.	 Mol Cancer Ther	 Preclinical data suggest that combining a checkpoint inhibition with  immunomodulatory derivative can increase anticancer response. We designed a  dose-escalation study using a 3 + 3 design to determine the safety, maximum  tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting  toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3 mg/kg  intravenously every 28 days x 4) and lenalidomide (10-25 mg orally daily for 21  of 28 days until disease progression or unacceptable toxicity) in advanced  cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma,   4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior  therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and  lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3  patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other  than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3  thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis,   and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per  immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+  months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling,   a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of   the patients achieving a PR demonstrated intermediate mutation burden. In  conclusion, combination of ipilimumab and lenalidomide is well tolerated and  demonstrated preliminary signals of activity in patients with refractory Hodgkin   lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671-6. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001519	29237802	Clinical research	5 Melanoma, 3 Thyroid cancer, 2 Adrenocortical cancer, 2 Adenoid cystic cancer, 4 Leiomyosarcoma, 7 Hodgkin Lymphoma, 3 Renal cell carcinoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus lenalidomide	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); lenalidomide (DB00480); 	36	N/A	A phase I Dose-Escalation Study	Combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers.	DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). 	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Phase I Dose-Escalation Study of Anti-CTLA-4 Antibody Ipilimumab and Lenalidomide  in Patients with Advanced Cancers.	 Mol Cancer Ther	 Preclinical data suggest that combining a checkpoint inhibition with  immunomodulatory derivative can increase anticancer response. We designed a  dose-escalation study using a 3 + 3 design to determine the safety, maximum  tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting  toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3 mg/kg  intravenously every 28 days x 4) and lenalidomide (10-25 mg orally daily for 21  of 28 days until disease progression or unacceptable toxicity) in advanced  cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma,   4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior  therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and  lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3  patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other  than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3  thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis,   and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per  immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+  months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling,   a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of   the patients achieving a PR demonstrated intermediate mutation burden. In  conclusion, combination of ipilimumab and lenalidomide is well tolerated and  demonstrated preliminary signals of activity in patients with refractory Hodgkin   lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671-6. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001520	29237802	Clinical research	5 Melanoma, 3 Thyroid cancer, 2 Adrenocortical cancer, 2 Adenoid cystic cancer, 4 Leiomyosarcoma, 7 Hodgkin Lymphoma, 3 Renal cell carcinoma	Leiomyosarcoma	EFO:0000564	Soft tissue	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus lenalidomide	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); lenalidomide (DB00480); 	36	N/A	A phase I Dose-Escalation Study	Combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers.	DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). 	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Phase I Dose-Escalation Study of Anti-CTLA-4 Antibody Ipilimumab and Lenalidomide  in Patients with Advanced Cancers.	 Mol Cancer Ther	 Preclinical data suggest that combining a checkpoint inhibition with  immunomodulatory derivative can increase anticancer response. We designed a  dose-escalation study using a 3 + 3 design to determine the safety, maximum  tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting  toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3 mg/kg  intravenously every 28 days x 4) and lenalidomide (10-25 mg orally daily for 21  of 28 days until disease progression or unacceptable toxicity) in advanced  cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma,   4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior  therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and  lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3  patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other  than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3  thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis,   and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per  immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+  months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling,   a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of   the patients achieving a PR demonstrated intermediate mutation burden. In  conclusion, combination of ipilimumab and lenalidomide is well tolerated and  demonstrated preliminary signals of activity in patients with refractory Hodgkin   lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671-6. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001521	29237802	Clinical research	5 Melanoma, 3 Thyroid cancer, 2 Adrenocortical cancer, 2 Adenoid cystic cancer, 4 Leiomyosarcoma, 7 Hodgkin Lymphoma, 3 Renal cell carcinoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus lenalidomide	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); lenalidomide (DB00480); 	36	N/A	A phase I Dose-Escalation Study	Combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers.	DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). 	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Phase I Dose-Escalation Study of Anti-CTLA-4 Antibody Ipilimumab and Lenalidomide  in Patients with Advanced Cancers.	 Mol Cancer Ther	 Preclinical data suggest that combining a checkpoint inhibition with  immunomodulatory derivative can increase anticancer response. We designed a  dose-escalation study using a 3 + 3 design to determine the safety, maximum  tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting  toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3 mg/kg  intravenously every 28 days x 4) and lenalidomide (10-25 mg orally daily for 21  of 28 days until disease progression or unacceptable toxicity) in advanced  cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma,   4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior  therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and  lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3  patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other  than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3  thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis,   and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per  immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+  months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling,   a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of   the patients achieving a PR demonstrated intermediate mutation burden. In  conclusion, combination of ipilimumab and lenalidomide is well tolerated and  demonstrated preliminary signals of activity in patients with refractory Hodgkin   lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671-6. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001522	29237802	Clinical research	5 Melanoma, 3 Thyroid cancer, 2 Adrenocortical cancer, 2 Adenoid cystic cancer, 4 Leiomyosarcoma, 7 Hodgkin Lymphoma, 3 Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus lenalidomide	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); lenalidomide (DB00480); 	36	N/A	A phase I Dose-Escalation Study	Combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers.	DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). 	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Phase I Dose-Escalation Study of Anti-CTLA-4 Antibody Ipilimumab and Lenalidomide  in Patients with Advanced Cancers.	 Mol Cancer Ther	 Preclinical data suggest that combining a checkpoint inhibition with  immunomodulatory derivative can increase anticancer response. We designed a  dose-escalation study using a 3 + 3 design to determine the safety, maximum  tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting  toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3 mg/kg  intravenously every 28 days x 4) and lenalidomide (10-25 mg orally daily for 21  of 28 days until disease progression or unacceptable toxicity) in advanced  cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma,   4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior  therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and  lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3  patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other  than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3  thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis,   and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per  immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+  months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling,   a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of   the patients achieving a PR demonstrated intermediate mutation burden. In  conclusion, combination of ipilimumab and lenalidomide is well tolerated and  demonstrated preliminary signals of activity in patients with refractory Hodgkin   lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671-6. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001523	29237802	Clinical research	5 Melanoma, 3 Thyroid cancer, 2 Adrenocortical cancer, 2 Adenoid cystic cancer, 4 Leiomyosarcoma, 7 Hodgkin Lymphoma, 3 Renal cell carcinoma	Thyroid cancer	MONDO:0002108	Thyroid	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus lenalidomide	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); lenalidomide (DB00480); 	36	N/A	A phase I Dose-Escalation Study	Combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers.	DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). 	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Phase I Dose-Escalation Study of Anti-CTLA-4 Antibody Ipilimumab and Lenalidomide  in Patients with Advanced Cancers.	 Mol Cancer Ther	 Preclinical data suggest that combining a checkpoint inhibition with  immunomodulatory derivative can increase anticancer response. We designed a  dose-escalation study using a 3 + 3 design to determine the safety, maximum  tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting  toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3 mg/kg  intravenously every 28 days x 4) and lenalidomide (10-25 mg orally daily for 21  of 28 days until disease progression or unacceptable toxicity) in advanced  cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma,   4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior  therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and  lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3  patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other  than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3  thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis,   and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per  immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+  months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling,   a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of   the patients achieving a PR demonstrated intermediate mutation burden. In  conclusion, combination of ipilimumab and lenalidomide is well tolerated and  demonstrated preliminary signals of activity in patients with refractory Hodgkin   lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671-6. (c)2017 AACR.CI  - (c)2017 American Association for Cancer Research.
CANIT0001524	29248319	Clinical research	Metastatic urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus gemcitabine and cisplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); cisplatin (DB00515); gemcitabine (DB00441); 	36	N/A	A multicenter single arm phase II study	Ipilimumab plus gemcitabine and cisplatin (GC) did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones, and potential predictive biomarkers.	Grade 3 adverse events occurred in 81% of patients, the majority of which were hematologic. 	N/A	N/A	N/A	N/A	N/A	 2018 May	 Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with  Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on   Outcomes.	 Eur Urol	 BACKGROUND: Chemotherapy may exert immunomodulatory effects, thereby combining  favorably with the immune checkpoint blockade. The pharmacodynamic effects of  such combinations, and potential predictive biomarkers, remain unexplored.  OBJECTIVE: To determine the safety, efficacy, and immunomodulatory effects of  gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic   DNA damage response gene alterations on antitumor activity. DESIGN, SETTING, AND   PARTICIPANTS: Multicenter single arm phase 2 study enrolling 36  chemotherapy-naive patients with metastatic urothelial cancer. Peripheral blood  flow cytometry was performed serially on all patients and whole exome sequencing   of archival tumor tissue was performed on 28/36 patients. INTERVENTION: Two  cycles of GC followed by four cycles of GC plus ipilimumab. OUTCOME MEASUREMENTS   AND STATISTICAL ANALYSIS: The primary endpoint was 1-yr overall survival (OS).  Secondary endpoints included safety, objective response rate, and  progression-free survival. RESULTS AND LIMITATIONS: Grade >/=3 adverse events  occurred in 81% of patients, the majority of which were hematologic. The  objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence  interval: 51%). On exploratory analysis, there were no significant changes in the  composition and frequency of circulating immune cells after GC alone. However,  there was a significant expansion of circulating CD4 cells with the addition of  ipilimumab which correlated with improved survival. The response rate was  significantly higher in patients with deleterious somatic DNA damage response  mutations (sensitivity=47.6%, specificity=100%, positive predictive value=100%,  and negative predictive value=38.9%). Limitations are related to the sample size   and single-arm design. CONCLUSIONS: GC+ipilimumab did not achieve the primary  endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%.  However, within the context of a small single-arm trial, the results may inform  current approaches combining chemotherapy plus immunotherapy from the standpoint   of feasibility, appropriate cytotoxic backbones, and potential predictive  biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT01524991. PATIENT SUMMARY:   Combining chemotherapy and immune checkpoint blockade in patients with metastatic  urothelial cancer is feasible. Further studies are needed to refine optimal  combinations and evaluate tests that might identify patients most likely to  benefit.CI  - Copyright (c) 2017 European Association of Urology. Published by Elsevier B.V.  All rights reserved.
CANIT0001525	29248319	Clinical research	Metastatic urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus gemcitabine and cisplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); cisplatin (DB00515); gemcitabine (DB00441); 	36	N/A	A multicenter single arm phase II study	The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity=47.6%, specificity=100%, positive predictive value=100%, and negative predictive value=38.9%).	Grade 3 adverse events occurred in 81% of patients, the majority of which were hematologic. 	N/A	N/A	N/A	Deleterious somatic DNA damage response mutations	Mutational status	 2018 May	 Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with  Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on   Outcomes.	 Eur Urol	 BACKGROUND: Chemotherapy may exert immunomodulatory effects, thereby combining  favorably with the immune checkpoint blockade. The pharmacodynamic effects of  such combinations, and potential predictive biomarkers, remain unexplored.  OBJECTIVE: To determine the safety, efficacy, and immunomodulatory effects of  gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic   DNA damage response gene alterations on antitumor activity. DESIGN, SETTING, AND   PARTICIPANTS: Multicenter single arm phase 2 study enrolling 36  chemotherapy-naive patients with metastatic urothelial cancer. Peripheral blood  flow cytometry was performed serially on all patients and whole exome sequencing   of archival tumor tissue was performed on 28/36 patients. INTERVENTION: Two  cycles of GC followed by four cycles of GC plus ipilimumab. OUTCOME MEASUREMENTS   AND STATISTICAL ANALYSIS: The primary endpoint was 1-yr overall survival (OS).  Secondary endpoints included safety, objective response rate, and  progression-free survival. RESULTS AND LIMITATIONS: Grade >/=3 adverse events  occurred in 81% of patients, the majority of which were hematologic. The  objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence  interval: 51%). On exploratory analysis, there were no significant changes in the  composition and frequency of circulating immune cells after GC alone. However,  there was a significant expansion of circulating CD4 cells with the addition of  ipilimumab which correlated with improved survival. The response rate was  significantly higher in patients with deleterious somatic DNA damage response  mutations (sensitivity=47.6%, specificity=100%, positive predictive value=100%,  and negative predictive value=38.9%). Limitations are related to the sample size   and single-arm design. CONCLUSIONS: GC+ipilimumab did not achieve the primary  endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%.  However, within the context of a small single-arm trial, the results may inform  current approaches combining chemotherapy plus immunotherapy from the standpoint   of feasibility, appropriate cytotoxic backbones, and potential predictive  biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT01524991. PATIENT SUMMARY:   Combining chemotherapy and immune checkpoint blockade in patients with metastatic  urothelial cancer is feasible. Further studies are needed to refine optimal  combinations and evaluate tests that might identify patients most likely to  benefit.CI  - Copyright (c) 2017 European Association of Urology. Published by Elsevier B.V.  All rights reserved.
CANIT0001526	29248319	Clinical research	Metastatic urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus gemcitabine and cisplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); cisplatin (DB00515); gemcitabine (DB00441); 	36	N/A	A multicenter single arm phase II study	There was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival.	Grade 3 adverse events occurred in 81% of patients, the majority of which were hematologic. 	N/A	N/A	N/A	Expansion of circulating CD4 cells	Cell percentage/counts in blood	 2018 May	 Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with  Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on   Outcomes.	 Eur Urol	 BACKGROUND: Chemotherapy may exert immunomodulatory effects, thereby combining  favorably with the immune checkpoint blockade. The pharmacodynamic effects of  such combinations, and potential predictive biomarkers, remain unexplored.  OBJECTIVE: To determine the safety, efficacy, and immunomodulatory effects of  gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic   DNA damage response gene alterations on antitumor activity. DESIGN, SETTING, AND   PARTICIPANTS: Multicenter single arm phase 2 study enrolling 36  chemotherapy-naive patients with metastatic urothelial cancer. Peripheral blood  flow cytometry was performed serially on all patients and whole exome sequencing   of archival tumor tissue was performed on 28/36 patients. INTERVENTION: Two  cycles of GC followed by four cycles of GC plus ipilimumab. OUTCOME MEASUREMENTS   AND STATISTICAL ANALYSIS: The primary endpoint was 1-yr overall survival (OS).  Secondary endpoints included safety, objective response rate, and  progression-free survival. RESULTS AND LIMITATIONS: Grade >/=3 adverse events  occurred in 81% of patients, the majority of which were hematologic. The  objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence  interval: 51%). On exploratory analysis, there were no significant changes in the  composition and frequency of circulating immune cells after GC alone. However,  there was a significant expansion of circulating CD4 cells with the addition of  ipilimumab which correlated with improved survival. The response rate was  significantly higher in patients with deleterious somatic DNA damage response  mutations (sensitivity=47.6%, specificity=100%, positive predictive value=100%,  and negative predictive value=38.9%). Limitations are related to the sample size   and single-arm design. CONCLUSIONS: GC+ipilimumab did not achieve the primary  endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%.  However, within the context of a small single-arm trial, the results may inform  current approaches combining chemotherapy plus immunotherapy from the standpoint   of feasibility, appropriate cytotoxic backbones, and potential predictive  biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT01524991. PATIENT SUMMARY:   Combining chemotherapy and immune checkpoint blockade in patients with metastatic  urothelial cancer is feasible. Further studies are needed to refine optimal  combinations and evaluate tests that might identify patients most likely to  benefit.CI  - Copyright (c) 2017 European Association of Urology. Published by Elsevier B.V.  All rights reserved.
CANIT0001527	29254497	Clinical research	High grade gliomas	Glioma	EFO:0005543	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	A retrospective cohort study	While response rates are low, a few patients had a prolonged PFS. Pembrolizumab was tolerated with few serious toxicities, even in patients receiving concomitant therapy.	PD-1 inhibitor related adverse events included LFT elevations, hypothyroidism, diarrhea, myalgias/arthralgias, and rash.	N/A	N/A	N/A	N/A	N/A	 2017 Dec 19	 Retrospective review of safety and efficacy of programmed cell death-1 inhibitors  in refractory high grade gliomas.	 J Immunother Cancer	 BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression has been reported  in up to 61% of high grade gliomas (HGG). The purpose of this study was to  describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs.  METHODS: This Institutional Review Board approved single center retrospective  study included adult patients with pathologically confirmed HGG who received a  PD-1 inhibitor from 9/2014-10/2016 outside of a clinical trial at Memorial Sloan   Kettering Cancer Center. RESULTS: Twenty five HGG patients received pembrolizumab  as part of a compassionate use program. Median age was 50 years (range 30-72);  44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2  anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma  (4%). Median prior lines of treatments were 4 (range 1-9). Nineteen (76%)  previously failed bevacizumab. Median KPS was 80 (range 50-100). Concurrent  treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2  (8%) patients. Median number of doses administered was 3 (range 1-14). Outcomes  were assessed in 24 patients. PD-1 inhibitor related adverse events included LFT   elevations, hypothyroidism, diarrhea, myalgias/arthralgias, and rash. Best  radiographic response was partial response (n = 2), stable disease (n = 5), and  progressive disease (n = 17). Median progression free survival (PFS) was 1.4  months (range 0.2-9.4) and median overall survival (OS) was 4 months (range  0.5-13.8). Three-month PFS was 12% and 6-month OS was 28%. CONCLUSION: While  response rates are low, a few patients had a prolonged PFS. Pembrolizumab was  tolerated with few serious toxicities, even in patients receiving concomitant  therapy.
CANIT0001528	29254501	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Diabetic ketoacidosis	N/A	N/A	N/A	N/A	N/A	 2017 Dec 19	 Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic  melanoma.	 J Immunother Cancer	 BACKGROUND: There has been a significant improvement in survival of advanced  malignancies with the advent of checkpoint inhibitors. These newer treatment  modalities come with a wide spectrum of unique side effects, termed immune  related adverse events (irAE), ranging from mild skin rash to severe colitis.  Included in that spectrum is the rare side effect of autoimmune diabetes  mellitus. Despite a few case reports illustrating the incidence of autoimmune  diabetes associated with immunotherapy, there has not been much mentioned about  exacerbation or acceleration of hyperglycemia in non-autoimmune settings leading   to de novo diagnosis of type 2 diabetes mellitus. CASE PRESENTATION: We report  the case of a 42 year old man with metastatic melanoma and no prior history of  diabetes mellitus, who presented with diabetic ketoacidosis (DKA) after 3 cycles   of combination checkpoint inhibitor therapy using nivolumab and ipilimumab. New  onset diabetes mellitus was diagnosed on the basis of elevated hemoglobin A1c, in  the absence of prior personal or family history. Autoimmune or type 1 diabetes  mellitus was ruled out with normal levels of anti-glutamic acid decarboxylase 65   (GAD65) antibody, zinc transporter 8 (ZnT8) antibody, and islet antigen-2 (IA-2)   antibody. CONCLUSIONS: This case report highlights the importance of recognizing   rare but serious adverse events related to immunotherapy and incorporation of  appropriate tools for early identification and management in national cancer  treatment guidelines.
CANIT0001529	29254508	Basic research	Hepatocellular carcinoma (HCC) cell line HepG2, the chronic myelogenous leukemia cell line K-562, and primary human hepatocytes; murine cancer cell lines by assaying the growth of CT26, LLC, B16, and 4T1 cell lines	Colorectal cancer	EFO:0005842	Intestines	ARG1 (P05089); 	ARG1; 	CB-1158	N/A	Immune checkpoint therapy	CB-1158 (DB15286); 	Cell lines/ animal models	N/A	Basic research	Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with  CB-1158 shifts the immune landscape toward a pro-inflammatory environment, blunting myeloid cell-mediated immune evasion and reducing tumor growth. Furthermore, our results suggest that arginase blockade by CB-1158 may be an  effective therapy in multiple types of cancer and combining CB-1158 with  standard-of-care chemotherapy or other immunotherapies may yield improved  clinical responses.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2017 Dec 19	 Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression  in the tumor microenvironment.	 J Immunother Cancer	 BACKGROUND: Myeloid cells are an abundant leukocyte in many types of tumors and  contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a  defining feature of immunosuppressive myeloid cells and leads to depletion of  L-arginine, a nutrient required for T cell and natural killer (NK) cell  proliferation. Here we use CB-1158, a potent and orally-bioavailable  small-molecule inhibitor of arginase, to investigate the role of Arg1 in  regulating anti-tumor immunity. METHODS: CB-1158 was tested for the ability to  block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for   tumor growth inhibition in syngeneic mouse models of cancer as a single agent and  in combination with other therapies. Tumors from animals treated with CB-1158  were profiled for changes in immune cell subsets, expression of immune-related  genes, and cytokines. Human tumor tissue microarrays were probed for Arg1  expression by immunohistochemistry and immunofluorescence. Cancer patient plasma   samples were assessed for Arg1 protein and L-arginine by ELISA and mass  spectrometry, respectively. RESULTS: CB-1158 blocked myeloid cell-mediated  suppression of T cell proliferation in vitro and reduced tumor growth in multiple  mouse models of cancer, as a single agent and in combination with checkpoint  blockade, adoptive T cell therapy, adoptive NK cell therapy, and the chemotherapy  agent gemcitabine. Profiling of the tumor microenvironment revealed that CB-1158   increased tumor-infiltrating CD8(+) T cells and NK cells, inflammatory cytokines,  and expression of interferon-inducible genes. Patient tumor samples from multiple  histologies expressed an abundance of tumor-infiltrating Arg1(+) myeloid cells.  Plasma samples from cancer patients exhibited elevated Arg1 and reduced  L-arginine compared to healthy volunteers. CONCLUSIONS: These results demonstrate  that Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with  CB-1158 shifts the immune landscape toward a pro-inflammatory environment,  blunting myeloid cell-mediated immune evasion and reducing tumor growth.  Furthermore, our results suggest that arginase blockade by CB-1158 may be an  effective therapy in multiple types of cancer and combining CB-1158 with  standard-of-care chemotherapy or other immunotherapies may yield improved  clinical responses.
CANIT0001530	29254508	Basic research	Hepatocellular carcinoma (HCC) cell line HepG2, the chronic myelogenous leukemia cell line K-562, and primary human hepatocytes; murine cancer cell lines by assaying the growth of CT26, LLC, B16, and 4T1 cell lines	Hepatocellular carcinoma	EFO:0000182	Liver	ARG1 (P05089); 	ARG1; 	CB-1158	N/A	Immune checkpoint therapy	CB-1158 (DB15286); 	Cell lines/ animal models	N/A	Basic research	Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with  CB-1158 shifts the immune landscape toward a pro-inflammatory environment, blunting myeloid cell-mediated immune evasion and reducing tumor growth. Furthermore, our results suggest that arginase blockade by CB-1158 may be an  effective therapy in multiple types of cancer and combining CB-1158 with  standard-of-care chemotherapy or other immunotherapies may yield improved  clinical responses.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2017 Dec 19	 Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression  in the tumor microenvironment.	 J Immunother Cancer	 BACKGROUND: Myeloid cells are an abundant leukocyte in many types of tumors and  contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a  defining feature of immunosuppressive myeloid cells and leads to depletion of  L-arginine, a nutrient required for T cell and natural killer (NK) cell  proliferation. Here we use CB-1158, a potent and orally-bioavailable  small-molecule inhibitor of arginase, to investigate the role of Arg1 in  regulating anti-tumor immunity. METHODS: CB-1158 was tested for the ability to  block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for   tumor growth inhibition in syngeneic mouse models of cancer as a single agent and  in combination with other therapies. Tumors from animals treated with CB-1158  were profiled for changes in immune cell subsets, expression of immune-related  genes, and cytokines. Human tumor tissue microarrays were probed for Arg1  expression by immunohistochemistry and immunofluorescence. Cancer patient plasma   samples were assessed for Arg1 protein and L-arginine by ELISA and mass  spectrometry, respectively. RESULTS: CB-1158 blocked myeloid cell-mediated  suppression of T cell proliferation in vitro and reduced tumor growth in multiple  mouse models of cancer, as a single agent and in combination with checkpoint  blockade, adoptive T cell therapy, adoptive NK cell therapy, and the chemotherapy  agent gemcitabine. Profiling of the tumor microenvironment revealed that CB-1158   increased tumor-infiltrating CD8(+) T cells and NK cells, inflammatory cytokines,  and expression of interferon-inducible genes. Patient tumor samples from multiple  histologies expressed an abundance of tumor-infiltrating Arg1(+) myeloid cells.  Plasma samples from cancer patients exhibited elevated Arg1 and reduced  L-arginine compared to healthy volunteers. CONCLUSIONS: These results demonstrate  that Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with  CB-1158 shifts the immune landscape toward a pro-inflammatory environment,  blunting myeloid cell-mediated immune evasion and reducing tumor growth.  Furthermore, our results suggest that arginase blockade by CB-1158 may be an  effective therapy in multiple types of cancer and combining CB-1158 with  standard-of-care chemotherapy or other immunotherapies may yield improved  clinical responses.
CANIT0001531	29254508	Basic research	Hepatocellular carcinoma (HCC) cell line HepG2, the chronic myelogenous leukemia cell line K-562, and primary human hepatocytes; murine cancer cell lines by assaying the growth of CT26, LLC, B16, and 4T1 cell lines	Melanoma	EFO:0000756	Skin	ARG1 (P05089); 	ARG1; 	CB-1158	N/A	Immune checkpoint therapy	CB-1158 (DB15286); 	Cell lines/ animal models	N/A	Basic research	Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with  CB-1158 shifts the immune landscape toward a pro-inflammatory environment, blunting myeloid cell-mediated immune evasion and reducing tumor growth. Furthermore, our results suggest that arginase blockade by CB-1158 may be an  effective therapy in multiple types of cancer and combining CB-1158 with  standard-of-care chemotherapy or other immunotherapies may yield improved  clinical responses.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2017 Dec 19	 Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression  in the tumor microenvironment.	 J Immunother Cancer	 BACKGROUND: Myeloid cells are an abundant leukocyte in many types of tumors and  contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a  defining feature of immunosuppressive myeloid cells and leads to depletion of  L-arginine, a nutrient required for T cell and natural killer (NK) cell  proliferation. Here we use CB-1158, a potent and orally-bioavailable  small-molecule inhibitor of arginase, to investigate the role of Arg1 in  regulating anti-tumor immunity. METHODS: CB-1158 was tested for the ability to  block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for   tumor growth inhibition in syngeneic mouse models of cancer as a single agent and  in combination with other therapies. Tumors from animals treated with CB-1158  were profiled for changes in immune cell subsets, expression of immune-related  genes, and cytokines. Human tumor tissue microarrays were probed for Arg1  expression by immunohistochemistry and immunofluorescence. Cancer patient plasma   samples were assessed for Arg1 protein and L-arginine by ELISA and mass  spectrometry, respectively. RESULTS: CB-1158 blocked myeloid cell-mediated  suppression of T cell proliferation in vitro and reduced tumor growth in multiple  mouse models of cancer, as a single agent and in combination with checkpoint  blockade, adoptive T cell therapy, adoptive NK cell therapy, and the chemotherapy  agent gemcitabine. Profiling of the tumor microenvironment revealed that CB-1158   increased tumor-infiltrating CD8(+) T cells and NK cells, inflammatory cytokines,  and expression of interferon-inducible genes. Patient tumor samples from multiple  histologies expressed an abundance of tumor-infiltrating Arg1(+) myeloid cells.  Plasma samples from cancer patients exhibited elevated Arg1 and reduced  L-arginine compared to healthy volunteers. CONCLUSIONS: These results demonstrate  that Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with  CB-1158 shifts the immune landscape toward a pro-inflammatory environment,  blunting myeloid cell-mediated immune evasion and reducing tumor growth.  Furthermore, our results suggest that arginase blockade by CB-1158 may be an  effective therapy in multiple types of cancer and combining CB-1158 with  standard-of-care chemotherapy or other immunotherapies may yield improved  clinical responses.
CANIT0001532	29258674	Clinical research	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Neoadjuvant chemotherapy plus ipilimumab followed by surgery	Preoperative chemotherapy without ipilimumab followed by surgery	Immune checkpoint therapy followed by Surgery	Neoadjuvant chemotherapy (NCIT:C15665); surgery (NCIT:C17173); preoperative chemotherapy without ipilimumab (NCIT:C68770); surgery (NCIT:C17173); ipilimumab (DB06186); 	13	42	 an open label  phase II trial	This report is the first to demonstrate the safety and feasibility of surgical resection after treatment with ipilimumab and chemotherapy in stage II-IIIA non-small-cell lung cancer.	Immune-related adverse events considered to be related to ipilimumab were as follows: grade 2 pneumonitis (n = 1, 4%); grade 3 adrenal insufficiency (n = 4, 17%); and diarrhea/colitis (grade 1 or 2, n = 6, 25%; grade 3, n = 3, 13%).	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Surgical Outcomes After Neoadjuvant Chemotherapy and Ipilimumab for Non-Small  Cell Lung Cancer.	 Ann Thorac Surg	 BACKGROUND: The objective of this study was to evaluate the safety and  feasibility of using neoadjuvant chemotherapy plus ipilimumab followed by surgery  as a treatment strategy for stage II-IIIA non-small cell lung cancer. METHODS:  From 2013 to 2017, postoperative data from patients who underwent surgery after  neoadjuvant chemotherapy plus ipilimumab in the TOP1201 trial, an open label  phase II trial (NCT01820754), were prospectively collected. The surgical outcomes  from TOP1201 were compared with outcomes in a historical cohort of patients  receiving standard preoperative chemotherapy followed by surgery identified from   our institution's prospectively collected thoracic surgery database. RESULTS: In   the TOP1201 trial, 13 patients were treated with preoperative chemotherapy and  ipilimumab followed by surgery. In the historical cohort, 42 patients received  preoperative chemotherapy by a platinum doublet regimen preoperative chemotherapy  by a platinum doublet regimen without ipilimumab followed by lobectomy or  pneumonectomy. The 30-day mortality in both groups was 0%. The most frequently  occurring perioperative complications in the TOP1201 group were prolonged air  leak (n = 2, 15%) and urinary tract infection (n = 2, 15%). The most common  perioperative complication in the preoperative chemotherapy alone group was  atrial fibrillation (n = 6, 14%). One patient (8%) had atrial fibrillation in the  TOP1201 group. There was no apparent increased occurrence of adverse surgical  outcomes for patients in the TOP1201 group compared with patients receiving  standard of care neoadjuvant chemotherapy alone before surgery for stage II-IIIA   non-small cell lung cancer. CONCLUSIONS: This report is the first to demonstrate   the safety and feasibility of surgical resection after treatment with ipilimumab   and chemotherapy in stage II-IIIA non-small-cell lung cancer.CI  - Copyright (c) 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc.  All rights reserved.
CANIT0001533	29260625	Case report	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Immune-mediated thrombocytopenia and hypothyroidism	N/A	N/A	N/A	N/A	N/A	 2018 Feb	 Immune-mediated thrombocytopenia and hypothyroidism in a lung cancer patient  treated with nivolumab.	 Immunotherapy	 Patients treated with immune checkpoint inhibitors can develop various  immunological complications; however, few cases of immune thrombocytopenia  occurring in association with the administration of these agents have so far been  reported. We herein report the case of a 62-year-old Japanese man with  non-small-cell lung cancer who developed immune thrombocytopenia and  hypothyroidism during nivolumab therapy. After the second administration of the  drug, his peripheral blood platelet count rapidly decreased to 1.6 x 10(4)/mul  with a petechial rash and symptoms associated with a low thyroid function.  Nivolumab-induced immune thrombocytopenia and hypothyroidism were suspected based  on the presence of platelet-associated IgG, an increased level of autoantibodies   to thyroglobulin and thyroid peroxidase and an enlarged thyroid gland. The  patient eventually made a full recovery after treatment with oral prednisolone  and levothyroxine. Further investigations and the accumulation of data are  necessary to elucidate the precise mechanisms underlying the autoimmune responses  that occur in patients treated with immune checkpoint inhibitors.
CANIT0001534	29268948	Clinical research	Locally advanced or metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Chemotherapy	Immune checkpoint therapy	Atezolizumab (DB11595); chemotherapy (NCIT:C15632); 	467	464	A multicentre, open-label, phase III randomised controlled	Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was  favourable compared with chemotherapy, Exploratory analysis of the  intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting.	In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3-4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Feb 24	 Atezolizumab versus chemotherapy in patients with platinum-treated locally  advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre,  open-label, phase 3 randomised controlled trial.	 Lancet	 BACKGROUND: Few options exist for patients with locally advanced or metastatic  urothelial carcinoma after progression with platinum-based chemotherapy. We aimed  to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1  [PD-L1]) versus chemotherapy in this patient population. METHODS: We conducted  this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at  217 academic medical centres and community oncology practices mainly in Europe,  North America, and the Asia-Pacific region. Patients (aged >/=18 years) with  metastatic urothelial carcinoma who had progressed after platinum-based  chemotherapy were randomly assigned (1:1), via an interactive voice and web  response system with a permuted block design (block size of four), to receive  atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m(2),  paclitaxel 175 mg/m(2), or 75 mg/m(2) docetaxel) intravenously every 3 weeks.  Randomisation was stratified by PD-L1 expression (expression on <1% [IC0] or 1%  to <5% [IC1] of tumour-infiltrating immune cells vs >/=5% of tumour-infiltrating   immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver  metastases (yes vs no), and number of prognostic factors (none vs one, two, or  three). Patients and investigators were aware of group allocation. Patients,  investigators, and the sponsor were masked to PD-L1 expression status. The  primary endpoint of overall survival was tested hierarchically in prespecified  populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat  population. This study, which is ongoing but not recruiting participants, is  registered with ClinicalTrials.gov, number NCT02302807. FINDINGS: Between Jan 13,  2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to  receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population  (n=234), overall survival did not differ significantly between patients in the  atezolizumab group and those in the chemotherapy group (median 11.1 months [95%  CI 8.6-15.5; n=116] vs 10.6 months [8.4-12.2; n=118]; stratified hazard ratio  [HR] 0.87, 95% CI 0.63-1.21; p=0.41), thus precluding further formal statistical   analysis. Confirmed objective response rates were similar between treatment  groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an  objective response in the atezolizumab group compared with 25 (22%) of 116  patients in the chemotherapy group. Duration of response was numerically longer  in the atezolizumab group than in the chemotherapy group (median 15.9 months [95%  CI 10.4 to not estimable] vs 8.3 months [5.6-13.2]; HR 0.57, 95% CI 0.26-1.26).  In the intention-to-treat population, patients receiving atezolizumab had fewer  grade 3-4 treatment-related adverse events than did those receiving chemotherapy   (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading   to treatment discontinuation (34 [7%] vs 78 [18%] patients). INTERPRETATION:  Atezolizumab was not associated with significantly longer overall survival than  chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma  overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was  favourable compared with chemotherapy, Exploratory analysis of the  intention-to-treat population showed well-tolerated, durable responses in line  with previous phase 2 data for atezolizumab in this setting. FUNDING: F  Hoffmann-La Roche, Genentech.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001535	29269008	Clinical research	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	73	N/A	N/A	Our findings suggested that the density of PD-L1-positive CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a diagnostic factor to supplement PD-L1 expression in tumor cells and predict the response to PD-1/PD-L1 blockade immunotherapy in NSCLC.	N/A	N/A	N/A	Treg cells (CL:0000815); PD-L1 (Q9NZQ7); CD25 (P01589); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	PD-L1-positive CD4-positive CD25-positive Tregs	Gene expression signature on/in immune cell	 2018 Apr	 Stromal PD-L1-Positive Regulatory T cells and PD-1-Positive CD8-Positive T cells   Define the Response of Different Subsets of Non-Small Cell Lung Cancer to  PD-1/PD-L1 Blockade Immunotherapy.	 J Thorac Oncol	 INTRODUCTION: Inhibition of programmed cell death-1 (PD-1) and its ligand  programmed death ligand 1 (PD-L1) by using an immune checkpoint inhibitor has  emerged as a promising immunotherapy for NSCLC. The correlation of PD-L1  expression in tumor cells with treatment outcomes has been reported in many  pivotal trials; however, the relationship remains unclear. Here, we demonstrate  that those patients with both high density of PD-1-positive CD8 and  PD-L1-positive CD4-positive CD25-positive (PD-1(hi) PD-L1(hi)) regulatory T cells  (Tregs) have a better response to PD1/PD-L1 blockade. METHODS: In our study  between April 1, 2014, and May 30, 2017, a total of 73 NSCLC peripheral blood  samples and fresh tumor specimens were collected for study. Of these, 42 large  (10-mm(3)) fresh tumor specimens were obtained from surgical procedures and  checked for expression of immunology biomarkers, including PD-L1, PD-1, CD8, CD4,  and CD25, in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow  cytometry, immunohistochemistry, and immunofluorescence (IF). Moreover, 31 small   biopsy specimens from patients who received immunotherapy (pembrolizumab or  nivolumab) were analyzed by immunohistochemistry and IF. The correlation between   flow cytometry and IF detected for TILs' density was evaluated by Spearman's rank  correlation test; the primary end point was progression-free survival. For the  PD-1/PD-L1 blockade assay, the TILs and peripheral blood mononuclear CD8 T cells   were cultured (1x10(5) per well) with anti-PD-1 (clone MIH4), anti-PD-L1 (clone  MIH1). The cytotoxic activity of TILs in killing NSCLC cells after stimulation by  anti-PD-1 and anti-PD-L1 was measured by a conventional (51)Cr release assay.  RESULTS: We first identified a population of high-PD-L1-expressing CD25-positive   CD4-positive T cells (PD-L1(hi) Tregs) in the tumor microenvironment. The  frequency of PD-L1(hi) Tregs was higher in tumor tissue (mean 48.6 +/- 14.3% in  CD25-positive CD3-positive CD4-positive T cells) than in blood (mean 35.4 +/-  10.2% in CD25-positive CD3-positive CD4-positive T cells) and normal tissue (mean  38.6 +/- 9.7% in CD25-positive CD3-positive CD4-positive T cells) (p < 0.05), as   determined by flow cytometry. The frequency of PD-L1(hi) Tregs was positively  correlated with PD-1-positive CD8 in Tregs. In addition, the TILs from these  patients (PD-1(hi) PD-L1(hi)) showed PD-1/PD-L1 pathway dependence and could  induce a greater killing effect of TILs by PD-1/PD-L1 blockade treatment. The  patients with PD-L1-positive NSCLC with PD-1(hi) PD-L1(hi) TILs showed a better  clinical outcome than those with a low frequency of PD-1(hi) CD8 or PD-L1(hi)  Tregs (median progression-free survival not reached versus 2 months).  CONCLUSIONS: Our findings suggested that the density of PD-L1-positive  CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a  diagnostic factor to supplement PD-L1 expression in tumor cells and predict the  response to PD-1/PD-L1 blockade immunotherapy in NSCLC.CI  - Copyright (c) 2017 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0001536	29269008	Clinical research	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	73	N/A	N/A	Our findings suggested that the density of PD-L1-positive CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a diagnostic factor to supplement PD-L1 expression in tumor cells and predict the response to PD-1/PD-L1 blockade immunotherapy in NSCLC.	N/A	N/A	N/A	Treg cells (CL:0000815); PD-L1 (Q9NZQ7); CD25 (P01589); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	PD-L1-positive CD4-positive CD25-positive Tregs	Gene expression signature on/in immune cell	 2018 Apr	 Stromal PD-L1-Positive Regulatory T cells and PD-1-Positive CD8-Positive T cells   Define the Response of Different Subsets of Non-Small Cell Lung Cancer to  PD-1/PD-L1 Blockade Immunotherapy.	 J Thorac Oncol	 INTRODUCTION: Inhibition of programmed cell death-1 (PD-1) and its ligand  programmed death ligand 1 (PD-L1) by using an immune checkpoint inhibitor has  emerged as a promising immunotherapy for NSCLC. The correlation of PD-L1  expression in tumor cells with treatment outcomes has been reported in many  pivotal trials; however, the relationship remains unclear. Here, we demonstrate  that those patients with both high density of PD-1-positive CD8 and  PD-L1-positive CD4-positive CD25-positive (PD-1(hi) PD-L1(hi)) regulatory T cells  (Tregs) have a better response to PD1/PD-L1 blockade. METHODS: In our study  between April 1, 2014, and May 30, 2017, a total of 73 NSCLC peripheral blood  samples and fresh tumor specimens were collected for study. Of these, 42 large  (10-mm(3)) fresh tumor specimens were obtained from surgical procedures and  checked for expression of immunology biomarkers, including PD-L1, PD-1, CD8, CD4,  and CD25, in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow  cytometry, immunohistochemistry, and immunofluorescence (IF). Moreover, 31 small   biopsy specimens from patients who received immunotherapy (pembrolizumab or  nivolumab) were analyzed by immunohistochemistry and IF. The correlation between   flow cytometry and IF detected for TILs' density was evaluated by Spearman's rank  correlation test; the primary end point was progression-free survival. For the  PD-1/PD-L1 blockade assay, the TILs and peripheral blood mononuclear CD8 T cells   were cultured (1x10(5) per well) with anti-PD-1 (clone MIH4), anti-PD-L1 (clone  MIH1). The cytotoxic activity of TILs in killing NSCLC cells after stimulation by  anti-PD-1 and anti-PD-L1 was measured by a conventional (51)Cr release assay.  RESULTS: We first identified a population of high-PD-L1-expressing CD25-positive   CD4-positive T cells (PD-L1(hi) Tregs) in the tumor microenvironment. The  frequency of PD-L1(hi) Tregs was higher in tumor tissue (mean 48.6 +/- 14.3% in  CD25-positive CD3-positive CD4-positive T cells) than in blood (mean 35.4 +/-  10.2% in CD25-positive CD3-positive CD4-positive T cells) and normal tissue (mean  38.6 +/- 9.7% in CD25-positive CD3-positive CD4-positive T cells) (p < 0.05), as   determined by flow cytometry. The frequency of PD-L1(hi) Tregs was positively  correlated with PD-1-positive CD8 in Tregs. In addition, the TILs from these  patients (PD-1(hi) PD-L1(hi)) showed PD-1/PD-L1 pathway dependence and could  induce a greater killing effect of TILs by PD-1/PD-L1 blockade treatment. The  patients with PD-L1-positive NSCLC with PD-1(hi) PD-L1(hi) TILs showed a better  clinical outcome than those with a low frequency of PD-1(hi) CD8 or PD-L1(hi)  Tregs (median progression-free survival not reached versus 2 months).  CONCLUSIONS: Our findings suggested that the density of PD-L1-positive  CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a  diagnostic factor to supplement PD-L1 expression in tumor cells and predict the  response to PD-1/PD-L1 blockade immunotherapy in NSCLC.CI  - Copyright (c) 2017 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0001537	29275889	Case report	An elderly patient with metastatic pulmonary adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	This case illustrates a severe cardiovascular complication of immunotherapy and highlights to cardiologists the importance of aggressive treatments in patients with metastatic cancers whose prognosis has improved dramatically.	This report discusses an autoimmune fulminant myocarditis in an elderly patient with metastatic pulmonary adenocarcinoma in whom the most advanced invasive heart failure therapies were used successfully. She was treated with nivolumab.	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 Immune Checkpoint Inhibitor-Associated Myocarditis: A New Challenge for  Cardiologists.	 Can J Cardiol	 The ever-increasing use of immune checkpoint inhibitors in cancer is leading to a  high incidence of autoimmune side effects. This report discusses an autoimmune  fulminant myocarditis in an elderly patient with metastatic pulmonary  adenocarcinoma in whom the most advanced invasive heart failure therapies were  used successfully. She was treated with nivolumab. This case illustrates a severe  cardiovascular complication of immunotherapy and highlights to cardiologists the   importance of aggressive treatments in patients with metastatic cancers whose  prognosis has improved dramatically.CI  - Copyright (c) 2017 Canadian Cardiovascular Society. Published by Elsevier Inc.  All rights reserved.
CANIT0001538	29277453	Case report	 stage IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Undergoing complete remission.  Considering sarcoidosis as a potential side-effect of pembrolizumab treatment is crucial to avoid misdiagnosis with malignant lesions, hence careful description and reporting of such cases is primordial for patient care and may also provide us with insightful knowledge on the pathogenesis of immune-related diseases.	 Coincident development of sarcoidosis and metastatic melanoma as illustrated by this case report poses a diagnostic challenge because, in contrast to other irAEs, both diseases share common features such as pulmonary lesions, hilar adenopathies and skin nodules.	N/A	N/A	N/A	N/A	N/A	 2018 Feb	 Sarcoidosis post-anti-PD-1 therapy, mimicking relapse of metastatic melanoma in a  patient undergoing complete remission.	 Rev Med Interne	 Novel treatments of metastatic melanoma include the usage of checkpoint  inhibitors such as anti-cytotoxic-T-lymphocyte-associated antigen (CTLA-4) or  anti-programmed death-1 (PD-1) antibodies, which are immunomodulatory antibodies   that enhance the immune response against tumors. While they have substantially  improved the prognosis for patients, these therapies are associated with a large   spectrum of immune-related adverse effects (irAEs). We report a patient  developing pulmonary and cutaneous sarcoidosis after pembrolizumab therapy while   complete regression of stage IV melanoma was perceived. Coincident development of  sarcoidosis and metastatic melanoma as illustrated by this case report poses a  diagnostic challenge because, in contrast to other irAEs, both diseases share  common features such as pulmonary lesions, hilar adenopathies and skin nodules.  Considering sarcoidosis as a potential side-effect of pembrolizumab treatment is   crucial to avoid misdiagnosis with malignant lesions, hence careful description  and reporting of such cases is primordial for patient care and may also provide  us with insightful knowledge on the pathogenesis of immune-related diseases.CI  - Copyright (c) 2017 Societe Nationale Francaise de Medecine Interne (SNFMI).  Published by Elsevier SAS. All rights reserved.
CANIT0001539	29277824	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	189	N/A	A multicentre, retrospective cohort study	In patients with NSCLC treated with nivolumab, higher carcinoembryonic antigen was associated with inferior PFS.	N/A	N/A	N/A	Carcinoembryonic antigen (P06731); 	Carcinoembryonic antigen	Gene expression signature on/in tumor cell	 2018 Jan	 Carcinoembryonic Antigen as a Predictive Biomarker of Response to Nivolumab in  Non-small Cell Lung Cancer.	 Anticancer Res	 AIM: To find new predictive factors for the efficient use of immune checkpoint  inhibitors in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND  METHODS: In this multicenter retrospective cohort study, we evaluated consecutive  patients treated with nivolumab between January and October 2016 after  second-line systemic chemotherapy. The endpoint was progression-free survival  (PFS), as defined by Response Evaluation Criteria in Solid Tumors version 1.1.  RESULTS: A total of 189 patients were included in the study. Sixty-four percent  had received two or more prior systemic therapies. In Cox proportional hazard  analyses, Eastern Cooperative Oncology Group Performance Status of 2 or more,  lactate dehydrogenase (LDH) >/=217 mg/dl, and carcinoembryonic antigen >/=13.8  ng/ml were independently associated with inferior PFS. LDH was not associated in   the sensitivity analysis. CONCLUSION: In patients with NSCLC treated with  nivolumab, worse pretreatment performance status, and higher carcinoembryonic  antigen were associated with inferior PFS.CI  - Copyright(c) 2018, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001540	29277824	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	189	N/A	A multicentre, retrospective cohort study	In patients with NSCLC treated with nivolumab, worse pretreatment performance status was associated with inferior PFS.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2018 Jan	 Carcinoembryonic Antigen as a Predictive Biomarker of Response to Nivolumab in  Non-small Cell Lung Cancer.	 Anticancer Res	 AIM: To find new predictive factors for the efficient use of immune checkpoint  inhibitors in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND  METHODS: In this multicenter retrospective cohort study, we evaluated consecutive  patients treated with nivolumab between January and October 2016 after  second-line systemic chemotherapy. The endpoint was progression-free survival  (PFS), as defined by Response Evaluation Criteria in Solid Tumors version 1.1.  RESULTS: A total of 189 patients were included in the study. Sixty-four percent  had received two or more prior systemic therapies. In Cox proportional hazard  analyses, Eastern Cooperative Oncology Group Performance Status of 2 or more,  lactate dehydrogenase (LDH) >/=217 mg/dl, and carcinoembryonic antigen >/=13.8  ng/ml were independently associated with inferior PFS. LDH was not associated in   the sensitivity analysis. CONCLUSION: In patients with NSCLC treated with  nivolumab, worse pretreatment performance status, and higher carcinoembryonic  antigen were associated with inferior PFS.CI  - Copyright(c) 2018, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001541	29279030	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	This case report demonstrates a rare and serious complication associated with ipilimumab therapy. Granulomatous lymphadenitis can be a troublesome and concerning adverse event secondary to ipilimumab, particularly when treating melanoma with ipilimumab in the metastatic setting, as it can resemble progression of disease. This is an important adverse event for clinicians to be aware of; cases of lymphadenitis on PET/CT evaluation in this particular patient population should be confirmed with biopsy in order to rule out progression of disease or other disorders.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Case Report of Ipilimumab-Induced Diffuse, Nonnecrotizing Granulomatous  Lymphadenitis and Granulomatous Vasculitis.	 J Pharm Pract	 Ipilimumab is indicated for the treatment of melanoma in both the metastatic and   adjuvant setting. Ipilimumab inhibits cytotoxic T-lymphocyte antigen 4, leading  to the augmentation of T-cell activity and an antitumor immune system response.  The side effect profile of ipilimumab consists of autoimmune-like events such as   dermatitis, colitis, and thyroiditis. These immune-related adverse events can be   serious, often resulting in the need for systemic immunosuppression with  corticosteroids. We present a case of diffuse, nonnecrotizing granulomatous  lymphadenitis and granulomatous vasculitis in a heavily pretreated patient with  metastatic melanoma. After completion of 4 cycles of ipilimumab for the treatment  of metastatic melanoma, our patient complained of increasing fatigue, drenching  night sweats, and chills. Imaging revealed diffuse adenopathy involving several  lymph nodes. Biopsy was positive for nonnecrotizing granulomatous lymphadenitis  and granulomatous vasculitis. High-dose prednisone was initiated and tapered  gradually over 6 weeks, resulting in complete resolution of the granulomatous  disease.
CANIT0001542	29279482	Case report	Non-small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Consideration of immune-related adverse events up to several years after the initiation of nivolumab is important.	Immune-related Colitis Induced by the Long-term Use of Nivolumab	N/A	N/A	N/A	N/A	N/A	 2018 May 1	 Immune-related Colitis Induced by the Long-term Use of Nivolumab in a Patient  with Non-small Cell Lung Cancer.	 Intern Med	 We herein report a case of immune-related colitis induced by the long-term use of  nivolumab. A 62-year-old Japanese man was treated with nivolumab at 3 mg/kg every  2 weeks for advanced lung adenocarcinoma. The patient was admitted to our  hospital due to non-bloody watery diarrhea after the 70th dose of nivolumab. A  biopsy specimen of the colon mucosa revealed evidence of colitis with cryptitis  and crypt microabscesses. He was diagnosed with immune-related colitis and  started on predonisolone 60 mg/day. Subsequently, his symptoms remarkably  resolved. Consideration of immune-related adverse events up to several years  after the initiation of nivolumab is important.
CANIT0001543	29279511	Case report	Postoperative recurrence of lung squamous cell carcinoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	IgA nephropathy	N/A	N/A	N/A	N/A	N/A	 2018 May 1	 IgA Nephropathy after Nivolumab Therapy for Postoperative Recurrence of Lung  Squamous Cell Carcinoma.	 Intern Med	 Immune checkpoint inhibitors (ICIs) are becoming a common and important cancer  therapy. ICIs are associated with a unique category of side effects, termed  immune-related adverse events (irAEs). We herein report the case of a 72-year-old  man with postoperative recurrence of lung squamous cell carcinoma who was treated  with nivolumab and who developed proteinuria and a worsening kidney function. A  kidney biopsy revealed IgA nephropathy. After drug withdrawal, the proteinuria  improved and the deterioration of the patient's renal function was halted.  Although renal irAEs are considered to be rare and glomerulonephritis is not  typical presentation, physicians need to pay more attention to renal irAEs and  glomerular injury.
CANIT0001544	29284010	Clinical research	Advanced colorectal carcinoma	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	N/A	Pembrolizumab demonstrated a favorable safety profile in advanced PD-L1-positive CRC. Antitumor activity was observed in a single patient with MSI-high CRC, warranting further evaluation in this patient population.	Median follow-up was 5.3 months, and 8 patients (35%) reported treatment-related adverse events (AEs), most commonly fatigue (n = 3, 13%), stomatitis (n = 2, 9%), and asthenia (n = 2, 9%). One patient (4%) experienced grade 4 treatment-related increased blood bilirubin. No grade 3 AEs, discontinuations, or deaths were attributed to treatment.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	2017	 Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients  with advanced colorectal carcinoma.	 PLoS One	 BACKGROUND: Colorectal cancers (CRCs) expressing programmed death ligand 1  (PD-L1) have poor prognosis. In the multicohort KEYNOTE-028 trial, the anti-PD-1   antibody pembrolizumab was evaluated in 20 PD-L1-positive advanced solid tumors.   Herein, we report results for the advanced CRC cohort. METHODS: Patients with  advanced, treatment-resistant PD-L1-positive carcinoma of the colon or rectum  were enrolled, regardless of microsatellite instability (MSI) status.  Pembrolizumab 10 mg/kg was administered every 2 weeks for up to 2 years or until   disease progression/unacceptable toxicity. Response was assessed every 8 weeks  for the first 6 months and every 12 weeks thereafter. Primary end points were  safety and overall response rate by investigator review per Response Evaluation  Criteria in Solid Tumors version 1.1. Data cutoff was June 20, 2016. RESULTS: Of   137 patients with CRC and samples evaluable for PD-L1 expression, 33 (24%) had  PD-L1-positive tumors, of which 23 were enrolled. Median follow-up was 5.3  months, and 8 patients (35%) reported treatment-related adverse events (AEs),  most commonly fatigue (n = 3, 13%), stomatitis (n = 2, 9%), and asthenia (n = 2,   9%). One patient (4%) experienced grade 4 treatment-related increased blood  bilirubin. No grade 3 AEs, discontinuations, or deaths were attributed to  treatment. Most patients (n = 15, 65%) experienced progressive disease. One  partial response occurred in a patient (4%) with MSI-high CRC. CONCLUSION:  Pembrolizumab demonstrated a favorable safety profile in advanced PD-L1-positive   CRC. Antitumor activity was observed in a single patient with MSI-high CRC,  warranting further evaluation in this patient population. (Clinicaltrials.gov  registration: NCT02054806).
CANIT0001545	29284202	Clinical research	Advanced head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	26	N/A	A phase Ib, multicohort	Pembrolizumab was well tolerated and had durable antitumor activity in patients with HNSCC from the Asia-Pacific region.	Sixteen (62%) patients experienced a treatment-related adverse event of any grade, including two (8%) patients who experienced one or more events of grade 3 severity. No treatment-related deaths occurred.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Pembrolizumab in Asia-Pacific patients with advanced head and neck squamous cell   carcinoma: Analyses from KEYNOTE-012.	 Cancer Sci	 KEYNOTE-012 was a phase Ib, multicohort study designed to investigate efficacy  and safety of pembrolizumab in advanced solid tumors. Results from the subset of   patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)   from the Asia-Pacific region are reported. Patients with recurrent/metastatic  HNSCC, measurable disease (RECIST version 1.1), and ECOG performance status (PS)   0-1 were eligible for enrollment in the HNSCC expansion cohort. Patients received  pembrolizumab 200 mg every 3 weeks. Response was assessed every 8 weeks.  Co-primary end-points were safety and overall response rate (RECIST version 1.1,   central review). Secondary end-points included overall survival and response  duration. Patients enrolled at any of the five centers throughout the  Asia-Pacific region were included in these analyses. Twenty-six patients with  HNSCC from the Asia-Pacific region received pembrolizumab. The median age was 62   years, 65% of patients had ECOG PS 1, and 62% had received two or more prior  therapies for recurrent/metastatic disease. Sixteen (62%) patients experienced a   treatment-related adverse event of any grade, including two (8%) patients who  experienced one or more events of grade 3 severity. No treatment-related deaths  occurred. The overall response rate was 19% (95% confidence interval, 7%-39%).  After a median follow-up of 12 months (range, 2-21 months), a median response  duration was not reached (range, 6 to 17+ months); four of five responses lasted   >/=6 months. Median overall survival was 11.6 months (95% confidence interval,  4.7-17.7 months). Pembrolizumab was well tolerated and had durable antitumor  activity in patients with HNSCC from the Asia-Pacific region. (Trial registration  no. NCT01848834.).CI  - (c) 2017 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0001546	29290261	Clinical research	Progressed metastatic lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	267	N/A	In 20 general hospitals	Upon implementation of nivolumab therapy in general hospitals, the case mix was characterized by a more heavily pretreated population with a substantial fraction of patients with ECOG score 2. The median overall survival is slightly inferior to what was published in the randomized phase III trials. An ECOG score 2 and the presence of liver metastasis correlated strongly with a worse survival. We report a high prevalence of serious adverse events.	Treatment related adverse events grade 3 or 4 were reported in 21%, colitis (4%) and pneumonitis (7%) were most frequent.	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2018 Jan	 Does nivolumab for progressed metastatic lung cancer fulfill its promises  An  efficacy and safety analysis in 20 general hospitals.	 Lung Cancer	 OBJECTIVES: In patients with refractory or recurrent non-small-cell lung cancer  (NSCLC) after first line chemotherapy, phase III trials showed superiority of  nivolumab, an IgG4 programmed death-1 immune-checkpoint-inhibitor antibody, over   docetaxel. We evaluated case mix, effectiveness and safety of nivolumab upon  implementation in general practice. MATERIALS AND METHODS: In 20 general  hospitals, all consecutive NSCLC patients treated with nivolumab within the  medical need program (inclusion period 12 months) in Flanders - Belgium were  evaluated. RESULTS: There were 267 patients, Eastern Cooperative Oncology Group  (ECOG) score was 2 in 24% and 0-1 in 76%. In 48%, two or more systemic regimens  were given before nivolumab. The median overall survival was 7.8 months (95%  confidence interval (CI) 6.3-9.3). At one year, the overall survival rate was  36.5+/-0.34%. Median progression-free survival was 3.7 months (95% CI 2.9-4.5).  An objective response was obtained in 23.2%. ECOG score 2 and presence of liver  metastasis strongly correlated with worse survival (p<0.00001). Treatment related  adverse events grade 3 or 4 were reported in 21%, colitis (4%) and pneumonitis  (7%) were most frequent. CONCLUSION: Upon implementation of nivolumab therapy in   general hospitals, the case mix was characterized by a more heavily pretreated  population with a substantial fraction of patients with ECOG score 2. The median   overall survival is slightly inferior to what was published in the randomized  phase III trials. An ECOG score 2 and the presence of liver metastasis correlated  strongly with a worse survival. We report a high prevalence of serious adverse  events.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001547	29290265	Clinical research	Non-small cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	There was a correlation between irAE and efficacy in NSCLC patients treated with nivolumab.	Interstitial pneumonia,hypothyroidism,hypopituitarism, liver dysfunction, rash, and elevated thyroid stimulating hormone levels	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2018 Jan	 Correlation between immune-related adverse events and efficacy in non-small cell   lung cancer treated with nivolumab.	 Lung Cancer	 OBJECTIVES: Patients treated with nivolumab often experience its unique adverse  events, called immune-related adverse events (irAEs). Regarding the mechanisms of  immune-checkpoint inhibitors (ICIs), the occurrence of irAEs may also reflect  antitumor responses. Here, we report the clinical correlation between irAEs and  efficacy in NSCLC patients treated with nivolumab. MATERIALS AND METHODS: Between  December 2015 and February 2017, 38 advanced NSCLC patients were treated in our  institution. All the patients were enrolled in our single-institutional,  prospective, observational cohort study (UMIN000024414). IrAEs were defined as  having a potential immunological basis that required more frequent monitoring and  potential intervention. We divided the patients into two groups (irAEs group or  no-irAEs group) and evaluated the objective response rate (ORR) and  progression-free survival (PFS). RESULTS: The median age of the patients was 68.5  years (range 49-86 years); male/female ratio was 28/10; squamous/non-squamous  cell carcinoma cases were 10/28; performance status was 0-1/2/3, 7/26/5. Among  the overall population, ORR was 23.7% and median PFS was 91days. At the data  cutoff, 14 irAEs were observed. The most common irAE was interstitial pneumonia  (n=5). Other irAEs were hypothyroidism (n=4), hyperthyroidism, hypopituitarism,  liver dysfunction, rash, and elevated thyroid stimulating hormone levels (n=1,  each). Patients with irAEs had significantly higher ORRs compared with no-irAE  patients (63.6% versus 7.4%, p <0.01). Similarly, the PFS among irAE patients was  longer (median: not reached [95% confidence interval {CI}: 91days to not  applicable]) than no-irAE patients (median 49days [95% CI: 36-127days], hazard  ratio [HR] 0.10 [95% CI: 0.02-0.37, p<0.001]). Landmark analysis of patients who   achieved PFS >/=60days demonstrated similar tendencies, but this was not  significant (HR 0.28 [95% CI: 0.04-1.46], p=0.13). CONCLUSION: There was a  correlation between irAE and efficacy in NSCLC patients treated with nivolumab.CI  - Copyright (c) 2017 The Author(s). Published by Elsevier B.V. All rights reserved.
CANIT0001548	29305519	Basic research	TC-1 cell line, derived by co-transfection of human papilloma-virus strain 16 (HPV16) early proteins 6 and 7 (E6 and E7) and activated h-ras oncogene into primary lung epithelial cells, 	Lung carcinoma	EFO:0001071	Lung	IDO1 (P14902); OX40 (P23510); 	IDO1; OX40	Indoximod plus anti-OX40 agonist	Anti-OX40 agonist	Immune checkpoint therapy plus Target therapy	Anti-OX40 agonist (NCIT:C161864); indoximod (DB12827); 	C57BL/6 female mice	C57BL/6 female mice	Basic research	Although the addition of anti-OX40 to the vaccine moderately enhances therapeutic efficacy, incorporation of indoximod into this treatment leads to enhanced tumor regression and cure of established tumors in 60% of treated mice.  Our findings suggest a translatable strategy to enhance the overall efficacy of cancer immunotherapy. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2018 Feb	 Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the   IDO Inhibitor Indoximod.	 Cancer Immunol Res	 Although an immune response to tumors may be generated using vaccines, so far,  this approach has only shown minimal clinical success. This is attributed to the   tendency of cancer to escape immune surveillance via multiple immune suppressive   mechanisms. Successful cancer immunotherapy requires targeting these inhibitory  mechanisms along with enhancement of antigen-specific immune responses to promote  sustained tumor-specific immunity. Here, we evaluated the effect of indoximod, an  inhibitor of the immunosuppressive indoleamine-(2,3)-dioxygenase (IDO) pathway,  on antitumor efficacy of anti-OX40 agonist in the context of vaccine in the  IDO(-) TC-1 tumor model. We demonstrate that although the addition of anti-OX40  to the vaccine moderately enhances therapeutic efficacy, incorporation of  indoximod into this treatment leads to enhanced tumor regression and cure of  established tumors in 60% of treated mice. We show that the mechanisms by which  the IDO inhibitor leads to this therapeutic potency include (i) an increment of  vaccine-induced tumor-infiltrating effector T cells that is facilitated by  anti-OX40 and (ii) a decrease of IDO enzyme activity produced by nontumor cells  within the tumor microenvironment that results in enhancement of the specificity   and the functionality of vaccine-induced effector T cells. Our findings suggest a  translatable strategy to enhance the overall efficacy of cancer immunotherapy.  Cancer Immunol Res; 6(2); 201-8. (c)2018 AACR.CI  - (c)2018 American Association for Cancer Research.
CANIT0001549	29306769	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	25	N/A	A phase II clinical trial	Ipilimumab demonstrated clinically relevant activity within this biomarker-defined population. NY-ESO-1 positivity, as a surrogate for a preexisting immune response against tumour antigens, might help identifying patients with a superior outcome from immune checkpoint blockade.	Treatment-related grade 3 AEs occurred in 36% with no grade 4-5 AEs.	N/A	N/A	NY-ESO-1 (P78358); 	NY-ESO-1-seropositive	Gene expression signature on/in tumor cell	 2018 Feb	 Phase II trial of ipilimumab in melanoma patients with preexisting humoural  immune response to NY-ESO-1.	 Eur J Cancer	 BACKGROUND: Immune checkpoint therapy has dramatically changed treatment options   in patients with metastatic melanoma. However, a relevant part of patients still   does not respond to treatment. Data regarding the prognostic or predictive  significance of preexisting immune responses against tumour antigens are  conflicting. Retrospective data suggested a higher clinical benefit of ipilimumab  in melanoma patients with preexisting NY-ESO-1-specific immunity. PATIENTS AND  METHODS: Twenty-five patients with previously untreated or treated metastatic  melanoma and preexisting humoural immune response against NY-ESO-1 received  ipilimumab at a dose of 10 mg/kg in week 1, 4, 7, 10 followed by 3-month  maintenance treatment for a maximum of 48 weeks. Primary endpoint was the disease  control rate (irCR, irPR or irSD) according to immune-related response criteria  (irRC). Secondary endpoints included the disease control rate according to RECIST  criteria, progression-free survival and overall survival (OS). Humoural and  cellular immune responses against NY-ESO-1 were analysed from blood samples.  RESULTS: Disease control rate according to irRC was 52%, irPR was observed in 36%  of patients. Progression-free survival according to irRC was 7.8 months,  according to RECIST criteria it was 2.9 months. Median OS was 22.7 months; the  corresponding 1-year survival rate was 66.8%. Treatment-related grade 3 AEs  occurred in 36% with no grade 4-5 AEs. No clear association was found between the  presence of NY-ESO-1-specific cellular or humoural immune responses and clinical   activity. CONCLUSION: Ipilimumab demonstrated clinically relevant activity within  this biomarker-defined population. NY-ESO-1 positivity, as a surrogate for a  preexisting immune response against tumour antigens, might help identifying  patients with a superior outcome from immune checkpoint blockade. CLINICAL TRIAL   INFORMATION: NCT01216696.CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
CANIT0001550	29309091	Case report	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Toxic injury to the gastrointestinal tract	Toxic injury to the gastrointestinal tract	N/A	N/A	N/A	N/A	N/A	 2018 Jan 1	 Toxic Injury to the Gastrointestinal Tract After Ipilimumab Therapy for Advanced   Melanoma.	 J Am Osteopath Assoc	 Ipilimumab, cytotoxic T-lymphocyte-associated protein 4-blocking antibody, is  known to precipitate tissue-specific immune-related adverse events. The second  most common site for immune-related adverse events is the gastrointestinal tract,  with toxic injury resulting in diarrhea, colitis, and enterocolitis. In the  present case, a woman who received ipilimumab 2 weeks prior was found to have  severe, diffuse corticosteroid-refractory gastrointestinal tract toxic injury  affecting the stomach, small bowel, and colon.
CANIT0001551	29329663	Case report	Metastatic clear-cell renal cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by pazopanib	Nivolumab	Immune checkpoint therapy followed by Target therapy	Nivolumab (DB09035); pazopanib (DB06589); 	1	N/A	Case	Reintroducing pazopanib reverses the primary resistance of nivolumab in a patient with metastatic clear-cell renal cell carcinoma.	No significant hematologic toxicity, hepatitis or immunotherapy related adverse effect (irAE) was documented.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Reintroducing Pazopanib Reverses the Primary Resistance of Nivolumab in a Patient  With Metastatic Clear-cell Renal Cell Carcinoma.	 Clin Genitourin Cancer	Unable to provide
CANIT0001552	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Glioblastoma multiforme	EFO:0000519	Brain	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001553	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001554	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001555	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001556	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001557	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001558	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001559	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001560	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001561	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001562	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001563	29332184	Case report	5 Melanoma, 2 RCC, 1 Glioblastoma, 1 Hodgkin lymphoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	9	N/A	Case	This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.	Neurologic complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 Neurologic complications of immune checkpoint inhibitors.	 J Neurooncol	 Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment  for cancer. These agents, transforming the field of oncology, are not devoid of  toxicity and cause immune-related side effects which can involve any organ  including the nervous system. In this study, we present 9 patients (7 men and 2  women) with neurologic complications secondary to ICPI treatment. These included   meningoencephalitis, limbic encephalitis, polyradiculitis, cranial  polyneuropathy, myasthenic syndrome and myositis. Four patients received dual  ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte  associated protein-4 blocking antibodies. Median time to onset of neurologic  adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5  days-19 weeks). In all patients ICPIs were stopped and corticosteroids were  initiated, resulting in a marked improvement in seven out of nine patients. Two  patients, one with myositis and one with myasthenic syndrome, died. In two  patients ICPI therapy was resumed after resolution of the neurological adverse  event with no additional neurologic complications. This series highlights the  very broad spectrum of neurological complications of ICPIs, emphasizes the need  for expedited diagnosis and suggests that withholding treatment early,  accompanied with steroid therapy, carries the potential of complete resolution of  the neurological immune-mediated condition. Thus, a high level of suspicion and  rapid initiation of corticosteroids are mandatory to prevent uncontrolled  clinical deterioration, which might be fatal.
CANIT0001564	29333945	Case report	Breast cancer	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus albumin-bound paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); albumin-bound paclitaxel (DB01229); 	2	N/A	Case	 The results indicate that regimen of pembrolizumab combination  with albumin-bound paclitaxel might produce response in patients with  HER2-positive metastatic breast cancer who have failed to multi-anti-HER2  targeted therapy.	N/A	N/A	N/A	HER2 (P04626); 	HER2 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Apr 3	 Remarkable response with pembrolizumab plus albumin-bound paclitaxel in 2 cases  of HER2-positive metastatic breast cancer who have failed to multi-anti-HER2  targeted therapy.	 Cancer Biol Ther	 In clinical practice, one subgroup patients of breast cancer might have developed  resistance to multi-anti-HER2 targeted drugs(trastuzumab, lapatinib and/or T-DM1)  and can not benefit from the anti-HER2 targeted therapy continuously. We attempt   to change the next therapic way for these patients. Two patients with metastatic   breast cancer who have failed to multi-anti-HER2 targeted therapy were treated  with pembrolizumab (2 mg/Kg, day1) plus albumin-bound paclitaxel (125 mg/m(2),  day1,8) every 3 weeks. CT evaluation and HER2 ECD test were performed every 2  cycles. Both of the two patients achieved remarkable response with Partial  Remission (PR), meanwhile serum HER2 ECD levels (the upper normal limit is 15  ng/ml) showed a remarkable decreases(compared to the base line decreases 75% and   60% respectively). The results indicate that regimen of pembrolizumab combination  with albumin-bound paclitaxel might produce response in patients with  HER2-positive metastatic breast cancer who have failed to multi-anti-HER2  targeted therapy.
CANIT0001565	29336323	Case report	Recurrent cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Case	Clinical effective and tolerable for heavily pre-treated patients with metastatic CSCC.	So far, no severe adverse effects have occurred.	N/A	N/A	N/A	N/A	N/A	 2018 Feb 1	 Nivolumab for recurrent cutaneous squamous cell carcinoma: three cases.	 Eur J Dermatol	 Programmed cell death ligand 1 (PD-L1) is frequently expressed in cutaneous  squamous cell cancer (CSCC) and preliminary data from an ongoing clinical trial  suggest that programmed death receptor 1 (PD-1) checkpoint inhibitors may be  useful to treat patients with metastatic non-melanoma skin cancer. To report a  series of three patients with advanced CSCC treated with nivolumab, showing that   commercially available PD-1 checkpoint inhibitors may be useful in non-melanoma  skin cancer patients without access to a clinical trial. All patients had  previous chemotherapy. All cancers were PD-1 ligand (PD-L1)-positive based on  immunohistochemistry. Patients consented to off-label therapy with nivolumab,  which is commercially available in Switzerland. Two patients had a partial tumour  response, and have been receiving therapy for more than 12 months. One patient  had stable disease after three months, and therapy is also ongoing. So far, no  severe adverse effects have occurred. Our cases confirm previous reports  demonstrating a clinical effect and tolerability of PD-1 checkpoint inhibitors  for heavily pre-treated patients with metastatic CSCC. Commercially available  PD-1 checkpoint inhibitors may be useful in these patients who should be  considered for PD-1 checkpoint inhibitor therapy, preferentially within clinical   trials.
CANIT0001566	29339377	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); T-LYMPHOCYTE (N/A); 	CTLA-4; T-LYMPHOCYTE	Ipilimumab plus melphalan	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); melphalan (DB01042); 	26	N/A	A phase II clinical trial	Local chemotherapy combined with checkpoint blockade-based immunotherapy results in a durable response to cancer therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	T-Lymphocyte (NCIT:C12476); 	Tumor-infiltrating T-cell 	Tumor-infiltrating immune cell	 2018 Feb	 Robust Antitumor Responses Result from Local Chemotherapy and CTLA-4 Blockade.	 Cancer Immunol Res	 Clinical responses to immunotherapy have been associated with augmentation of  preexisting immune responses, manifested by heightened inflammation in the tumor   microenvironment. However, many tumors have a noninflamed microenvironment, and  response rates to immunotherapy in melanoma have been <50%. We approached this  problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy  to induce local inflammation. In murine models of melanoma and prostate cancer,  the combination of chemotherapy and CTLA-4 blockade induced a shift in the  cellular composition of the tumor microenvironment, with infiltrating CD8(+) and   CD4(+) T cells increasing the CD8/Foxp3 T-cell ratio. These changes were  associated with improved survival of the mice. To translate these findings into a  clinical setting, 26 patients with advanced melanoma were treated locally by  isolated limb infusion with the nitrogen mustard alkylating agent melphalan  followed by systemic administration of CTLA-4 blocking antibody (ipilimumab) in a  phase II trial. This combination of local chemotherapy with systemic checkpoint  blockade inhibitor resulted in a response rate of 85% at 3 months (62% complete  and 23% partial response rate) and a 58% progression-free survival at 1 year. The  clinical response was associated with increased T-cell infiltration, similar to  that seen in the murine models. Together, our findings suggest that local  chemotherapy combined with checkpoint blockade-based immunotherapy results in a  durable response to cancer therapy. Cancer Immunol Res; 6(2); 189-200. (c)2018  AACR.CI  - (c)2018 American Association for Cancer Research.
CANIT0001567	29341936	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	400	N/A	N/A	Our findings underscore that rheumatic iAE are part of the side effect profile of ICIs and require heightened awareness as these therapies are becoming the standard of care for various malignancies. We show that these appear later in the course of iAEs and respond preferentially to high dose steroids. MTX appears effective as a steroid sparing agent.	Rheumatic manifestations were encountered in 14 of 400 patients (3.5%) who had received immunotherapy between January 1st 2013 and April 30th, 2017. The most common rheumatic manifestation was inflammatory arthritis (85%) for which a third (4/11) had a clear cut predisposing factor such as a personal or family history of psoriasis, a prior episode of uveitis or ACPA positivity. Pulmonary sarcoidosis and biopsy-proven eosinophilic fasciitis were diagnosed in two additional patients. Treatment with NSAIDS was mostly unsuccessful while steroid therapy was beneficial in doses 20 mg/d. Methotrexate enabled steroid tapering without an excess of side effects or tumor progression in the short follow-up available. Overall, rheumatic manifestations tended to occur later in the course of immunotherapy as compared to other iAE.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Rheumatic manifestations among cancer patients treated with immune checkpoint  inhibitors.	 Autoimmun Rev	 BACKGROUND: The use of immune checkpoint inhibitors (ICI) has grown incessantly  since they were first approved in 2014. These monoclonal antibodies inhibit T  cell activation, yielding a dramatic tumor response with improved survival.  However, immunotherapy is frequently hampered by immune adverse events (iAE) such  as hypophysitis, colitis, hepatitis, pneumonitis and rash. Until recently,  rheumatic side effects were only infrequently reported. AIM: To describe the  rheumatic manifestations encountered among patients treated with ICIs in a large   tertiary cancer center in Israel METHODS: The cancer center's patient registry  was screened for patients who had ever been treated with ipilimumab,  pembrolizumab and/or nivolumab with relevant data gathered from clinical charts.   RESULTS: Rheumatic manifestations were encountered in 14 of 400 patients (3.5%)  who had received immunotherapy between January 1st 2013 and April 30th, 2017. The  most common rheumatic manifestation was inflammatory arthritis (85%) for which a   third (4/11) had a clear cut predisposing factor such as a personal or family  history of psoriasis, a prior episode of uveitis or ACPA positivity. Pulmonary  sarcoidosis and biopsy-proven eosinophilic fasciitis were diagnosed in two  additional patients. Treatment with NSAIDS was mostly unsuccessful while steroid   therapy was beneficial in doses >/=20mg/d. Methotrexate enabled steroid tapering   without an excess of side effects or tumor progression in the short follow-up  available. Overall, rheumatic manifestations tended to occur later in the course   of immunotherapy as compared to other iAE. CONCLUSIONS: Our findings underscore  that rheumatic iAE are part of the side effect profile of ICIs and require  heightened awareness as these therapies are becoming the standard of care for  various malignancies. We show that these appear later in the course of iAEs and  respond preferentially to high dose steroids. MTX appears effective as a steroid   sparing agent.CI  - Copyright (c) 2018. Published by Elsevier B.V.
CANIT0001568	29341936	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	400	N/A	N/A	Our findings underscore that rheumatic iAE are part of the side effect profile of ICIs and require heightened awareness as these therapies are becoming the standard of care for various malignancies. We show that these appear later in the course of iAEs and respond preferentially to high dose steroids. MTX appears effective as a steroid sparing agent.	Rheumatic manifestations were encountered in 14 of 400 patients (3.5%) who had received immunotherapy between January 1st 2013 and April 30th, 2017. The most common rheumatic manifestation was inflammatory arthritis (85%) for which a third (4/11) had a clear cut predisposing factor such as a personal or family history of psoriasis, a prior episode of uveitis or ACPA positivity. Pulmonary sarcoidosis and biopsy-proven eosinophilic fasciitis were diagnosed in two additional patients. Treatment with NSAIDS was mostly unsuccessful while steroid therapy was beneficial in doses 20 mg/d. Methotrexate enabled steroid tapering without an excess of side effects or tumor progression in the short follow-up available. Overall, rheumatic manifestations tended to occur later in the course of immunotherapy as compared to other iAE.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Rheumatic manifestations among cancer patients treated with immune checkpoint  inhibitors.	 Autoimmun Rev	 BACKGROUND: The use of immune checkpoint inhibitors (ICI) has grown incessantly  since they were first approved in 2014. These monoclonal antibodies inhibit T  cell activation, yielding a dramatic tumor response with improved survival.  However, immunotherapy is frequently hampered by immune adverse events (iAE) such  as hypophysitis, colitis, hepatitis, pneumonitis and rash. Until recently,  rheumatic side effects were only infrequently reported. AIM: To describe the  rheumatic manifestations encountered among patients treated with ICIs in a large   tertiary cancer center in Israel METHODS: The cancer center's patient registry  was screened for patients who had ever been treated with ipilimumab,  pembrolizumab and/or nivolumab with relevant data gathered from clinical charts.   RESULTS: Rheumatic manifestations were encountered in 14 of 400 patients (3.5%)  who had received immunotherapy between January 1st 2013 and April 30th, 2017. The  most common rheumatic manifestation was inflammatory arthritis (85%) for which a   third (4/11) had a clear cut predisposing factor such as a personal or family  history of psoriasis, a prior episode of uveitis or ACPA positivity. Pulmonary  sarcoidosis and biopsy-proven eosinophilic fasciitis were diagnosed in two  additional patients. Treatment with NSAIDS was mostly unsuccessful while steroid   therapy was beneficial in doses >/=20mg/d. Methotrexate enabled steroid tapering   without an excess of side effects or tumor progression in the short follow-up  available. Overall, rheumatic manifestations tended to occur later in the course   of immunotherapy as compared to other iAE. CONCLUSIONS: Our findings underscore  that rheumatic iAE are part of the side effect profile of ICIs and require  heightened awareness as these therapies are becoming the standard of care for  various malignancies. We show that these appear later in the course of iAEs and  respond preferentially to high dose steroids. MTX appears effective as a steroid   sparing agent.CI  - Copyright (c) 2018. Published by Elsevier B.V.
CANIT0001569	29341936	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	400	N/A	N/A	Our findings underscore that rheumatic iAE are part of the side effect profile of ICIs and require heightened awareness as these therapies are becoming the standard of care for various malignancies. We show that these appear later in the course of iAEs and respond preferentially to high dose steroids. MTX appears effective as a steroid sparing agent.	Rheumatic manifestations were encountered in 14 of 400 patients (3.5%) who had received immunotherapy between January 1st 2013 and April 30th, 2017. The most common rheumatic manifestation was inflammatory arthritis (85%) for which a third (4/11) had a clear cut predisposing factor such as a personal or family history of psoriasis, a prior episode of uveitis or ACPA positivity. Pulmonary sarcoidosis and biopsy-proven eosinophilic fasciitis were diagnosed in two additional patients. Treatment with NSAIDS was mostly unsuccessful while steroid therapy was beneficial in doses 20 mg/d. Methotrexate enabled steroid tapering without an excess of side effects or tumor progression in the short follow-up available. Overall, rheumatic manifestations tended to occur later in the course of immunotherapy as compared to other iAE.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Rheumatic manifestations among cancer patients treated with immune checkpoint  inhibitors.	 Autoimmun Rev	 BACKGROUND: The use of immune checkpoint inhibitors (ICI) has grown incessantly  since they were first approved in 2014. These monoclonal antibodies inhibit T  cell activation, yielding a dramatic tumor response with improved survival.  However, immunotherapy is frequently hampered by immune adverse events (iAE) such  as hypophysitis, colitis, hepatitis, pneumonitis and rash. Until recently,  rheumatic side effects were only infrequently reported. AIM: To describe the  rheumatic manifestations encountered among patients treated with ICIs in a large   tertiary cancer center in Israel METHODS: The cancer center's patient registry  was screened for patients who had ever been treated with ipilimumab,  pembrolizumab and/or nivolumab with relevant data gathered from clinical charts.   RESULTS: Rheumatic manifestations were encountered in 14 of 400 patients (3.5%)  who had received immunotherapy between January 1st 2013 and April 30th, 2017. The  most common rheumatic manifestation was inflammatory arthritis (85%) for which a   third (4/11) had a clear cut predisposing factor such as a personal or family  history of psoriasis, a prior episode of uveitis or ACPA positivity. Pulmonary  sarcoidosis and biopsy-proven eosinophilic fasciitis were diagnosed in two  additional patients. Treatment with NSAIDS was mostly unsuccessful while steroid   therapy was beneficial in doses >/=20mg/d. Methotrexate enabled steroid tapering   without an excess of side effects or tumor progression in the short follow-up  available. Overall, rheumatic manifestations tended to occur later in the course   of immunotherapy as compared to other iAE. CONCLUSIONS: Our findings underscore  that rheumatic iAE are part of the side effect profile of ICIs and require  heightened awareness as these therapies are becoming the standard of care for  various malignancies. We show that these appear later in the course of iAEs and  respond preferentially to high dose steroids. MTX appears effective as a steroid   sparing agent.CI  - Copyright (c) 2018. Published by Elsevier B.V.
CANIT0001570	29342442	Case report	HIV-related Refractory Hodgkin Lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Complete Response	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Feb	 HIV-related Refractory Hodgkin Lymphoma: A Case Report of Complete Response to  Nivolumab.	 Clin Lymphoma Myeloma Leuk	Unable to provide
CANIT0001571	29343652	Case report	Advanced renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Preceding painless thyroiditis with positive thyroid autoantibodies observed in the present case, however, raises the possibility that autoimmune mechanisms are involved in the pathogenesis of nivolumab-induced fulminant type 1 diabetes mellitus.	Painless Thyroiditis and Fulminant Type 1 Diabetes Mellitus	N/A	N/A	N/A	N/A	N/A	 2018 Jan	 Painless Thyroiditis and Fulminant Type 1 Diabetes Mellitus in a Patient Treated   with an Immune Checkpoint Inhibitor, Nivolumab.	 Tohoku J Exp Med	 The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in  immune checkpoint therapy for cancer. Nivolumab, an anti-PD-1 monoclonal  antibody, blocks PD-1 and can restore anti-cancer immune responses by disrupting   the signal that inhibits T-cell activation. Nivolumab may induce  endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis,  and type 1 diabetes mellitus. Here we report a 68-year-old female patient with  advanced renal cell carcinoma who was treated with nivolumab. She had positive  anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies with  slightly elevated thyroid-stimulating hormone (9.048 muU/mL), and was diagnosed  as chronic thyroiditis with subclinical hypothyroidism before nivolumab therapy.   She developed painless thyroiditis after the first cycle of the therapy (Day 14).  At the 7th cycle of nivolumab therapy (Day 98), hyperglycemia (473 mg/dL) was  noted, whereas glycated hemoglobin level was 6.9%. Islet-related autoantibodies  were all negative. The glucagon tolerance test showed complete depletion of  insulin. Human leukocyte antigen typing showed haplotype DRB1*09:01-DQB1*03:03,  which was reported to be closely associated with type 1 diabetes mellitus in  Japan. Fulminant type 1 diabetes mellitus was diagnosed, and she was immediately   treated with multiple daily injections of insulin. Fulminant type 1 diabetes  mellitus is characterized by rapid-onset diabetic ketoacidosis, and negative  islet-related autoantibodies, and was proposed as a novel subtype of  non-autoimmune diabetes. Preceding painless thyroiditis with positive thyroid  autoantibodies observed in the present case, however, raises the possibility that  autoimmune mechanisms are involved in the pathogenesis of nivolumab-induced  fulminant type 1 diabetes mellitus.
CANIT0001572	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001573	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001574	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001575	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Glioblastoma multiforme	EFO:0000519	Brain	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001576	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001577	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001578	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001579	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001580	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001581	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Lung carcinoma	EFO:0001071	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001582	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001583	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001584	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001585	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001586	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001587	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Rectum cancer	EFO:1000657	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001588	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Rectum cancer	EFO:1000657	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001589	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Rectum cancer	EFO:1000657	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001590	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001591	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001592	29353396	Clinical research	Cancer of colon (37%), lung (16%), malignant melanoma (16%), rectum (12%), glioblastoma (7%), renal (7%) and refractory Hodgkins Lymphoma (5%). 	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	43	N/A	N/A	An assessment of side effects by healthcare providers in patients with cancer may be challenging due to an increased workload in clinics and undistinguishable symptoms of side effects and cancer itself. Therefore, a new care model which increases an interprofessional communication may improve pharmaceutical care in oncology outpatient clinics.	During the study, 204 visits for 43 patients with a total of 5508 side effect assessments were recorded where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments, 473 of them were graded higher by a clinical pharmacist whereas 664 were graded higher by nurses. Statistically significant differences were detected in the assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood changes, anxiety, hearing impairment, and allergic reactions.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 The differences in the assessments of side effects at an oncology outpatient  clinic.	 Int J Clin Pharm	 Background There is a growing interest in the use of targeted and immunotherapies  in oncology. However, the assessment of side effects can be different due to  interpretation of patients' health status by healthcare professionals in oncology  outpatient clinics. Objective To demonstrate the differences in the assessments  of side effects conducted independently by a clinical pharmacist and nurses in  patients who receive targeted therapies at an oncology outpatient clinic. Setting  The study was conducted at the University Oncology Hospital in an outpatient  clinic from October 2015 to March 2016. Method Patients receiving ipilimumab,  nivolumab, pembrolizumab, bevacizumab, panitumumab or cetuximab during study  period were included. The assessment of side effects was conducted by a  pharmacist and nurse independently using the NCI-CTCAE version-2. Main outcome  measure To compare the severity assessments of side effects between a clinical  pharmacist and nurses in an outpatient clinic. Results During the study, 204  visits for 43 patients with a total of 5508 side effect assessments were recorded  where 1137 (20.64%) assessments were graded differently. Out of 1137 assessments,  473 of them were graded higher by a clinical pharmacist whereas 664 were graded  higher by nurses. Statistically significant differences were detected in the  assessment of vomiting, taste changes, sense changes, alopecia, fatigue, mood  changes, anxiety, hearing impairment, and allergic reactions. Conclusion An  assessment of side effects by healthcare providers in patients with cancer may be  challenging due to an increased workload in clinics and undistinguishable  symptoms of side effects and cancer itself. Therefore, a new care model which  increases an interprofessional communication may improve pharmaceutical care in  oncology outpatient clinics.
CANIT0001593	29356789	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus stereotactic radiosurgery	Stereotactic radiosurgery	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); stereotactic ablative radiotherapy (NCIT:C157991); stereotactic ablative radiotherapy (NCIT:C157991); 	25	74	A retrospective cohort study	SRS combined with PB was well tolerated and achieved local control in 80% of the lesions. Prolonged OS was observed compared with that currently yielded in this population of patients.	Radiation necrosis, occurring within a median time of 6.5 months, was observed for four MBM (6.8%) in four patients. No other significant SRS-related adverse event was observed. 	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed  cell death-1 (pembrolizumab) for melanoma brain metastases.	 Melanoma Res	 Anti-programmed cell death-1 (anti-PD1) antibodies are currently the first-line  treatment for patients with metastatic BRAF wild-type melanoma, alone or combined  with the anti-CTLA4 monoclonal antibody, ipilimumab. To date, data on safety and   the outcomes of patients treated with the anti-PD1 monoclonal antibodies,  pembrolizumab (PB), or nivolumab, combined with stereotactic radiosurgery (SRS),   for melanoma brain metastases (MBM) are scarce. We retrospectively reviewed all  patients with MBM treated with PB combined with SRS between 2012 and 2015. The  primary endpoint was neurotoxicity. The secondary endpoints were local, distant  intracranial controls and overall survival (OS). Among 74 patients with MBM  treated with SRS, 25 patients with a total of 58 MBM treated with PB combined  with SRS within 6 months were included. Radiation necrosis, occurring within a  median time of 6.5 months, was observed for four MBM (6.8%) in four patients. No   other significant SRS-related adverse event was observed. After a median  follow-up of 8.4 months, local control was achieved in 46 (80%) metastases and 17  (68%) patients. Perilesional oedema and intratumour haemorrhage appearing or  increasing after SRS were associated with local progression (P<0.001). The median  OS was 15.3 months (95% confidence interval: 4.6-26). The timing between SRS and   PB administration did not seem to influence the risk of radiation necrosis,  intracranial control or OS. SRS combined with PB was well tolerated and achieved   local control in 80% of the lesions. Prolonged OS was observed compared with that  currently yielded in this population of patients. Prospective studies are  required to explore further the optimal ways to combine immunotherapy and SRS.
CANIT0001594	29361819	Case report	Refractory metastatic myxofibrosarcoma	Myxofibrosarcoma	MONDO:0019202	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Partial response	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Oct	 Pembrolizumab for Refractory Metastatic Myxofibrosarcoma: A Case Report.	 Cancer Res Treat	 Myxofibrosarcoma is a rare tumor, refractory to cytotoxic chemotherapy and  radiotherapy. Pembrolizumab is an innovative immunotherapy drug consisting of  programmed death receptor ligand 1 antibody proven to be useful for numerous  types of cancer cells. A patient had been diagnosed with metastatic  myxofibrosarcoma, refractory to radiotherapy and conventional cytotoxic  chemotherapy. The patient achieved a partial response during palliative  chemotherapy with pembrolizumab for 14 cycles. To the best of our knowledge, this  is the first case report demonstrating the efficacy of pembrolizumab for  refractory myxofibrosarcoma.
CANIT0001595	29361915	Case report	Lung squamous cell carcinoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Neuromyelitis optica spectrum disorder	A 75-year-old Japanese man with lung squamous cell carcinoma was administered nivolumab as second-line treatment. Two months after treatment with nivolumab, he presented acute paralysis in the bilateral lower limbs, sensory loss. Spinal magnetic resonance imaging showed T2 hyperintense lesions between C5-6 and Th12-L1. He was diagnosed with neuromyelitis optica spectrum disorder (NMOSD) by anti-aquaporin-4 antibody-positive in the serum and other examinations. After treatment, steroid reactivity was poor.	N/A	N/A	N/A	N/A	N/A	 2018 Jan 24	 Neuromyelitis optica spectrum disorder secondary to treatment with anti-PD-1  antibody nivolumab: the first report.	 BMC Cancer	 BACKGROUND: Immune checkpoint blockade is developed as standard treatment for  non-small cell lung cancer. However immune-related adverse events (irAE) have  still unknown complications. Here, we report a patient with lung squamous cell  carcinoma who developed neuromyelitis optica spectrum disorder with nivolumab.  CASE PRESENTATION: A 75-year-old Japanese man with lung squamous cell carcinoma  was administered nivolumab as second-line treatment. Two months after treatment  with nivolumab, he presented acute paralysis in the bilateral lower limbs,  sensory loss. Spinal magnetic resonance imaging showed T2 hyperintense lesions  between C5-6 and Th12-L1. He was diagnosed with neuromyelitis optica spectrum  disorder (NMOSD) by anti-aquaporin-4 antibody-positive in the serum and other  examinations. After treatment, steroid reactivity was poor. CONCLUSION: This is  the first patient who developed anti-AQP4 antibody-positive NMOSD as a  nivolumab-induced irAE. Clinicians should be aware of this kind of potential  neurological complication by using immune check point inhibitor and start the  treatment of this irAE as soon as possible.
CANIT0001596	29363290	Clinical research	Cancer patients with preexisting rheumatic disease	Lung carcinoma	EFO:0001071	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	16	N/A	A retrospective cohort study	This represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.	Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other immune-related adverse effects.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Brief Report: Cancer Immunotherapy in Patients With Preexisting Rheumatic  Disease: The Mayo Clinic Experience.	 Arthritis Rheumatol	 OBJECTIVE: To determine the risk of rheumatic disease flare and adverse effects  in patients with preexisting rheumatic disease who were receiving immune  checkpoint inhibitor (ICI) therapy. METHODS: A retrospective medical record  review was performed to identify all patients who received ICI therapy at Mayo  Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with   a preexisting rheumatic disease were identified using specific diagnostic codes.   RESULTS: Sixteen patients were identified (81% female, median age 68.5 years).  The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia  rheumatica (n = 5), Sjogren's syndrome (n = 2), and systemic lupus erythematosus   (n = 2). Seven patients were receiving immunosuppressive therapy or  glucocorticoids for their rheumatic disease at the time of initiation of the ICI.  The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or  hematologic (n = 2). In most cases, ICIs were offered only after failure of  several other therapies. Immune-related adverse effects (IRAEs) occurred in 6  patients, and all were treated successfully with glucocorticoids and  discontinuation of the ICI therapy. There were no significant differences in time  from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex  between the patients with and those without IRAEs. CONCLUSION: To our knowledge,   this represents the largest single-center cohort of patients with rheumatic  diseases who were exposed to modern cancer immunotherapy. Only a minority of  these patients experienced a flare of their preexisting rheumatic disease or any   other IRAE.CI  - (c) 2017, American College of Rheumatology.
CANIT0001597	29363290	Clinical research	Cancer patients with preexisting rheumatic disease	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	16	N/A	A retrospective cohort study	This represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.	Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other immune-related adverse effects.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Brief Report: Cancer Immunotherapy in Patients With Preexisting Rheumatic  Disease: The Mayo Clinic Experience.	 Arthritis Rheumatol	 OBJECTIVE: To determine the risk of rheumatic disease flare and adverse effects  in patients with preexisting rheumatic disease who were receiving immune  checkpoint inhibitor (ICI) therapy. METHODS: A retrospective medical record  review was performed to identify all patients who received ICI therapy at Mayo  Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with   a preexisting rheumatic disease were identified using specific diagnostic codes.   RESULTS: Sixteen patients were identified (81% female, median age 68.5 years).  The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia  rheumatica (n = 5), Sjogren's syndrome (n = 2), and systemic lupus erythematosus   (n = 2). Seven patients were receiving immunosuppressive therapy or  glucocorticoids for their rheumatic disease at the time of initiation of the ICI.  The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or  hematologic (n = 2). In most cases, ICIs were offered only after failure of  several other therapies. Immune-related adverse effects (IRAEs) occurred in 6  patients, and all were treated successfully with glucocorticoids and  discontinuation of the ICI therapy. There were no significant differences in time  from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex  between the patients with and those without IRAEs. CONCLUSION: To our knowledge,   this represents the largest single-center cohort of patients with rheumatic  diseases who were exposed to modern cancer immunotherapy. Only a minority of  these patients experienced a flare of their preexisting rheumatic disease or any   other IRAE.CI  - (c) 2017, American College of Rheumatology.
CANIT0001598	29363290	Clinical research	Cancer patients with preexisting rheumatic disease	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	N/A	A retrospective cohort study	This represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.	Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other immune-related adverse effects.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Brief Report: Cancer Immunotherapy in Patients With Preexisting Rheumatic  Disease: The Mayo Clinic Experience.	 Arthritis Rheumatol	 OBJECTIVE: To determine the risk of rheumatic disease flare and adverse effects  in patients with preexisting rheumatic disease who were receiving immune  checkpoint inhibitor (ICI) therapy. METHODS: A retrospective medical record  review was performed to identify all patients who received ICI therapy at Mayo  Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with   a preexisting rheumatic disease were identified using specific diagnostic codes.   RESULTS: Sixteen patients were identified (81% female, median age 68.5 years).  The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia  rheumatica (n = 5), Sjogren's syndrome (n = 2), and systemic lupus erythematosus   (n = 2). Seven patients were receiving immunosuppressive therapy or  glucocorticoids for their rheumatic disease at the time of initiation of the ICI.  The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or  hematologic (n = 2). In most cases, ICIs were offered only after failure of  several other therapies. Immune-related adverse effects (IRAEs) occurred in 6  patients, and all were treated successfully with glucocorticoids and  discontinuation of the ICI therapy. There were no significant differences in time  from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex  between the patients with and those without IRAEs. CONCLUSION: To our knowledge,   this represents the largest single-center cohort of patients with rheumatic  diseases who were exposed to modern cancer immunotherapy. Only a minority of  these patients experienced a flare of their preexisting rheumatic disease or any   other IRAE.CI  - (c) 2017, American College of Rheumatology.
CANIT0001599	29363290	Clinical research	Cancer patients with preexisting rheumatic disease	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	16	N/A	A retrospective cohort study	This represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.	Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other immune-related adverse effects.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Brief Report: Cancer Immunotherapy in Patients With Preexisting Rheumatic  Disease: The Mayo Clinic Experience.	 Arthritis Rheumatol	 OBJECTIVE: To determine the risk of rheumatic disease flare and adverse effects  in patients with preexisting rheumatic disease who were receiving immune  checkpoint inhibitor (ICI) therapy. METHODS: A retrospective medical record  review was performed to identify all patients who received ICI therapy at Mayo  Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with   a preexisting rheumatic disease were identified using specific diagnostic codes.   RESULTS: Sixteen patients were identified (81% female, median age 68.5 years).  The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia  rheumatica (n = 5), Sjogren's syndrome (n = 2), and systemic lupus erythematosus   (n = 2). Seven patients were receiving immunosuppressive therapy or  glucocorticoids for their rheumatic disease at the time of initiation of the ICI.  The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or  hematologic (n = 2). In most cases, ICIs were offered only after failure of  several other therapies. Immune-related adverse effects (IRAEs) occurred in 6  patients, and all were treated successfully with glucocorticoids and  discontinuation of the ICI therapy. There were no significant differences in time  from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex  between the patients with and those without IRAEs. CONCLUSION: To our knowledge,   this represents the largest single-center cohort of patients with rheumatic  diseases who were exposed to modern cancer immunotherapy. Only a minority of  these patients experienced a flare of their preexisting rheumatic disease or any   other IRAE.CI  - (c) 2017, American College of Rheumatology.
CANIT0001600	29363290	Clinical research	Cancer patients with preexisting rheumatic disease	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	16	N/A	A retrospective cohort study	This represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.	Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other immune-related adverse effects.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Brief Report: Cancer Immunotherapy in Patients With Preexisting Rheumatic  Disease: The Mayo Clinic Experience.	 Arthritis Rheumatol	 OBJECTIVE: To determine the risk of rheumatic disease flare and adverse effects  in patients with preexisting rheumatic disease who were receiving immune  checkpoint inhibitor (ICI) therapy. METHODS: A retrospective medical record  review was performed to identify all patients who received ICI therapy at Mayo  Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with   a preexisting rheumatic disease were identified using specific diagnostic codes.   RESULTS: Sixteen patients were identified (81% female, median age 68.5 years).  The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia  rheumatica (n = 5), Sjogren's syndrome (n = 2), and systemic lupus erythematosus   (n = 2). Seven patients were receiving immunosuppressive therapy or  glucocorticoids for their rheumatic disease at the time of initiation of the ICI.  The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or  hematologic (n = 2). In most cases, ICIs were offered only after failure of  several other therapies. Immune-related adverse effects (IRAEs) occurred in 6  patients, and all were treated successfully with glucocorticoids and  discontinuation of the ICI therapy. There were no significant differences in time  from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex  between the patients with and those without IRAEs. CONCLUSION: To our knowledge,   this represents the largest single-center cohort of patients with rheumatic  diseases who were exposed to modern cancer immunotherapy. Only a minority of  these patients experienced a flare of their preexisting rheumatic disease or any   other IRAE.CI  - (c) 2017, American College of Rheumatology.
CANIT0001601	29363290	Clinical research	Cancer patients with preexisting rheumatic disease	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	N/A	A retrospective cohort study	This represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.	Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other immune-related adverse effects.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Brief Report: Cancer Immunotherapy in Patients With Preexisting Rheumatic  Disease: The Mayo Clinic Experience.	 Arthritis Rheumatol	 OBJECTIVE: To determine the risk of rheumatic disease flare and adverse effects  in patients with preexisting rheumatic disease who were receiving immune  checkpoint inhibitor (ICI) therapy. METHODS: A retrospective medical record  review was performed to identify all patients who received ICI therapy at Mayo  Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with   a preexisting rheumatic disease were identified using specific diagnostic codes.   RESULTS: Sixteen patients were identified (81% female, median age 68.5 years).  The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia  rheumatica (n = 5), Sjogren's syndrome (n = 2), and systemic lupus erythematosus   (n = 2). Seven patients were receiving immunosuppressive therapy or  glucocorticoids for their rheumatic disease at the time of initiation of the ICI.  The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or  hematologic (n = 2). In most cases, ICIs were offered only after failure of  several other therapies. Immune-related adverse effects (IRAEs) occurred in 6  patients, and all were treated successfully with glucocorticoids and  discontinuation of the ICI therapy. There were no significant differences in time  from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex  between the patients with and those without IRAEs. CONCLUSION: To our knowledge,   this represents the largest single-center cohort of patients with rheumatic  diseases who were exposed to modern cancer immunotherapy. Only a minority of  these patients experienced a flare of their preexisting rheumatic disease or any   other IRAE.CI  - (c) 2017, American College of Rheumatology.
CANIT0001602	29367376	Case report	Metastatic non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Programmed death receptor-1 inhibition can cause a spectrum of autoimmune adverse events requiring clinical monitoring and periodic screenings.	Pembrolizumab-induced myocarditis	N/A	N/A	N/A	N/A	N/A	 2018 Jan 23	 New drugs and new toxicities: pembrolizumab-induced myocarditis.	 BMJ Case Rep	 Pembrolizumab is an immune checkpoint inhibitor that significantly improves  clinical outcomes in numerous solid organ malignancies. Despite successful  therapeutic responses, this new drug comes with a constellation of adverse  reactions. Herein, we chronicle the case of a patient with metastatic  non-small-cell lung cancer treated with pembrolizumab. After two cycles, he  developed new-onset dyspnoea on exertion. Electrocardiogram showed  idioventricular rhythm with diffuse ST-segment elevations. Echocardiography  revealed severe biventricular cardiac dysfunction. Based on diagnostic workup and  exclusion of probable aetiologies, the patient was diagnosed with  pembrolizumab-induced myocarditis. The treatment was initiated with  corticosteroids and guideline-conform heart failure therapy. He demonstrated a  marked clinical response with resolution of congestive heart failure symptoms.  This article summarises the clinical evidence regarding the epidemiology,  pathophysiology, clinical features, diagnostic modalities and management of  patients with pembrolizumab-associated myocarditis. In addition, it highlights  that programmed death receptor-1 inhibition can cause a spectrum of autoimmune  adverse events requiring clinical monitoring and periodic screenings.CI  - (c) BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)  2018. All rights reserved. No commercial use is permitted unless otherwise  expressly granted.
CANIT0001603	29368144	Clinical research	Non-small-cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	175	N/A	A retrospective cohort study	More than one metastatic location was associated with poorer prognostic.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Organ metastasis	Disease status	 2018 Aug	 Predictive and prognostic clinical and pathological factors of nivolumab efficacy  in non-small-cell lung cancer patients.	 Clin Transl Oncol	 BACKGROUND: Immunotherapy increases overall response rate (ORR) and overall  survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and  predictive factors are a high need. PATIENTS AND METHODS: Retrospective review of  NSCLC patients treated with nivolumab was performed. Analyzed variables included   age, sex, stage, performance status (PS), location of metastases, presence of  tumour-related symptoms and comorbidities, number of metastasis locations,  previous chemotherapy, anti-angiogenic and radiotherapy treatments, and  analytical data from the standard blood count and biochemistry. RESULTS: A total   of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7%  were ECOG-PS 0-1, and 86.7% were included with stage IV disease. Histology was  non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%).  Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis  and 126 (72%) had more than one metastatic location. The ORR was 15.7% with  median Progression free survival (PFS) 2.8 months and median OS 5.81 months.  Stage III vs IV and time since the beginning of the previous line of treatment  >/= 6 vs < 6 months were associated with better response. PS 2, time since the  previous line of treatment < 6 vs >/= 6 months, and more than one metastatic  location were independently associated with shorter OS in multivariable analysis   (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time  since the previous treatment < 6 vs >/= 6 months and more than one metastatic  location were independently associated with shorter PFS in multivariable analysis  (4.3 vs 2.3 months and 4.7 vs 2.3 months). CONCLUSION: Poor PS, short period of  time since the previous treatment, and more than one metastatic location were  associated with poorer prognostic.
CANIT0001604	29368144	Clinical research	Non-small-cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	175	N/A	A retrospective cohort study	Poor performance status was associated with poorer prognostic.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2018 Aug	 Predictive and prognostic clinical and pathological factors of nivolumab efficacy  in non-small-cell lung cancer patients.	 Clin Transl Oncol	 BACKGROUND: Immunotherapy increases overall response rate (ORR) and overall  survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and  predictive factors are a high need. PATIENTS AND METHODS: Retrospective review of  NSCLC patients treated with nivolumab was performed. Analyzed variables included   age, sex, stage, performance status (PS), location of metastases, presence of  tumour-related symptoms and comorbidities, number of metastasis locations,  previous chemotherapy, anti-angiogenic and radiotherapy treatments, and  analytical data from the standard blood count and biochemistry. RESULTS: A total   of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7%  were ECOG-PS 0-1, and 86.7% were included with stage IV disease. Histology was  non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%).  Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis  and 126 (72%) had more than one metastatic location. The ORR was 15.7% with  median Progression free survival (PFS) 2.8 months and median OS 5.81 months.  Stage III vs IV and time since the beginning of the previous line of treatment  >/= 6 vs < 6 months were associated with better response. PS 2, time since the  previous line of treatment < 6 vs >/= 6 months, and more than one metastatic  location were independently associated with shorter OS in multivariable analysis   (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time  since the previous treatment < 6 vs >/= 6 months and more than one metastatic  location were independently associated with shorter PFS in multivariable analysis  (4.3 vs 2.3 months and 4.7 vs 2.3 months). CONCLUSION: Poor PS, short period of  time since the previous treatment, and more than one metastatic location were  associated with poorer prognostic.
CANIT0001605	29368144	Clinical research	Non-small-cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	175	N/A	A retrospective cohort study	Short period of time since the previous treatment was associated with poorer prognostic.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Period of time since the previous treatment	Exposure factors/status	 2018 Aug	 Predictive and prognostic clinical and pathological factors of nivolumab efficacy  in non-small-cell lung cancer patients.	 Clin Transl Oncol	 BACKGROUND: Immunotherapy increases overall response rate (ORR) and overall  survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and  predictive factors are a high need. PATIENTS AND METHODS: Retrospective review of  NSCLC patients treated with nivolumab was performed. Analyzed variables included   age, sex, stage, performance status (PS), location of metastases, presence of  tumour-related symptoms and comorbidities, number of metastasis locations,  previous chemotherapy, anti-angiogenic and radiotherapy treatments, and  analytical data from the standard blood count and biochemistry. RESULTS: A total   of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7%  were ECOG-PS 0-1, and 86.7% were included with stage IV disease. Histology was  non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%).  Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis  and 126 (72%) had more than one metastatic location. The ORR was 15.7% with  median Progression free survival (PFS) 2.8 months and median OS 5.81 months.  Stage III vs IV and time since the beginning of the previous line of treatment  >/= 6 vs < 6 months were associated with better response. PS 2, time since the  previous line of treatment < 6 vs >/= 6 months, and more than one metastatic  location were independently associated with shorter OS in multivariable analysis   (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time  since the previous treatment < 6 vs >/= 6 months and more than one metastatic  location were independently associated with shorter PFS in multivariable analysis  (4.3 vs 2.3 months and 4.7 vs 2.3 months). CONCLUSION: Poor PS, short period of  time since the previous treatment, and more than one metastatic location were  associated with poorer prognostic.
CANIT0001606	29370992	Clinical research	Metastatic sarcoma	Sarcoma	EFO:0000691	Soft tissue	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Nivolumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	38	38	Two open-label, non-comparative, randomised, phase II trials.	Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of nivolumab plus  ipilimumab in a randomised study is warranted.	The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance  A091401): two open-label, non-comparative, randomised, phase 2 trials.	 Lancet Oncol	 BACKGROUND: Patients with metastatic sarcoma have limited treatment options.  Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4,  respectively. We investigated the activity and safety of nivolumab alone or in  combination with ipilimumab in patients with locally advanced, unresectable, or  metastatic sarcoma. METHODS: We did a multicentre, open-label, non-comparative,  randomised, phase 2 study that enrolled patients aged 18 years or older and had  central pathology confirmation of sarcoma with at least one measurable lesion by   Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of  metastatic, locally advanced or unresectable disease, an ECOG performance status   of 0-1, and received at least one previous line of systemic therapy. Patients  were assigned to treatment in an unblinded manner, as this trial was conducted as  two independent, non-comparative phase 2 trials. Enrolled patients were assigned   (1:1) via a dynamic allocation algorithm to intravenous nivolumab 3 mg/kg every 2  weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses.  Thereafter, all patients received nivolumab monotherapy (3 mg/kg) every 2 weeks  for up to 2 years. The primary endpoint was the proportion of patients with  locally advanced, unresectable or metastatic soft tissue sarcoma achieving a  confirmed objective response. Analysis was per protocol. This study is ongoing  although enrolment is closed. It is registered with ClinicalTrials.gov, number  NCT02500797. FINDINGS: Between Aug 13, 2015, and March 17, 2016, 96 patients from  15 sites in the USA underwent central pathology review for eligibility and 85  eligible patients, including planned over-enrolment, were allocated to receive  either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42  patients). The primary endpoint analysis was done according to protocol  specifications in the first 76 eligible patients (38 patients per group). The  number of confirmed responses was two (5% [92% CI 1-16] of 38 patients) in the  nivolumab group and six (16% [7-30] of 38 patients) in the nivolumab plus  ipilimumab group. The most common grade 3 or worse adverse events were anaemia  (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration,   increased lipase, pain, pleural effusion, respiratory failure, secondary benign  neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42  patients in the nivolumab group and anaemia (eight [19%] patients), hypotension  (four [10%] patients), and pain and urinary tract infection (three [7%] patients   each) among the 42 patients in the nivolumab plus ipilimumab group. Serious  treatment-related adverse events occurred in eight (19%) of 42 patients receiving  monotherapy and 11 (26%) of 42 patients receiving combination therapy, and  included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea,  fatigue, fever, increased creatinine, increased alanine aminotransferase,  increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and   pruritus. There were no treatment-related deaths. INTERPRETATION: Nivolumab alone  does not warrant further study in an unselected sarcoma population given the  limited efficacy. Nivolumab combined with ipilimumab demonstrated promising  efficacy in certain sarcoma subtypes, with a manageable safety profile comparable  to current available treatment options. The combination therapy met its  predefined primary study endpoint; further evaluation of nivolumab plus  ipilimumab in a randomised study is warranted. FUNDING: Alliance Clinical Trials   in Oncology, National Cancer Institute Cancer Therapy Evaluation Program,  Bristol-Myers Squibb, Cycle for Survival.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001607	29380110	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	46	N/A	A retrospective cohort study	TSH fall 80% may be an early marker of IH. Serial TSH measurement during ipilimumab therapy may be an inexpensive tool to expedite IH diagnosis.	Ipilimumab-induced hypophysitis	N/A	N/A	Thyroid stimulating hormone (NCIT:C2280); 	Fall in thyroid stimulating hormone	Gene expression signature in serum	 2018 Jun	 Fall in thyroid stimulating hormone (TSH) may be an early marker of  ipilimumab-induced hypophysitis.	 Pituitary	 PURPOSE: Hypophysitis develops in up to 19% of melanoma patients treated with  ipilimumab, a cytotoxic T-lymphocyte antigen-4 antibody. Early detection may  avert life-threatening hypopituitarism. We aimed to assess the incidence of  ipilimumab-induced hypophysitis (IH) at a quaternary melanoma referral centre,  and to determine whether cortisol or thyroid stimulating hormone (TSH) monitoring  could predict IH onset. METHODS: We performed a retrospective cohort study of  ipilimumab-treated patients at a quaternary melanoma referral centre in  Australia. The inclusion criteria were patients with metastatic or unresectable  melanoma treated with ipilimumab monotherapy, and cortisol and TSH measurements  prior to >/= 2 infusions. The main outcomes were IH incidence and TSH and  cortisol patterns in patients who did and did not develop IH. RESULTS: Of 78  ipilimumab-treated patients, 46 met the study criteria and 9/46 (20%) developed  IH at a median duration of 13.0 weeks (range 7.7-18.1) following ipilimumab  initiation. All patients whose TSH fell >/= 80% compared to baseline developed  IH, and, in 5/9 patients with IH, TSH fell prior to cortisol fall and IH  diagnosis. Pre-cycle-4 TSH was significantly lower in those who developed IH  (0.31 vs. 1.73 mIU/L, P = 0.006). TSH fall was detected at a median time of 9.2  (range 7.7-16.4) weeks after commencing ipilimumab, and a median of 3.6 (range of  - 1.4 to 9.7) weeks before IH diagnosis. There was no difference in TSH between  the groups before cycles 1-3 or in cortisol before cycles 1-4. CONCLUSIONS: TSH  fall >/= 80% may be an early marker of IH. Serial TSH measurement during  ipilimumab therapy may be an inexpensive tool to expedite IH diagnosis.
CANIT0001608	29381409	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	A fatal and severe diffuse panmyositis that involved the cardiac, respiratory, and extraocular muscles	In this case report, we describe a fatal and severe diffuse panmyositis that involved the cardiac, respiratory, and extraocular muscles in a patient with metastatic melanoma secondary to combination treatment with Ipilimumab/Nivolumab.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	 Complete ophthalmoplegia in Ipilmumab and Nivolumab combination treatment for  metastatic melanoma.	 Orbit	 Ipilimumab and Nivolumab are novel monoclonal antibodies that have recently been   used successfully for treatment of metastatic melanoma. Ipilimumab is a human  monoclonal antibody against Cytotoxic T Lymphocyte Antigen 4 (CTLA4) receptor,  which suppresses T-cell proliferation and stimulates an inflammatory response  against cancer cells. Nivolumab is an IgG4 monoclonal antibody against the  cytotoxic T lymphocyte associated programmed death 1 receptor (PD-1). Ipilimumab   and Nivolumab combination treatment has been shown to induce remission and  prolong survival in patients with metastatic melanoma. The side effect profile of  these medications has not been well studied. One entity of the side effects  reported in the literature is immune-related adverse events (irAEs). There have  been few case reports where these events were serious and irreversible. In this  case report, we describe a fatal and severe diffuse panmyositis that involved the  cardiac, respiratory, and extraocular muscles in a patient with metastatic  melanoma secondary to combination treatment with Ipilimumab/Nivolumab.
CANIT0001609	29384770	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	The case of a 66-year-old man with metastatic melanoma treated with nivolumab and ipilimumab presented to the emergency department with marked hyperglycemia and elevated anion gap 19 days after receiving both agents is discussed. The patient received a diagnosis of immune-mediated diabetes requiring ongoing insulin even after discontinuation of ICIs.  As treatment with this class of agents expands, emergency department providers will need to become familiar with the identification of their adverse reactions to provide the proper management of care.	Drug-Induced Severe Endocrinopathies	N/A	N/A	N/A	N/A	N/A	 2018 Jan/Mar	 A Case of Drug-Induced Severe Endocrinopathies: What Providers in the Emergency  Department Need to Know.	 Adv Emerg Nurs J	 The purpose of this article is to present a discussion of immune checkpoint  inhibitors (ICIs) that are relatively new, yet growing, form of cancer therapy.  Immune checkpoint inhibitors increase host immune response against neoplastic  cells. Strengthened immunological response increases the potential for adverse  events such as life-threatening endocrinopathies. The case of a 66-year-old man  with metastatic melanoma treated with nivolumab and ipilimumab presented to the  emergency department with marked hyperglycemia and elevated anion gap 19 days  after receiving both agents is discussed. The patient received a diagnosis of  immune-mediated diabetes requiring ongoing insulin even after discontinuation of   ICIs. As treatment with this class of agents expands, emergency department  providers will need to become familiar with the identification of their adverse  reactions to provide the proper management of care.
CANIT0001610	29384959	Clinical research	Recurrent/metastatic head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	22	N/A	N/A	Pembrolizumab is beneficial and well-tolerated for some patients with refractory R/M HNSCC.	One patient developed immune-related pneumonitis that resolved quickly after steroid treatment. Another patient developed itchy skin rashes immediately after administration of pembrolizumab, and this was controlled by an antihistamine. There were no other severe adverse effects.	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Pembrolizumab for recurrent/metastatic head and neck squamous cell carcinoma in  an Asian population.	 Medicine (Baltimore)	 Head and neck squamous cell carcinoma (HNSCC) has a high prevalence and is a  major cause of cancer deaths in Taiwan. However, there is still no effective  salvage therapy that prolongs the life expectancy of patients with  recurrent/metastatic (R/M) HNSCC. Immune checkpoint therapy that targets the  programmed cell death protein 1 (PD-1) may provide clinical benefit for these  patients. We analyzed 22 R/M HNSCC patients who received pembrolizumab, a  monoclonal antibody against PD-1, as salvage therapy. Intravenous pembrolizumab  was given at a fixed dosage of 100 or 200 mg every 3 weeks. Three patients also  received local palliative radiotherapy, but no patients received chemotherapy or   targeted drugs. Seventeen patients (77.3%) received at least 3 cycles of  pembrolizumab. Based on Response Evaluation Criteria in Solid Tumors criteria  (ver. 1.1), 2 patients (9.1%) had complete response, 5 (22.7%) had partial  response, and 6 (27.3%) had stable disease, corresponding to a disease control  rate of 59.1%. Four patients had confirmed disease progression, 2 of whom had  continuous progression over the target lesion after shrinkage of other  metastases. One patient developed immune-related pneumonitis that resolved  quickly after steroid treatment. Another patient developed itchy skin rashes  immediately after administration of pembrolizumab, and this was controlled by an   antihistamine. There were no other severe adverse effects. Pembrolizumab is  beneficial and well-tolerated for some patients with refractory R/M HNSCC.  However, it is important to identify biomarkers to identify the most responsive  patients when designing future trials.CI  - Copyright (c) 2017 The Authors. Published by Wolters Kluwer Health, Inc. All  rights reserved.
CANIT0001611	29386195	Clinical research	Acute myeloid leukemi	Acute myeloid leukemia	EFO:0000222	Blood and lymph nodes	WT1 (P19544); 	WT1; 	WT1 peptide cancer vaccine	N/A	Tumor vaccine	WT1 vaccine (NCIT:C104738); 	22	N/A	A phase II clinical trial	The WT1 vaccine was well tolerated, stimulated a specific IR, and was associated with survival in excess of 5 years in this cohort of patients.	The vaccine was well tolerated, with the most common toxicities being grade 1/2 injection site reactions (46%), fatigue (32%), and skin induration (32%).	N/A	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD4(+) or CD8(+) T immune responses	Gene expression signature on/in immune cell	 2018 Feb 13	 Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute  myeloid leukemia.	 Blood Adv	 A National Cancer Institute consensus study on prioritization of cancer antigens   ranked the Wilms tumor 1 (WT1) protein as the top immunotherapy target in cancer.  We previously reported a pilot study of a multivalent WT1 peptide vaccine  (galinpepimut-S) in acute myeloid leukemia (AML) patients. We have now conducted   a phase 2 study investigating this vaccine in adults with AML in first complete  remission (CR1). Patients received 6 vaccinations administered over 10 weeks with  the potential to receive 6 additional monthly doses if they remained in CR1.  Immune responses (IRs) were evaluated after the 6th and 12th vaccinations by  CD4(+) T-cell proliferation, CD8(+) T-cell interferonG secretion  (enzyme-linked immunospot), or the CD8-relevant WT1 peptide major  histocompatibility complex tetramer assay (HLA-A*02 patients only). Twenty-two  patients (7 males; median age, 64 years) were treated. Fourteen patients (64%)  completed >/=6 vaccinations, and 9 (41%) received all 12 vaccine doses. Fifteen  patients (68%) relapsed, and 10 (46%) died. The vaccine was well tolerated, with   the most common toxicities being grade 1/2 injection site reactions (46%),  fatigue (32%), and skin induration (32%). Median disease-free survival from CR1  was 16.9 months, whereas the overall survival from diagnosis has not yet been  reached but is estimated to be >/=67.6 months. Nine of 14 tested patients (64%)  had an IR in >/=1 assay (CD4 or CD8). These results indicated that the WT1  vaccine was well tolerated, stimulated a specific IR, and was associated with  survival in excess of 5 years in this cohort of patients. This trial was  registered at www.clinicaltrials.gov as #NCT01266083.CI  - (c) 2018 by The American Society of Hematology.
CANIT0001612	29387968	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Vemurafenib	Immune checkpoint therapy	Vemurafenib (DB08881); ipilimumab (DB06186); 	40	40	N/A	Our real-life experience shows that long-term survival is possible with using both therapeutic agents, vemurafenib and ipilimumab. Pattern of metastases and laboratory values might be of interest in decision making for a specific therapeutic approach.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jan 31	 Long-term survival with modern therapeutic agents against metastatic  melanoma-vemurafenib and ipilimumab in a daily life setting.	 Med Oncol	 Despite new therapeutic options, metastatic melanoma remains to be one of the  most fatal tumors. With the development of BRAF inhibitors and immune checkpoint   inhibitors, overall survival could be prolonged significantly for the first time.  Clinical studies implied that even long-term survival is possible with both types  of drugs, but predictive markers are so far missing. In this study, we analyzed  survival data from patients that received the first-in-class substances  vemurafenib and ipilimumab, respectively, during the time period from  registration of the drugs until availability of combination treatments. We aimed   to evaluate the possibility of long-term survival in a daily life setting and to   characterize patients that benefit from these drugs in order to gain insight into  predictive attributes. Eighty patients were evaluated who were treated with  either vemurafenib (n = 40) or ipilimumab (n = 40), and overall survival was  analyzed. Subgroup analysis was performed for patients who were still alive 24  months after induction of therapy (long-term survival). Median overall survival  (OS) was 8.0 months for patients treated with vemurafenib and 10.0 months for  patients treated with ipilimumab (log-rank P value = 0.689). Long-term survival  was achieved in 32.5% of patients (42.3% vemurafenib, 57.7% ipilimumab). Negative  predictors of long-term survival in the vemurafenib group were brain and liver  metastases, as well as elevated LDH, S100ss and liver enzymes. For ipilimumab, an  increase in lymphocytes and eosinophils during course of treatment correlated  with long-term survival. Our real-life experience shows that long-term survival  is possible with using both therapeutic agents, vemurafenib and ipilimumab.  Pattern of metastases and laboratory values might be of interest in decision  making for a specific therapeutic approach. Combination of drugs and  observational studies in larger patient cohorts are necessary to further validate  our findings.
CANIT0001613	29390427	Case report	Primary adrenal melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus surgery	N/A	Immune checkpoint therapy plus Surgery	Surgery (NCIT:C17173); ipilimumab (DB06186); 	1	N/A	Case	When this article was completed, the patient was still alive and the survival has been already up to 20 months.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Primary adrenal malignant melanoma: A case report and review of literature.	 Medicine (Baltimore)	 RATIONALE: The primary adrenal melanoma (PAM) was an extremely rare occurrence,  which was demonstrated as the few cases described in the medical literature.  PATIENT CONCERNS: We reported a 58-year-old man who was admitted to hospital  because of intermittent left flank pain which lasted for a month. The renal  computed tomography (CT) scan showed that a large retroperitoneal tumor measuring  15.5 cm x 12.1 cm x 13.0 cm seemed to have its origin in the left adrenal gland.   DIAGNOSES: According to clinical symptoms, previous history, physical  examination, and postoperative pathology, the patient was diagnosed as PAM.  INTERVENTIONS: The patient was treated with an open procedure for resection of  retroperitoneal tumor. After the surgery, the patient participated in the  clinical drug trial and received treatment with ipilimumab as adjuvant medical  therapy. OUTCOMES: When this article was completed, the patient was still alive  and the survival has been already up to 20 months. LESSONS: The PAM was extremely  rare in clinic, and its diagnosis and differential diagnosis were difficult.  Therefore, clinical physicians should attach great importance to this disease.CI  - Copyright (c) 2017 The Authors. Published by Wolters Kluwer Health, Inc. All  rights reserved.
CANIT0001614	29390572	Case report	Pulmonary metastatic liver cancer	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	N/A	Acute liver failure	N/A	N/A	N/A	N/A	N/A	 2017 Dec	 Acute liver failure caused by pembrolizumab in a patient with pulmonary  metastatic liver cancer: A case report.	 Medicine (Baltimore)	 RATIONALE: Keytruda (pembrolizumab) is an inhibitor of programmed cell death  receptor-1 (PD-1), which was approved to treat advanced melanoma and nonsmall  cell lung cancer patients who do not respond to other treatment. However, its  efficacy and security in the treatment of advanced liver cancer is still under  investigation. PATIENT CONCERNS: A 60-year-old man was diagnosed with pulmonary  metastatic liver cancer who accepted pembrolizumab treatment after the failure of  sorafenib. When injected pembrolizumab, in spite of pulmonary metastatic lesion  shrink, the patient experienced severe liver dysfunction. DIAGNOSES: Based on the  features of the clinical signs and laboratory examination,the patient was  diagnosed with pembrolizumab-induced immune-related hepatitis by excluding other   etiologies and drug-induced side effects. INTERVENTIONS: The patient received  glucocorticoid and artificial liver (plasma exchange) therapy after failed  conservative liver protection treatment. OUTCOMES: The patient's liver  dysfunction continuously progressed and he finally died of liver failure and its   complications during his hospitalization. LESSONS: Pembrolizumab showed efficacy   in an advanced hepatocellular carcinoma patient with lung metastases. However, it  can generate immune-related adverse events such as immune-related hepatitis which  can be lethal.CI  - Copyright (c) 2017 The Authors. Published by Wolters Kluwer Health, Inc. All  rights reserved.
CANIT0001615	29394570	Case report	Transverse colon cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 [A Case of Duodenum Dissemination after Surgery for Transverse Colon Carcinoma  Which Was Unresponsive to Chemotherapy, but Immunotherapy Was Significantly  Effective].	 Gan To Kagaku Ryoho	 The patient was a 73-year-old woman who received surgery for transverse colon  cancer(laparoscopic right hemicolectomy) in December 2014. Histopathologic  examination findings were tub2, pT4b, pN1, sH0, sM0, ly2, v0, Stage III a. XELOX   2 courses-->FOLFIRI plus panitumumab(Pmab)12 courses was performed after surgery.  Stenosis due to duodenum dissemination was observed in the follow-up  period(December 2015), and a laparoscopic gastrojejunostomy was performed. Later,  the patient's tumor marker value significantly increased, and enlargement of  duodenum dissemination was observed by abdominalCT. From April 2016, treatment  was switched to mFOLFOX6 plus Pmab and 5 courses were subsequently performed.  Still, metastasis to the abdominal wall was observed. According to results of the  microsatellite instability test of MSIH, the patient was registered into a  clinicaltrialfor pembrolizumab, which is anti-PD-1, and administration began from  June. The tumor marker value significantly decreased, and a reduction in the size  of the duodenum dissemination over time could also be observed by abdominal CT.  Significant tumor reduction was observed, indicating that immune therapy may be  significantly effective in some cases.
CANIT0001616	29394654	Case report	Stage IV advanced sigmoid colon cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	He received FOLFOX plus bevacizumab(Bmab) as adjuvant chemotherapy. One year postoperatively, he experienced recurrence as multiple lung metastases. FOLFIRI plus panitumumab, SOX plus Bmab, CapeOX, nivolumab and FOLFIRI plus ramucirumab were then administered. The patient has survived for 4 years and 11 months from operation.	N/A	N/A	N/A	N/A	N/A	N/A	 2017 Nov	 [Case Report of Long-Term Survival for Stage IV Advanced Sigmoid Colon Cancer  with Para-Aortic Nodes by R0 Resection and Chemotherapy].	 Gan To Kagaku Ryoho	 The patient was a man in his early 30s. He underwent sigmoidectomy with D3+ #216   for advanced sigmoid colon cancer with metastatic para-aortic lymph nodes. The  pathological diagnosis was colon cancer(S), type 2, moderately differentiated,  pT4a(SE), pN3(19/33), pM1a(LYM), pStage IV , KRAS wild-type, EGFR(+). He received  FOLFOX plus bevacizumab(Bmab) as adjuvant chemotherapy. One year postoperatively,  he experienced recurrence as multiple lung metastases. FOLFIRI plus panitumumab,   SOX plus Bmab, CapeOX, nivolumab and FOLFIRI plus ramucirumab were then  administered. The patient has survived for 4 years and 11 months from operation.
CANIT0001617	29395863	Clinical research	Thymic carcinoma	Thymic cancer	MONDO:0002586	Thymus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	40	N/A	A single-arm, single-centre, phase II study	Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential.	The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre,  phase 2 study.	 Lancet Oncol	 BACKGROUND: Treatment options are limited for patients with thymic carcinoma.  These aggressive tumours are not typically associated with paraneoplastic  autoimmune disorders, and strong PD-L1 expression has been reported in thymic  epithelial tumours. We aimed to assess the activity of pembrolizumab, a  monoclonal antibody that targets PD-1, in patients with advanced thymic  carcinoma. METHODS: We completed a single-arm phase 2 study of pembrolizumab in  patients with recurrent thymic carcinoma who had progressed after at least one  line of chemotherapy. This was a single-centre study performed at Lombardi  Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key  inclusion criteria were an Eastern Cooperative Oncology Group performance status   of 0-2, no history of autoimmune disease or other malignancy requiring treatment   or laboratory abnormality, and adequate organ function. Patients received 200 mg   of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the  study was the proportion of patients who had achieved a response assessed with  Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per  protocol, in all eligible patients. The study is registered with  ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the  final analysis. FINDINGS: 41 patients were enrolled from March 12, 2015, to Dec  16, 2016, of whom 40 were eligible and evaluable and one was excluded because of   elevated liver enzymes at screening. The median follow-up was 20 months (IQR  14-26). The proportion of patients who achieved a response was 22.5% (95% CI  10.8-38.5); one (3%) patient achieved a complete response, eight (20%) patients  achieved partial responses, and 21 (53%) patients achieved stable disease. The  most common grade 3 or 4 adverse events were increased aspartate aminotransferase  and alanine aminotransferase (five [13%] patients each). Six (15%) patients  developed severe autoimmune toxicity, including two (5%) patients with  myocarditis. There were 17 deaths at the time of analysis, but no deaths due to  toxicity. INTERPRETATION: Pembrolizumab is a promising treatment option in  patients with thymic carcinoma. Because severe autoimmune disorders are more  frequent in thymic carcinoma than in other tumour types, careful monitoring is  essential. FUNDING: Merck & Co.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001618	29398578	Clinical research	 Advanced Non-Small-cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	142	N/A	A phase II clinical trial	The objective response rate, PFS, and adverse event profiles were comparable to those observed in previous clinical trials. EGFR/ALK mutation-negative status  might be key clinical characteristics associated with a positive treatment response. Our findings could aid in the efficient immunotherapeutic management of lung cancer.	EGFR/ALK mutational status	N/A	N/A	EGFR/ALK (P00533); 	EGFR/ALK mutational status	Mutational status	 2018 May	 Real-world Efficacy and Safety of Nivolumab for Advanced Non-Small-cell Lung  Cancer: A Retrospective Multicenter Analysis.	 Clin Lung Cancer	 BACKGROUND: Nivolumab, an immune checkpoint inhibitor, is now a standard  treatment for previously treated advanced non-small-cell lung cancer based on the  results from phase III clinical trials. We evaluated the real-world efficacy and   safety of nivolumab in a nonselected population and identified the clinical  characteristics that influence efficacy. MATERIALS AND METHODS: A total of 142  patients with advanced non-small-cell lung cancer who were administered nivolumab  at Keio University and affiliated hospitals in Japan from January to July 2016  were enrolled. The treatment efficacy and adverse events were retrospectively  reviewed, and the clinical characteristics associated with the nivolumab response  were evaluated using univariate and stratified analyses and the  Cochran-Mantel-Haenszel test. RESULTS: The objective response rate was 17.0% (95%  confidence interval [CI], 12.0%-24.0%), the median progression-free survival  (PFS) was 58 days (95% CI, 50-67 days), and the proportion of patients with  adverse events of any grade was 45.0%. EGFR/ALK mutation status was inversely  associated with the treatment response (P < .05), and the difference in PFS for  the mutation-positive versus mutation-negative patients was statistically  significant (49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2; P = .029).  Previous radiotherapy also had a positive association with the treatment response  (P = .012). CONCLUSION: The objective response rate, PFS, and adverse event  profiles were comparable to those observed in previous clinical trials. EGFR/ALK   mutation-negative status and previous radiotherapy might be key clinical  characteristics associated with a positive treatment response. Our findings could  aid in the efficient immunotherapeutic management of lung cancer.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001619	29398578	Clinical research	 Advanced Non-Small-cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	142	N/A	A phase III clinical trial	The objective response rate, PFS, and adverse event profiles were comparable to those observed in previous clinical trials. EGFR/ALK mutation-negative status  might be key clinical characteristics associated with a positive treatment response. Our findings could aid in the efficient immunotherapeutic management of lung cancer.	EGFR/ALK mutational status	N/A	N/A	Treatment history (NCIT:C160179); 	Previous radiotherapy	Exposure factors/status	 2018 May	 Real-world Efficacy and Safety of Nivolumab for Advanced Non-Small-cell Lung  Cancer: A Retrospective Multicenter Analysis.	 Clin Lung Cancer	 BACKGROUND: Nivolumab, an immune checkpoint inhibitor, is now a standard  treatment for previously treated advanced non-small-cell lung cancer based on the  results from phase III clinical trials. We evaluated the real-world efficacy and   safety of nivolumab in a nonselected population and identified the clinical  characteristics that influence efficacy. MATERIALS AND METHODS: A total of 142  patients with advanced non-small-cell lung cancer who were administered nivolumab  at Keio University and affiliated hospitals in Japan from January to July 2016  were enrolled. The treatment efficacy and adverse events were retrospectively  reviewed, and the clinical characteristics associated with the nivolumab response  were evaluated using univariate and stratified analyses and the  Cochran-Mantel-Haenszel test. RESULTS: The objective response rate was 17.0% (95%  confidence interval [CI], 12.0%-24.0%), the median progression-free survival  (PFS) was 58 days (95% CI, 50-67 days), and the proportion of patients with  adverse events of any grade was 45.0%. EGFR/ALK mutation status was inversely  associated with the treatment response (P < .05), and the difference in PFS for  the mutation-positive versus mutation-negative patients was statistically  significant (49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2; P = .029).  Previous radiotherapy also had a positive association with the treatment response  (P = .012). CONCLUSION: The objective response rate, PFS, and adverse event  profiles were comparable to those observed in previous clinical trials. EGFR/ALK   mutation-negative status and previous radiotherapy might be key clinical  characteristics associated with a positive treatment response. Our findings could  aid in the efficient immunotherapeutic management of lung cancer.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001620	29400292	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); CTLA-4 (P16410); 	PD-1; CTLA-4	Nivolumab followed by ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Case	N/A	No recurrence of nivolumab-induced idiopathic thrombocytopenic purpura in a metastatic melanoma patient switched to ipilimumab.	N/A	N/A	N/A	N/A	N/A	 2018 Feb 1	 No recurrence of nivolumab-induced idiopathic thrombocytopenic purpura in a  metastatic melanoma patient switched to ipilimumab.	 Eur J Dermatol	Unable to provide
CANIT0001621	29401149	Case report	Metastatic melanoma on nivolumab	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Our retrospective analysis demonstrated abnormal convex superior pituitary border visible on contrast and noncontrast CT and PET. This feature may aid diagnosis in the challenging cases.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Superior Pituitary Border Analysis in Immunotherapy-Induced Hypophysitis.	 Clin Nucl Med	 Immunotherapy-induced hypophysitis presents with headache, fatigue, and visual  disturbances. The diagnosis is supported by imaging findings of pituitary  swelling, enhancement, and hypermetabolism and established by low levels of  pituitary hormones. A 64-year-old man with metastatic melanoma on nivolumab  presented with a severe headache, initially attributed to sinus disease. Contrast  CT was interpreted as minor sinus disease and no pituitary abnormality.  Hypophysitis was eventually diagnosed and successfully treated based on PET and  laboratory findings. Our retrospective analysis demonstrated abnormal convex  superior pituitary border visible on contrast and noncontrast CT and PET. This  feature may aid diagnosis in the challenging cases.
CANIT0001622	29402438	Case report	Non -small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Remitting seronegative symmetrical synovitis with pitting edema	Remitting seronegative symmetrical synovitis with pitting edema after 18 months of active treatment with nivolumab.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	 Resolution of remitting seronegative symmetrical synovitis with pitting edema  (RS3PE) during Nivolumab therapy for non-small cell lung cancer: a case report.	 Semin Arthritis Rheum	Unable to provide
CANIT0001623	29402706	Clinical research	Metastatic Renal-Cell Carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	A retrospective cohort study	Pretreatment neutrophil/lymphocyte ratio(NLR) < 5.5 is associated with superior PFS and OS. NLR is a biomarker that can inform prognosis for patients with mRCC and should be further validated in larger cohorts and in prospective studies.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2018 Jun	 Association Between Pretreatment Neutrophil-to-Lymphocyte Ratio and Outcome of  Patients With Metastatic Renal-Cell Carcinoma Treated With Nivolumab.	 Clin Genitourin Cancer	 BACKGROUND: Biomarkers to guide treatment in metastatic renal-cell carcinoma  (mRCC) are lacking. We aimed to investigate the association between pretreatment   neutrophil-to-lymphocyte ratio (NLR) and outcome of patients with mRCC receiving   nivolumab. PATIENTS AND METHODS: Through retrospective chart review, we  identified 38 patients with mRCC treated with standard-of-care nivolumab between   2015 and 2016 at Winship Cancer Institute of Emory University. NLR was determined  from complete blood count collected before starting treatment, and imaging was  performed to assess progression. The NLR cutoff value of 5.5 was determined by  log-rank test, and the univariate association with overall survival (OS) or  progression-free survival (PFS) was assessed by the Cox proportional hazard model  and Kaplan-Meier method. RESULTS: The 38 patients had a median age of 69 years.  The PFS and OS for all patients at 12 months was 54% and 69%, respectively. The  median PFS was 2.6 months in the high NLR group but not reached in the low NLR  group. Low NLR was strongly associated with increased PFS with hazard ratio of  0.20 (95% confidence interval, 0.07-0.64; P = .006). The median OS was 2.7 months  in the high NLR group but not reached in the low NLR group. Low NLR was  significantly associated with a prolonged OS with hazard ratio of 0.06 (95%  confidence interval, 0.01-0.55; P = .012). CONCLUSION: Pretreatment NLR < 5.5 is   associated with superior PFS and OS. NLR is a biomarker that can inform prognosis  for patients with mRCC and should be further validated in larger cohorts and in  prospective studies.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001624	29403081	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	2	N/A	Case	In conclusion, liver injury caused by cancer immunotherapy shares some features with injury of autoimmune hepatitis; however, there are obvious differences between the two conditions. Checkpoint inhibitor-induced liver injury may represent an immune-mediated, less zone-selective hepatocyte necrosis not requiring the strong activation of helper T cells and immunoglobulin production.	Lobular hepatitis with milder portal inflammation	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases   in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver  injury.	 Mod Pathol	 The adverse effects of immune checkpoint inhibitors in various organs may be  attributed to immune-mediated processes triggered by disrupted self-tolerance;  however, it remains unclear whether they are similar or dissimilar to classic  organ-specific autoimmune diseases. The present study aimed to compare  clinicopathologic features between checkpoint inhibitor-induced liver injury and   acutely presenting autoimmune hepatitis or idiosyncratic drug-induced liver  injury. Seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2)  presented with liver dysfunction a median of 41 days (range 21-120) after the  initiation of immunotherapy. All patients had elevated liver enzymes, whereas  hyper-bilirubinemia was less common. None of the patients had antinuclear  antibodies or IgG elevations. Stopping the immunotherapy and additional  immunosuppression with corticosteroids normalized or decreased liver enzymes in  all patients treated. Histologically, all biopsies showed predominantly lobular  hepatitis with milder portal inflammation. Centrilobular confluent necrosis and  plasmacytosis were observed in a single case, and were markedly less common and  milder than those in autoimmune hepatitis (p = 0.017 and p < 0.001,  respectively). Bile duct injury, micro-abscesses, and extramedullary  hematopoiesis were also found in one case each. Immunostaining revealed the  presence of large numbers of CD3+ and CD8+ lymphocytes, whereas CD20+ B cells and  CD4+ T cells were fewer in checkpoint inhibitor-induced liver injury than in  autoimmune hepatitis or drug-induced liver injury. In conclusion, liver injury  caused by cancer immunotherapy shares some features with injury of autoimmune  hepatitis; however, there are obvious differences between the two conditions.  Checkpoint inhibitor-induced liver injury may represent an immune-mediated, less   zone-selective hepatocyte necrosis not requiring the strong activation of helper   T cells and immunoglobulin production.
CANIT0001625	29403081	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	4	N/A	Case	In conclusion, liver injury caused by cancer immunotherapy shares some features with injury of autoimmune hepatitis; however, there are obvious differences between the two conditions. Checkpoint inhibitor-induced liver injury may represent an immune-mediated, less zone-selective hepatocyte necrosis not requiring the strong activation of helper T cells and immunoglobulin production.	Lobular hepatitis with milder portal inflammation	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases   in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver  injury.	 Mod Pathol	 The adverse effects of immune checkpoint inhibitors in various organs may be  attributed to immune-mediated processes triggered by disrupted self-tolerance;  however, it remains unclear whether they are similar or dissimilar to classic  organ-specific autoimmune diseases. The present study aimed to compare  clinicopathologic features between checkpoint inhibitor-induced liver injury and   acutely presenting autoimmune hepatitis or idiosyncratic drug-induced liver  injury. Seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2)  presented with liver dysfunction a median of 41 days (range 21-120) after the  initiation of immunotherapy. All patients had elevated liver enzymes, whereas  hyper-bilirubinemia was less common. None of the patients had antinuclear  antibodies or IgG elevations. Stopping the immunotherapy and additional  immunosuppression with corticosteroids normalized or decreased liver enzymes in  all patients treated. Histologically, all biopsies showed predominantly lobular  hepatitis with milder portal inflammation. Centrilobular confluent necrosis and  plasmacytosis were observed in a single case, and were markedly less common and  milder than those in autoimmune hepatitis (p = 0.017 and p < 0.001,  respectively). Bile duct injury, micro-abscesses, and extramedullary  hematopoiesis were also found in one case each. Immunostaining revealed the  presence of large numbers of CD3+ and CD8+ lymphocytes, whereas CD20+ B cells and  CD4+ T cells were fewer in checkpoint inhibitor-induced liver injury than in  autoimmune hepatitis or drug-induced liver injury. In conclusion, liver injury  caused by cancer immunotherapy shares some features with injury of autoimmune  hepatitis; however, there are obvious differences between the two conditions.  Checkpoint inhibitor-induced liver injury may represent an immune-mediated, less   zone-selective hepatocyte necrosis not requiring the strong activation of helper   T cells and immunoglobulin production.
CANIT0001626	29403081	Case report	Squamous cell carcinoma of the tongue	Tongue squamous cell carcinoma	EFO:1000055	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	In conclusion, liver injury caused by cancer immunotherapy shares some features with injury of autoimmune hepatitis; however, there are obvious differences between the two conditions. Checkpoint inhibitor-induced liver injury may represent an immune-mediated, less zone-selective hepatocyte necrosis not requiring the strong activation of helper T cells and immunoglobulin production.	Lobular hepatitis with milder portal inflammation	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases   in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver  injury.	 Mod Pathol	 The adverse effects of immune checkpoint inhibitors in various organs may be  attributed to immune-mediated processes triggered by disrupted self-tolerance;  however, it remains unclear whether they are similar or dissimilar to classic  organ-specific autoimmune diseases. The present study aimed to compare  clinicopathologic features between checkpoint inhibitor-induced liver injury and   acutely presenting autoimmune hepatitis or idiosyncratic drug-induced liver  injury. Seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2)  presented with liver dysfunction a median of 41 days (range 21-120) after the  initiation of immunotherapy. All patients had elevated liver enzymes, whereas  hyper-bilirubinemia was less common. None of the patients had antinuclear  antibodies or IgG elevations. Stopping the immunotherapy and additional  immunosuppression with corticosteroids normalized or decreased liver enzymes in  all patients treated. Histologically, all biopsies showed predominantly lobular  hepatitis with milder portal inflammation. Centrilobular confluent necrosis and  plasmacytosis were observed in a single case, and were markedly less common and  milder than those in autoimmune hepatitis (p = 0.017 and p < 0.001,  respectively). Bile duct injury, micro-abscesses, and extramedullary  hematopoiesis were also found in one case each. Immunostaining revealed the  presence of large numbers of CD3+ and CD8+ lymphocytes, whereas CD20+ B cells and  CD4+ T cells were fewer in checkpoint inhibitor-induced liver injury than in  autoimmune hepatitis or drug-induced liver injury. In conclusion, liver injury  caused by cancer immunotherapy shares some features with injury of autoimmune  hepatitis; however, there are obvious differences between the two conditions.  Checkpoint inhibitor-induced liver injury may represent an immune-mediated, less   zone-selective hepatocyte necrosis not requiring the strong activation of helper   T cells and immunoglobulin production.
CANIT0001627	29406396	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	Patients with metastatic melanoma can be treated safely with PD-1 inhibitors in the context of HBV/HCV infection. However, we recommend that those with active viral hepatitis be monitored closely in consultation with a hepatologist and treated with antiviral therapy if indicated.	N/A	N/A	N/A	HCV (NCIT:C14312); HBV (NCIT:C14215); 	HBV/HCV-positive	Microbiota	 2018 Apr	 Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and  non-small-cell lung cancer in patients with viral hepatitis: a case series.	 Melanoma Res	 Anti-PD-1 monoclonal antibodies have shown durable long-term survival benefit in   patients with metastatic melanoma. Limited evidence exists on the safety and  efficacy of PD-1 inhibitors in patients with hepatitis B virus (HBV) and  hepatitis C virus (HCV) infections as these patients have traditionally been  excluded from clinical trials because of a theoretical risk of immune  reconstitution inflammatory syndrome. We aim to determine the safety and efficacy  of treatment with PD-1 inhibitors in seven patients with HBV/HCV infection and  concurrent metastatic melanoma or non-small-cell lung cancer (NSCLC). We describe  seven patients treated with PD-1 inhibitors nivolumab and pembrolizumab for  either metastatic melanoma or metastatic NSCLC in the setting of chronic or past   HBV/HCV infection. The safety and efficacy of treatment were analysed  retrospectively by examining response to treatment, alanine transaminase (ALT)  trends and viral load trends. One patient showed an increase in ALT of Common  Terminology Criteria for Adverse Events (CTCAE) grade 2 severity that returned to  the normal range following treatment of his HCV infection with ledipasvir 90  mg/sofosbuvir 400 mg. An additional four patients showed an increase in ALT of  CTCAE grade 1 severity. The remaining two patients experienced no hepatic  toxicity, with stable disease continuing after more than 24 cycles of nivolumab.   Efficacy was similar to the data of published trials. Our results indicate that  patients with metastatic melanoma and NSCLC can be treated safely with PD-1  inhibitors in the context of HBV/HCV infection. However, we recommend that those   with active viral hepatitis be monitored closely in consultation with a  hepatologist and treated with antiviral therapy if indicated.
CANIT0001628	29406396	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Case	Patients with metastatic melanoma can be treated safely with PD-1 inhibitors in the context of HBV/HCV infection. However, we recommend that those with active viral hepatitis be monitored closely in consultation with a hepatologist and treated with antiviral therapy if indicated.	N/A	N/A	N/A	HCV (NCIT:C14312); HBV (NCIT:C14215); 	HBV/HCV-positive	Microbiota	 2018 Apr	 Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and  non-small-cell lung cancer in patients with viral hepatitis: a case series.	 Melanoma Res	 Anti-PD-1 monoclonal antibodies have shown durable long-term survival benefit in   patients with metastatic melanoma. Limited evidence exists on the safety and  efficacy of PD-1 inhibitors in patients with hepatitis B virus (HBV) and  hepatitis C virus (HCV) infections as these patients have traditionally been  excluded from clinical trials because of a theoretical risk of immune  reconstitution inflammatory syndrome. We aim to determine the safety and efficacy  of treatment with PD-1 inhibitors in seven patients with HBV/HCV infection and  concurrent metastatic melanoma or non-small-cell lung cancer (NSCLC). We describe  seven patients treated with PD-1 inhibitors nivolumab and pembrolizumab for  either metastatic melanoma or metastatic NSCLC in the setting of chronic or past   HBV/HCV infection. The safety and efficacy of treatment were analysed  retrospectively by examining response to treatment, alanine transaminase (ALT)  trends and viral load trends. One patient showed an increase in ALT of Common  Terminology Criteria for Adverse Events (CTCAE) grade 2 severity that returned to  the normal range following treatment of his HCV infection with ledipasvir 90  mg/sofosbuvir 400 mg. An additional four patients showed an increase in ALT of  CTCAE grade 1 severity. The remaining two patients experienced no hepatic  toxicity, with stable disease continuing after more than 24 cycles of nivolumab.   Efficacy was similar to the data of published trials. Our results indicate that  patients with metastatic melanoma and NSCLC can be treated safely with PD-1  inhibitors in the context of HBV/HCV infection. However, we recommend that those   with active viral hepatitis be monitored closely in consultation with a  hepatologist and treated with antiviral therapy if indicated.
CANIT0001629	29406396	Case report	Metastatic non-small-cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Case	Patients with NSCLC can be treated safely with PD-1 inhibitors in the context of HBV/HCV infection. However, we recommend that those with active viral hepatitis be monitored closely in consultation with a hepatologist and treated with antiviral therapy if indicated.	N/A	N/A	N/A	HCV (NCIT:C14312); HBV (NCIT:C14215); 	HBV/HCV-positive	Microbiota	 2018 Apr	 Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and  non-small-cell lung cancer in patients with viral hepatitis: a case series.	 Melanoma Res	 Anti-PD-1 monoclonal antibodies have shown durable long-term survival benefit in   patients with metastatic melanoma. Limited evidence exists on the safety and  efficacy of PD-1 inhibitors in patients with hepatitis B virus (HBV) and  hepatitis C virus (HCV) infections as these patients have traditionally been  excluded from clinical trials because of a theoretical risk of immune  reconstitution inflammatory syndrome. We aim to determine the safety and efficacy  of treatment with PD-1 inhibitors in seven patients with HBV/HCV infection and  concurrent metastatic melanoma or non-small-cell lung cancer (NSCLC). We describe  seven patients treated with PD-1 inhibitors nivolumab and pembrolizumab for  either metastatic melanoma or metastatic NSCLC in the setting of chronic or past   HBV/HCV infection. The safety and efficacy of treatment were analysed  retrospectively by examining response to treatment, alanine transaminase (ALT)  trends and viral load trends. One patient showed an increase in ALT of Common  Terminology Criteria for Adverse Events (CTCAE) grade 2 severity that returned to  the normal range following treatment of his HCV infection with ledipasvir 90  mg/sofosbuvir 400 mg. An additional four patients showed an increase in ALT of  CTCAE grade 1 severity. The remaining two patients experienced no hepatic  toxicity, with stable disease continuing after more than 24 cycles of nivolumab.   Efficacy was similar to the data of published trials. Our results indicate that  patients with metastatic melanoma and NSCLC can be treated safely with PD-1  inhibitors in the context of HBV/HCV infection. However, we recommend that those   with active viral hepatitis be monitored closely in consultation with a  hepatologist and treated with antiviral therapy if indicated.
CANIT0001630	29406396	Case report	Metastatic non-small-cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Case	Patients with NSCLC can be treated safely with PD-1 inhibitors in the context of HBV/HCV infection. However, we recommend that those with active viral hepatitis be monitored closely in consultation with a hepatologist and treated with antiviral therapy if indicated.	N/A	N/A	N/A	HCV (NCIT:C14312); HBV (NCIT:C14215); 	HBV/HCV-positive	Microbiota	 2018 Apr	 Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and  non-small-cell lung cancer in patients with viral hepatitis: a case series.	 Melanoma Res	 Anti-PD-1 monoclonal antibodies have shown durable long-term survival benefit in   patients with metastatic melanoma. Limited evidence exists on the safety and  efficacy of PD-1 inhibitors in patients with hepatitis B virus (HBV) and  hepatitis C virus (HCV) infections as these patients have traditionally been  excluded from clinical trials because of a theoretical risk of immune  reconstitution inflammatory syndrome. We aim to determine the safety and efficacy  of treatment with PD-1 inhibitors in seven patients with HBV/HCV infection and  concurrent metastatic melanoma or non-small-cell lung cancer (NSCLC). We describe  seven patients treated with PD-1 inhibitors nivolumab and pembrolizumab for  either metastatic melanoma or metastatic NSCLC in the setting of chronic or past   HBV/HCV infection. The safety and efficacy of treatment were analysed  retrospectively by examining response to treatment, alanine transaminase (ALT)  trends and viral load trends. One patient showed an increase in ALT of Common  Terminology Criteria for Adverse Events (CTCAE) grade 2 severity that returned to  the normal range following treatment of his HCV infection with ledipasvir 90  mg/sofosbuvir 400 mg. An additional four patients showed an increase in ALT of  CTCAE grade 1 severity. The remaining two patients experienced no hepatic  toxicity, with stable disease continuing after more than 24 cycles of nivolumab.   Efficacy was similar to the data of published trials. Our results indicate that  patients with metastatic melanoma and NSCLC can be treated safely with PD-1  inhibitors in the context of HBV/HCV infection. However, we recommend that those   with active viral hepatitis be monitored closely in consultation with a  hepatologist and treated with antiviral therapy if indicated.
CANIT0001631	29413052	Clinical research	Non-small-cell lung cancer with brain metastases	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	43	N/A	A multicentre, retrospective cohort study	Nivolumab intracerebral activity was similar to its reported extracerebral efficacy, with an acceptable safety profile. 	Five neurological adverse events occurred, including 1 grade-4 transient ischemic attack of uncertain imputability and 1 grade-3 neurological deficit	N/A	N/A	N/A	N/A	N/A	 2018 Feb	 Intracerebral efficacy and tolerance of nivolumab in non-small-cell lung cancer  patients with brain metastases.	 Lung Cancer	 OBJECTIVES: Although nivolumab has shown efficacy against non-small-cell lung  cancers (NSCLCs), patients with active brain metastases (BMs) were excluded from   pivotal clinical trials. Hence, data regarding nivolumab intracerebral activity  and safety in NSCLC patients with BMs are scarce. MATERIALS AND METHODS: We  conducted a retrospective multicenter study on NSCLC patients with BMs treated  with nivolumab. The primary endpoint was intracerebral objective response rate  (IORR), according to RECIST criteria. Secondary endpoints included intracerebral   control rate, intracerebral and general progression-free survival (PFS), overall   survival (OS) and tolerance. RESULTS AND CONCLUSION: Forty-three patients were  included. BMs were locally pretreated in 34 (79%) patients and active in 16 (37%)  patients. Median follow-up was 5.7 (95% CI: 2.7-8.4) months. IORR and  extracerebral response rate were, respectively, 9% (95% CI: 3-23%) and 11% (95%  CI: 4-26%). Intracerebral control rate was 51% (95% CI: 37-66%). Median  intracerebral and general PFS lasted 3.9 (95% CI: 2.8-11.1) and 2.8 (95% CI:  1.8-4.6) months, respectively. Median OS was 7.5 (95% CI: 5.6-not reached)  months. Five neurological adverse events occurred, including 1 grade-4 transient   ischemic attack of uncertain imputability and 1 grade-3 neurological deficit;  neither required nivolumab discontinuation. Nivolumab intracerebral activity was   similar to its reported extracerebral efficacy, with an acceptable safety  profile. Prospective and controlled data are needed to determine nivolumab's  place in treatment of NSCLC patients with BMs.CI  - Copyright (c) 2017 Elsevier B.V. All rights reserved.
CANIT0001632	29418077	Case report	Advanced pulmonary squamous cell carcinoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We encountered a case that could be surgically treated after pembrolizumab administration. This treatment was safe and effective for advanced lung cancer.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Case of advanced pulmonary squamous cell carcinoma cured by resection through  preoperative induction of immune checkpoint inhibitor.	 Thorac Cancer	 The options for lung cancer treatment have increased due to the development of  immune checkpoint inhibitors, but there has been no report of inoperable cases  whereby the treatment effects rendered the case operable, an operation was  subsequently performed, and histological assessment of the surgical specimen was   carried out. Here, we report a 67-year-old man who was given pembrolizumab for  T3N0 lung squamous cell carcinoma suspected of pericardial infiltration and  judged inoperable. Treatment effect was evaluated after four courses. Computed  tomography indicated a partial response, and operability was feasible. Therefore,  thoracoscopic left upper lobectomy was performed after six courses of  pembrolizumab, and histological assessment of the treatment effect was determined  to be Ef 3, a complete response. The postoperative course was uneventful and he  was discharged on the third postoperative day. We encountered a case that could  be surgically treated after pembrolizumab administration. This treatment was safe  and effective for advanced lung cancer.CI  - (c) 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and   John Wiley & Sons Australia, Ltd.
CANIT0001633	29420369	Case report	Juvenile renal cell carcinoma (RCC)	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The reported adverse events in our patient were nevertheless particularly disabling. Although the longterm effects of nivolumab are unknown in children, pediatrician clinicians may consider anti-PD-1 therapy for rare cases of children with refractory juvenile RCC, at best in clinical trials (if available).	Nivolumab-related adverse events were fatigue (grade 2), decreased appetite (grade 2), hypothyroidism (grade 2), and diffuse pain (grade 2). Lansky performance status was estimated to be 40% and did not improve during treatment.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Efficacy and Toxicity of Fifth-line Nivolumab in a 15-Year-Old Girl With  Metastatic Juvenile Renal Cell Carcinoma.	 J Pediatr Hematol Oncol	Unable to provide
CANIT0001634	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001635	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001636	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001637	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001638	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001639	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001640	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001641	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001642	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001643	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001644	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001645	29424425	Clinical research	2,541 had melanoma (5 trials) and 2,192 had NSCLC (4 trials). Besides, 821 patients had renal-cell carcinoma (1 trial) and 542 patients had urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6096	N/A	N/A	A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Jul 1	 Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and  CTLA-4 inhibitors).	 Int J Cancer	 Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on  immune response, which is affected by sex difference, where both biological and  sociological factors are involved. The role of sex in ICI trials has been  overlooked. How sex correlates with ICI efficacy is incompletely understood.  Clinical trials evaluating ICI versus other therapies in male and female patients  were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall   survival (OS) and progression-free survival (PFS) were used. Six thousand and  ninety-six patients from 11 trials were included. More improvement of OS was  observed in males (HR, 0.62; 95% CI, 0.53-0.71; p < 0.001) treated with ICI  versus controls than females (HR, 0.74; 95% CI, 0.65-0.84; p < 0.001). ICIs  improved PFS more in males (HR, 0.57; 95% CI, 0.43-0.71; p < 0.001) than females   (HR, 0.71; 95% CI, 0.52-0.91; p < 0.001). The sex difference had more effect on  the overall survival in melanoma patients versus NSCLC patients. Overall survival  of patients treated with CTLA-4 inhibitor was more influenced by sex variable  compared with PD-1 inhibitors. A significant sex-related efficacy difference was   observed between female and male melanoma patients. Although male patients had  longer OS and PFS than females when treated with ICIs versus controls, the  difference was not significant. Sex difference should be more considered in  future clinical trials, guidelines and clinical practice.CI  - (c) 2018 UICC.
CANIT0001646	29434118	Case report	Lung adenocarcinoma with choriocarcinomatous features	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Our experience suggests that nivolumab has strong activity, even in patients with a rare form of lung cancer.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jun 15	 The Significant Antitumor Activity of Nivolumab in Lung Adenocarcinoma with  Choriocarcinomatous Features.	 Intern Med	 We report the case of a 60-year-old Japanese man with a metastatic brain tumor  that caused ataxia. As a consequence of resection of a cerebellar tumor, the  tumor was diagnosed as a poorly differentiated adenocarcinoma with  choriocarcinomatous features. The patient underwent bronchoscopy, leading to a  diagnosis of the same histology as the brain tumor. After the administration of  first-line chemotherapy and maintenance therapy due to progressive disease, he  was given nivolumab and obtained a partial response; however, 11-months later,  computed tomography showed tumor progression. Our experience suggests that  nivolumab has strong activity, even in patients with a rare form of lung cancer.
CANIT0001647	29434145	Case report	Primary neuroendocrine carcinoma of the trachea	Tracheal carcinoma	EFO:1000599	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Regardless of the disease stability, nivolumab has the potential to exacerbate an autoimmune disease, and we must pay close attention to each patient's medical history before administering this agent.	Relapsed myasthenia gravis	N/A	N/A	N/A	N/A	N/A	 2018 Jul 1	 Relapsed Myasthenia Gravis after Nivolumab Treatment.	 Intern Med	 Nivolumab is a newly introduced promising therapy for treating lung cancer that  restores the anti-tumor immunity by disrupting programmed cell death-1-mediated  immuno-suppressive signaling. Although new-onset autoimmune diseases are  well-known immune-related adverse events, whether or not nivolumab exacerbates  pre-existing autoimmune disease remains unclear. We herein report a patient  with pre-existing myasthenia gravis in whom nivolumab was administered that  flared up after the treatment with nivolumab. Regardless of the disease  stability, nivolumab has the potential to exacerbate an autoimmune disease, and  we must pay close attention to each patient's medical history before  administering this agent.
CANIT0001648	29437773	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Autoimmune fasciitis	However, in addition to developing incident autoimmune hypothyroidism, she also developed progressive fatigue, proximal weakness, myalgia and dysphagia. Initial investigations with blood tests, electrophysiology and a muscle biopsy were non-specific or normal. Subsequent examination revealed 'woody' thickening of the subcutaneous tissues of the forearms, thighs and calves consistent with fasciitis. MRI and a full-thickness skin-muscle biopsy were ultimately diagnostic of a likely iatrogenic autoimmune myofasciitis. The clinical manifestations only responded partly to prednisolone 30 mg orally and treatment was escalated to include intravenous immunoglobulin. At 3 months, this has only resulted in a modest incremental improvement.	N/A	N/A	N/A	N/A	N/A	 2018 Feb 8	 Autoimmune fasciitis triggered by the anti-programmed cell death-1 monoclonal  antibody nivolumab.	 BMJ Case Rep	 A 43-year-old woman with a history of recently diagnosed metastatic melanoma was   commenced on systemic therapy with nivolumab, an anti-programmed cell death-1  monoclonal antibody and one of an increasing group of the so-called 'immune  checkpoint inhibitors'. She experienced a dramatic complete response within 6  months of initiation. However, in addition to developing incident autoimmune  hypothyroidism, she also developed progressive fatigue, proximal weakness,  myalgia and dysphagia. Initial investigations with blood tests, electrophysiology  and a muscle biopsy were non-specific or normal. Subsequent examination revealed   'woody' thickening of the subcutaneous tissues of the forearms, thighs and calves  consistent with fasciitis. MRI and a full-thickness skin-muscle biopsy were  ultimately diagnostic of a likely iatrogenic autoimmune myofasciitis. The  clinical manifestations only responded partly to prednisolone 30 mg orally and  treatment was escalated to include intravenous immunoglobulin. At 3 months, this   has only resulted in a modest incremental improvement.CI  - (c) BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)  2018. All rights reserved. No commercial use is permitted unless otherwise  expressly granted.
CANIT0001649	29439857	Clinical research	Advanced renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Axitinib plus pembrolizumab	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); axitinib (DB06626); 	52	N/A	A non-randomised, open-label, dose-finding, and dose-expansion phase Ib trial	The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma.	No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Axitinib in combination with pembrolizumab in patients with advanced renal cell  cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b  trial.	 Lancet Oncol	 BACKGROUND: Previous studies combining PD-1 checkpoint inhibitors with tyrosine  kinase inhibitors of the VEGF pathway have been characterised by excess toxicity,  precluding further development. We hypothesised that axitinib, a more selective  VEGF inhibitor than others previously tested, could be combined safely with  pembrolizumab (anti-PD-1) and yield antitumour activity in patients with  treatment-naive advanced renal cell carcinoma. METHODS: In this ongoing,  open-label, phase 1b study, which was done at ten centres in the USA, we enrolled  patients aged 18 years or older who had advanced renal cell carcinoma  (predominantly clear cell subtype) with their primary tumour resected, and at  least one measureable lesion, Eastern Cooperative Oncology Group performance  status 0-1, controlled hypertension, and no previous systemic therapy for renal  cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a  dose-finding phase to estimate the maximum tolerated dose, and additional  patients were enrolled into a dose-expansion phase to further establish safety  and determine preliminary efficacy. Axitinib 5 mg was administered orally twice  per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed  safety in all patients who received at least one dose of axitinib or  pembrolizumab; antitumour activity was assessed in all patients who received  study treatment and had an adequate baseline tumour assessment. The primary  endpoint was investigator-assessed dose-limiting toxicity during the first two  cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2  dose. This study is registered with ClinicalTrials.gov, number NCT02133742.  FINDINGS: Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with  previously untreated advanced renal cell carcinoma to the dose-finding phase and   between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the  dose-expansion phase. All 52 patients were analysed together. No unexpected  toxicities were observed. Three dose-limiting toxicities were reported in the 11   patients treated during the 6-week observation period (dose-finding phase): one  patient had a transient ischaemic attack and two patients were only able to  complete less than 75% of the planned axitinib dose because of treatment-related   toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still   receiving study treatment. Grade 3 or worse treatment-related adverse events  occurred in 34 (65%) patients; the most common included hypertension (n=12  [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine  aminotransferase concentration (n=4 [8%]). The most common potentially  immune-related adverse events (probably related to pembrolizumab) included  diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9  [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism  (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related  serious adverse events. At data cutoff, 38 (73%; 95% CI 59.0-84.4) patients  achieved an objective response (complete or partial response). INTERPRETATION:  The treatment combination of axitinib plus pembrolizumab is tolerable and shows  promising antitumour activity in patients with treatment-naive advanced renal  cell carcinoma. Whether or not the combination works better than a sequence of  VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of  a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy   (NCT02853331). FUNDING: Pfizer Inc.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001650	29442139	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Nivolumab(60-min infusions)	Immune checkpoint therapy	Nivolumab (DB09035); 	369	368	An open-label, phase IIIb/4, predominantly community-based stud	Nivolumab infused over 30 min had a comparable safety profile to the 60-min infusion, including a low incidence of IRRs.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Safety profile of nivolumab administered as 30-min infusion: analysis of data  from CheckMate 153.	 Cancer Chemother Pharmacol	 PURPOSE: Nivolumab has been administered using a 60-min infusion time. Reducing  this time to 30 min would benefit both patients and infusion facilities. This  analysis compared the safety of 30- and 60-min infusions of nivolumab in patients  with previously treated advanced non-small cell lung cancer. METHODS: CheckMate  153 is an open-label, phase 3b/4, predominantly community-based study ongoing in   the United States and Canada. Patients with stage IIIB/IV disease with  progression/recurrence after at least one prior systemic therapy received  nivolumab 3 mg/kg every 2 weeks over 30 or 60 min for 1 year or until disease  progression. The primary outcome overall was to estimate the incidence of grade  3-5 treatment-related select adverse events; a retrospective objective was to  estimate the incidence of hypersensitivity/infusion-related reactions (IRRs) with  the 30-min infusion. Exploratory pharmacokinetic analyses were performed using a   population pharmacokinetics model. RESULTS: Of 1420 patients enrolled, 369  received only 30-min infusions and 368 received only 60-min infusions. Similar  frequencies of hypersensitivity/IRRs were noted in patients receiving 30-min [2%   (n = 8)] and 60-min [2% (n = 7)] infusions. Grade 3-4 treatment-related  hypersensitivity/IRRs led to treatment discontinuation in < 1% of patients in  each group; < 1% of patients in each group received systemic corticosteroids.  Hypersensitivity/IRRs were managed by dosing interruptions, with minimal impact  on total dose received. Nivolumab pharmacokinetics were predicted to be similar  in the two groups. CONCLUSIONS: Nivolumab infused over 30 min had a comparable  safety profile to the 60-min infusion, including a low incidence of IRRs.
CANIT0001651	29442281	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	The neutrophil-to-lymphocyte ratio (NLR)  at 2 and 4 weeks after treatment might be a useful marker for the prediction of the treatment response or disease progression in patients with advanced NSCLC receiving nivolumab.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2018 Aug	 Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with  advanced non-small-cell lung cancer treated with nivolumab.	 Int J Clin Oncol	 BACKGROUND: There is an unmet need to identify markers that predict the response   to nivolumab in patients with non-small-cell lung cancer (NSCLC). The  neutrophil-to-lymphocyte ratio (NLR) was recently recognized as an indicator of a  poor prognosis in patients with various cancers. In the present study, we  quantified the predictive impact of NLR in patients with NSCLC treated with  nivolumab. METHODS: We retrospectively analyzed 101 patients with advanced NSCLC   treated with nivolumab at Kansai Medical University Hospital from December 2015  to December 2016. Patients were administered nivolumab at a dose of 3 mg/kg every  2 weeks. The predictive value of NLR for disease progression before treatment and  2 and 4 weeks after nivolumab treatment was assessed. RESULTS: The median  progression-free survival (PFS) of patients with an NLR of < 3 before treatment  was 3.4 months, whereas that of patients with an NLR of >/= 3 was 2.9 months (p =  0.484). The median PFS of patients with an NLR of < 3 at 2 weeks after treatment   was 5.3 months, whereas that of patients with an NLR of >/= 3 was 2.1 months (p =  0.00528). The median PFS of patients with an NLR of < 3 at 4 weeks after  treatment was 5.3 months, whereas that of patients with an NLR of >/= 3 was 2.0  months (p = 0.00515). CONCLUSION: The NLR at 2 and 4 weeks after treatment might   be a useful marker for the prediction of the treatment response or disease  progression in patients with advanced NSCLC receiving nivolumab.
CANIT0001652	29443960	Clinical research	Metastatic urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	326	N/A	N/A	TGF shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Feb 22	 TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion  of T cells.	 Nature	 Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed  death-ligand 1 (PD-L1) pathway can induce robust and durable responses in  patients with various cancers, including metastatic urothelial cancer. However,  these responses only occur in a subset of patients. Elucidating the determinants   of response and resistance is key to improving outcomes and developing new  treatment strategies. Here we examined tumours from a large cohort of patients  with metastatic urothelial cancer who were treated with an anti-PD-L1 agent  (atezolizumab) and identified major determinants of clinical outcome. Response to  treatment was associated with CD8(+) T-effector cell phenotype and, to an even  greater extent, high neoantigen or tumour mutation burden. Lack of response was  associated with a signature of transforming growth factor beta (TGFbeta)  signalling in fibroblasts. This occurred particularly in patients with tumours,  which showed exclusion of CD8(+) T cells from the tumour parenchyma that were  instead found in the fibroblast- and collagen-rich peritumoural stroma; a common   phenotype among patients with metastatic urothelial cancer. Using a mouse model  that recapitulates this immune-excluded phenotype, we found that therapeutic  co-administration of TGFbeta-blocking and anti-PD-L1 antibodies reduced TGFbeta  signalling in stromal cells, facilitated T-cell penetration into the centre of  tumours, and provoked vigorous anti-tumour immunity and tumour regression.  Integration of these three independent biological features provides the best  basis for understanding patient outcome in this setting and suggests that TGFbeta  shapes the tumour microenvironment to restrain anti-tumour immunity by  restricting T-cell infiltration.
CANIT0001653	29449059	Clinical research	Pretreated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	71	N/A	N/A	This study demonstrates that the efficacy of the combination of nivolumab and ipilimumab is better in previously untreated patients than after single-agent immunotherapy failure or targeted therapy failure. This combination should be therefore considered as a first-line treatment option despite the significantly high rate of toxicity. Furthermore, this study shows an efficiency signal of combined immunotherapy in pretreated population suggesting that this treatment can be used in second-line treatment, including after single-agent immunotherapy failure. Larger prospective trials are needed to determine the optimal sequence and to clarify the risk-benefit profile of combined immunotherapy.	Significantly high rate of toxicity	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Benefit of the nivolumab and ipilimumab combination in pretreated advanced  melanoma.	 Eur J Cancer	Unable to provide
CANIT0001654	29449192	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	538	N/A	A retrospective cohort study	Obesity is associated with improved progression-free survival and overall survival especially in male patients treated with targeted or immune therapy.	N/A	N/A	N/A	Body mass index (NCIT:C16358); 	Body mass index	Personal feature	 2018 Mar	 Association of body-mass index and outcomes in patients with metastatic melanoma   treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective,  multicohort analysis.	 Lancet Oncol	 BACKGROUND: Obesity has been linked to increased mortality in several cancer  types; however, the relation between obesity and survival outcomes in metastatic   melanoma is unknown. The aim of this study was to examine the association between  body-mass index (BMI) and progression-free survival or overall survival in  patients with metastatic melanoma who received targeted therapy, immunotherapy,  or chemotherapy. METHODS: This retrospective study analysed independent cohorts  of patients with metastatic melanoma assigned to treatment with targeted therapy,  immunotherapy, or chemotherapy in randomised clinical trials and one  retrospective study of patients treated with immunotherapy. Patients were  classified according to BMI, following the WHO definitions, as underweight,  normal, overweight, or obese. Patients without BMI and underweight patients were   excluded. The primary outcomes were the associations between BMI and  progression-free survival or overall survival, stratified by treatment type and  sex. We did multivariable analyses in the independent cohorts, and combined  adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise  estimate of the association between BMI and survival outcomes; heterogeneity was   assessed with meta-regression analyses. Analyses were done on the predefined  intention-to-treat population in the randomised controlled trials and on all  patients included in the retrospective study. FINDINGS: The six cohorts consisted  of a total of 2046 patients with metastatic melanoma treated with targeted  therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016.  1918 patients were included in the analysis. Two cohorts containing patients from  randomised controlled trials treated with targeted therapy (dabrafenib plus  trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts  containing patients treated with immunotherapy (one randomised controlled trial  of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with  pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing  patients treated with chemotherapy (two randomised controlled trials of  dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694  [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled  analysis, obesity, compared with normal BMI, was associated with improved  survival in patients with metastatic melanoma (average adjusted hazard ratio [HR]  0.77 [95% CI 0.66-0.90] for progression-free survival and 0.74 [0.58-0.95] for  overall survival). The survival benefit associated with obesity was restricted to  patients treated with targeted therapy (HR 0.72 [0.57-0.91] for progression-free   survival and 0.60 [0.45-0.79] for overall survival) and immunotherapy (HR 0.75  [0.56-1.00] and 0.64 [0.47-0.86]). No associations were observed with  chemotherapy (HR 0.87 [0.65-1.17, pinteraction=0.61] for progression-free  survival and 1.03 [0.80-1.34, pinteraction=0.01] for overall survival). The  association of BMI with overall survival for patients treated with targeted and  immune therapies differed by sex, with inverse associations in men (HR 0.53  [0.40-0.70]), but no associations observed in women (HR 0.85 [0.61-1.18,  pinteraction=0.03]). INTERPRETATION: Our results suggest that in patients with  metastatic melanoma, obesity is associated with improved progression-free  survival and overall survival compared with those outcomes in patients with  normal BMI, and that this association is mainly seen in male patients treated  with targeted or immune therapy. These results have implications for the design  of future clinical trials for patients with metastatic melanoma and the magnitude  of the benefit found supports further investigation of the underlying mechanism  of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF  Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot  Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical  Research Foundation.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001655	29449192	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	 nivolumab (DB09035); 	538	N/A	A retrospective cohort study	Obesity is associated with improved progression-free survival and overall survival especially in male patients treated with targeted or immune therapy.	N/A	N/A	N/A	Body mass index (NCIT:C16358); 	Body mass index	Personal feature	 2018 Mar	 Association of body-mass index and outcomes in patients with metastatic melanoma   treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective,  multicohort analysis.	 Lancet Oncol	 BACKGROUND: Obesity has been linked to increased mortality in several cancer  types; however, the relation between obesity and survival outcomes in metastatic   melanoma is unknown. The aim of this study was to examine the association between  body-mass index (BMI) and progression-free survival or overall survival in  patients with metastatic melanoma who received targeted therapy, immunotherapy,  or chemotherapy. METHODS: This retrospective study analysed independent cohorts  of patients with metastatic melanoma assigned to treatment with targeted therapy,  immunotherapy, or chemotherapy in randomised clinical trials and one  retrospective study of patients treated with immunotherapy. Patients were  classified according to BMI, following the WHO definitions, as underweight,  normal, overweight, or obese. Patients without BMI and underweight patients were   excluded. The primary outcomes were the associations between BMI and  progression-free survival or overall survival, stratified by treatment type and  sex. We did multivariable analyses in the independent cohorts, and combined  adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise  estimate of the association between BMI and survival outcomes; heterogeneity was   assessed with meta-regression analyses. Analyses were done on the predefined  intention-to-treat population in the randomised controlled trials and on all  patients included in the retrospective study. FINDINGS: The six cohorts consisted  of a total of 2046 patients with metastatic melanoma treated with targeted  therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016.  1918 patients were included in the analysis. Two cohorts containing patients from  randomised controlled trials treated with targeted therapy (dabrafenib plus  trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts  containing patients treated with immunotherapy (one randomised controlled trial  of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with  pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing  patients treated with chemotherapy (two randomised controlled trials of  dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694  [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled  analysis, obesity, compared with normal BMI, was associated with improved  survival in patients with metastatic melanoma (average adjusted hazard ratio [HR]  0.77 [95% CI 0.66-0.90] for progression-free survival and 0.74 [0.58-0.95] for  overall survival). The survival benefit associated with obesity was restricted to  patients treated with targeted therapy (HR 0.72 [0.57-0.91] for progression-free   survival and 0.60 [0.45-0.79] for overall survival) and immunotherapy (HR 0.75  [0.56-1.00] and 0.64 [0.47-0.86]). No associations were observed with  chemotherapy (HR 0.87 [0.65-1.17, pinteraction=0.61] for progression-free  survival and 1.03 [0.80-1.34, pinteraction=0.01] for overall survival). The  association of BMI with overall survival for patients treated with targeted and  immune therapies differed by sex, with inverse associations in men (HR 0.53  [0.40-0.70]), but no associations observed in women (HR 0.85 [0.61-1.18,  pinteraction=0.03]). INTERPRETATION: Our results suggest that in patients with  metastatic melanoma, obesity is associated with improved progression-free  survival and overall survival compared with those outcomes in patients with  normal BMI, and that this association is mainly seen in male patients treated  with targeted or immune therapy. These results have implications for the design  of future clinical trials for patients with metastatic melanoma and the magnitude  of the benefit found supports further investigation of the underlying mechanism  of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF  Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot  Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical  Research Foundation.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001656	29449192	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	538	N/A	A retrospective cohort study	Obesity is associated with improved progression-free survival and overall survival especially in male patients treated with targeted or immune therapy.	N/A	N/A	N/A	Body mass index (NCIT:C16358); 	Body mass index	Personal feature	 2018 Mar	 Association of body-mass index and outcomes in patients with metastatic melanoma   treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective,  multicohort analysis.	 Lancet Oncol	 BACKGROUND: Obesity has been linked to increased mortality in several cancer  types; however, the relation between obesity and survival outcomes in metastatic   melanoma is unknown. The aim of this study was to examine the association between  body-mass index (BMI) and progression-free survival or overall survival in  patients with metastatic melanoma who received targeted therapy, immunotherapy,  or chemotherapy. METHODS: This retrospective study analysed independent cohorts  of patients with metastatic melanoma assigned to treatment with targeted therapy,  immunotherapy, or chemotherapy in randomised clinical trials and one  retrospective study of patients treated with immunotherapy. Patients were  classified according to BMI, following the WHO definitions, as underweight,  normal, overweight, or obese. Patients without BMI and underweight patients were   excluded. The primary outcomes were the associations between BMI and  progression-free survival or overall survival, stratified by treatment type and  sex. We did multivariable analyses in the independent cohorts, and combined  adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise  estimate of the association between BMI and survival outcomes; heterogeneity was   assessed with meta-regression analyses. Analyses were done on the predefined  intention-to-treat population in the randomised controlled trials and on all  patients included in the retrospective study. FINDINGS: The six cohorts consisted  of a total of 2046 patients with metastatic melanoma treated with targeted  therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016.  1918 patients were included in the analysis. Two cohorts containing patients from  randomised controlled trials treated with targeted therapy (dabrafenib plus  trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts  containing patients treated with immunotherapy (one randomised controlled trial  of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with  pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing  patients treated with chemotherapy (two randomised controlled trials of  dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694  [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled  analysis, obesity, compared with normal BMI, was associated with improved  survival in patients with metastatic melanoma (average adjusted hazard ratio [HR]  0.77 [95% CI 0.66-0.90] for progression-free survival and 0.74 [0.58-0.95] for  overall survival). The survival benefit associated with obesity was restricted to  patients treated with targeted therapy (HR 0.72 [0.57-0.91] for progression-free   survival and 0.60 [0.45-0.79] for overall survival) and immunotherapy (HR 0.75  [0.56-1.00] and 0.64 [0.47-0.86]). No associations were observed with  chemotherapy (HR 0.87 [0.65-1.17, pinteraction=0.61] for progression-free  survival and 1.03 [0.80-1.34, pinteraction=0.01] for overall survival). The  association of BMI with overall survival for patients treated with targeted and  immune therapies differed by sex, with inverse associations in men (HR 0.53  [0.40-0.70]), but no associations observed in women (HR 0.85 [0.61-1.18,  pinteraction=0.03]). INTERPRETATION: Our results suggest that in patients with  metastatic melanoma, obesity is associated with improved progression-free  survival and overall survival compared with those outcomes in patients with  normal BMI, and that this association is mainly seen in male patients treated  with targeted or immune therapy. These results have implications for the design  of future clinical trials for patients with metastatic melanoma and the magnitude  of the benefit found supports further investigation of the underlying mechanism  of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF  Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot  Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical  Research Foundation.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001657	29449192	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	538	N/A	A retrospective cohort study	Obesity is associated with improved progression-free survival and overall survival especially in male patients treated with targeted or immune therapy.	N/A	N/A	N/A	Body mass index (NCIT:C16358); 	Body mass index	Personal feature	 2018 Mar	 Association of body-mass index and outcomes in patients with metastatic melanoma   treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective,  multicohort analysis.	 Lancet Oncol	 BACKGROUND: Obesity has been linked to increased mortality in several cancer  types; however, the relation between obesity and survival outcomes in metastatic   melanoma is unknown. The aim of this study was to examine the association between  body-mass index (BMI) and progression-free survival or overall survival in  patients with metastatic melanoma who received targeted therapy, immunotherapy,  or chemotherapy. METHODS: This retrospective study analysed independent cohorts  of patients with metastatic melanoma assigned to treatment with targeted therapy,  immunotherapy, or chemotherapy in randomised clinical trials and one  retrospective study of patients treated with immunotherapy. Patients were  classified according to BMI, following the WHO definitions, as underweight,  normal, overweight, or obese. Patients without BMI and underweight patients were   excluded. The primary outcomes were the associations between BMI and  progression-free survival or overall survival, stratified by treatment type and  sex. We did multivariable analyses in the independent cohorts, and combined  adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise  estimate of the association between BMI and survival outcomes; heterogeneity was   assessed with meta-regression analyses. Analyses were done on the predefined  intention-to-treat population in the randomised controlled trials and on all  patients included in the retrospective study. FINDINGS: The six cohorts consisted  of a total of 2046 patients with metastatic melanoma treated with targeted  therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016.  1918 patients were included in the analysis. Two cohorts containing patients from  randomised controlled trials treated with targeted therapy (dabrafenib plus  trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts  containing patients treated with immunotherapy (one randomised controlled trial  of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with  pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing  patients treated with chemotherapy (two randomised controlled trials of  dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694  [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled  analysis, obesity, compared with normal BMI, was associated with improved  survival in patients with metastatic melanoma (average adjusted hazard ratio [HR]  0.77 [95% CI 0.66-0.90] for progression-free survival and 0.74 [0.58-0.95] for  overall survival). The survival benefit associated with obesity was restricted to  patients treated with targeted therapy (HR 0.72 [0.57-0.91] for progression-free   survival and 0.60 [0.45-0.79] for overall survival) and immunotherapy (HR 0.75  [0.56-1.00] and 0.64 [0.47-0.86]). No associations were observed with  chemotherapy (HR 0.87 [0.65-1.17, pinteraction=0.61] for progression-free  survival and 1.03 [0.80-1.34, pinteraction=0.01] for overall survival). The  association of BMI with overall survival for patients treated with targeted and  immune therapies differed by sex, with inverse associations in men (HR 0.53  [0.40-0.70]), but no associations observed in women (HR 0.85 [0.61-1.18,  pinteraction=0.03]). INTERPRETATION: Our results suggest that in patients with  metastatic melanoma, obesity is associated with improved progression-free  survival and overall survival compared with those outcomes in patients with  normal BMI, and that this association is mainly seen in male patients treated  with targeted or immune therapy. These results have implications for the design  of future clinical trials for patients with metastatic melanoma and the magnitude  of the benefit found supports further investigation of the underlying mechanism  of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF  Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot  Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical  Research Foundation.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001658	29463190	Clinical research	Advanced lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	50	N/A	A retrospective cohort study	A multivariate analysis identified a serum CYFRA 21-1 level 2.2 ng/mL as an independent predictor of a favorable outcome (hazard ratio, 0.44; 95% confidence interval, 0.23-0.85; p = 0.015; median progression-free survival, 155 vs 51.5 days). In conclusion, CYFRA 21-1 might be an independent predictor of outcome for patients with advanced lung adenocarcinoma treated with nivolumab.	N/A	N/A	N/A	CYFRA21-1 (P08727); 	Serum CYFRA21-2 levels	Gene expression signature in serum	 2018 Feb	 CYFRA 21-1 predicts the efficacy of nivolumab in patients with advanced lung  adenocarcinoma.	 Tumour Biol	 CYFRA 21-1 is a prognostic marker for non-small cell lung cancer. The serum CYFRA  21-1 level is also known as an adjunct for the diagnosis of lung squamous cell  carcinoma. This study aimed to examine whether CYFRA 21-1 has predictive  implications for nivolumab therapy in patients with advanced lung adenocarcinoma.  Of the 79 patients who were treated with nivolumab therapy at the Shizuoka Cancer  Center between December 2015 and September 2016, we retrospectively reviewed the   data of 50 patients. The patient characteristics were as follows: age <70/>/=70  years: 43 (86%)/7; male/female: 31 (62.0%)/19; Eastern Cooperative Oncology Group  performance status 0-1/2: 43 (86%)/7; smoking status: no/yes: 18 (36%)/32;  epidermal growth factor receptor mutation status negative/positive: 36 (72%)/14;   CYFRA 21-1 >/=2.2/<2.2 ng/mL: 28 (56%)/22; carcinoembryonic antigen >/=5/<5  ng/mL: 29 (58%)/21; and number of prior regimens 2-3/>/=4: 16 (32%)/34. With a  median follow-up of 263.5 (range, 64-352) days, the median progression-free  survival was 70 days. The clinical variables investigated using univariate  analysis were as follows: age (p = 0.423), carcinoembryonic antigen (p = 0.888),   epidermal growth factor receptor mutation status (p = 0.105), performance status   (p = 0.968), sex (p = 0.210), number of prior regimens (p = 0.146), CYFRA 21-1 (p  = 0.026), and smoking status (p = 0.041). A multivariate analysis identified a  serum CYFRA 21-1 level >/=2.2 ng/mL as an independent predictor of a favorable  outcome (hazard ratio, 0.44; 95% confidence interval, 0.23-0.85; p = 0.015;  median progression-free survival, 155 vs 51.5 days). In conclusion, CYFRA 21-1  might be an independent predictor of outcome for patients with advanced lung  adenocarcinoma treated with nivolumab.
CANIT0001659	29467463	Basic research	Human melanoma (A375) cell line  (cell lines and mice)	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	A-PDL1-TGFRIIecd	Atezolizumab or avelumab	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); Anti-PD-L1/TGFBRII Fusion Protein M7824 (NCIT:C124229); 	A375 or patient-derived tumor xenograft (PDX)-bearing mice	A375 or patient-derived tumor xenograft (PDX)-bearing mice	Basic research	A-PDL1-TGFRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab).	Immune tolerance	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2018 Feb 21	 Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously  disable TGFbeta enhance the efficacy of cancer immunotherapy.	 Nat Commun	 A majority of cancers fail to respond to immunotherapy with antibodies targeting   immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or  programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express  transforming growth factor-beta (TGFbeta), which drives immune dysfunction in the  tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting  CD8(+) and TH1 cells. To address this therapeutic challenge, we invent  bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting  CTLA-4 or PD-L1 fused to a TGFbeta receptor II ectodomain sequence that  simultaneously disables autocrine/paracrine TGFbeta in the target cell  microenvironment (a-CTLA4-TGFbetaRIIecd and a-PDL1-TGFbetaRIIecd).  a-CTLA4-TGFbetaRIIecd is more effective in reducing tumor-infiltrating Tregs and   inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab).  Likewise, a-PDL1-TGFbetaRIIecd exhibits superior antitumor efficacy compared with  PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps  counteract TGFbeta-mediated differentiation of Tregs and immune tolerance,  thereby providing a potentially more effective immunotherapeutic strategy against  cancers that are resistant to current immune checkpoint inhibitors.
CANIT0001660	29467463	Basic research	Human TNBC (MDA-MB-231-Luc) tumor cells  (cell lines and mice)	Triple-negative breast cancer	EFO:0005537	Breast	PD-L1 (Q9NZQ7); 	PD-L1; 	A-PDL1-TGFRIIecd	Atezolizumab or avelumab	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); Anti-PD-L1/TGFBRII Fusion Protein M7824 (NCIT:C124229); 	Cell lines/ animal models	Cell lines/ animal models	Basic research	A-PDL1-TGFRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab).	Immune tolerance	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2018 Feb 21	 Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously  disable TGFbeta enhance the efficacy of cancer immunotherapy.	 Nat Commun	 A majority of cancers fail to respond to immunotherapy with antibodies targeting   immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or  programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express  transforming growth factor-beta (TGFbeta), which drives immune dysfunction in the  tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting  CD8(+) and TH1 cells. To address this therapeutic challenge, we invent  bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting  CTLA-4 or PD-L1 fused to a TGFbeta receptor II ectodomain sequence that  simultaneously disables autocrine/paracrine TGFbeta in the target cell  microenvironment (a-CTLA4-TGFbetaRIIecd and a-PDL1-TGFbetaRIIecd).  a-CTLA4-TGFbetaRIIecd is more effective in reducing tumor-infiltrating Tregs and   inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab).  Likewise, a-PDL1-TGFbetaRIIecd exhibits superior antitumor efficacy compared with  PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps  counteract TGFbeta-mediated differentiation of Tregs and immune tolerance,  thereby providing a potentially more effective immunotherapeutic strategy against  cancers that are resistant to current immune checkpoint inhibitors.
CANIT0001661	29467463	Basic research	Melanoma   (cell lines and mice)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); TUMOR-INFILTRATING TREGS (N/A); 	CTLA-4; TUMOR-INFILTRATING TREGS	A-CTLA4-TGFRIIecd	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); a-CTLA-4-TGFRIIecd (NCIT:C128036); 	A375 or patient-derived tumor xenograft (PDX)-bearing mice	A375 or patient-derived tumor xenograft (PDX)-bearing mice	Basic research	A-CTLA4-TGFRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab)	Immune tolerance	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2018 Feb 21	 Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously  disable TGFbeta enhance the efficacy of cancer immunotherapy.	 Nat Commun	 A majority of cancers fail to respond to immunotherapy with antibodies targeting   immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or  programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express  transforming growth factor-beta (TGFbeta), which drives immune dysfunction in the  tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting  CD8(+) and TH1 cells. To address this therapeutic challenge, we invent  bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting  CTLA-4 or PD-L1 fused to a TGFbeta receptor II ectodomain sequence that  simultaneously disables autocrine/paracrine TGFbeta in the target cell  microenvironment (a-CTLA4-TGFbetaRIIecd and a-PDL1-TGFbetaRIIecd).  a-CTLA4-TGFbetaRIIecd is more effective in reducing tumor-infiltrating Tregs and   inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab).  Likewise, a-PDL1-TGFbetaRIIecd exhibits superior antitumor efficacy compared with  PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps  counteract TGFbeta-mediated differentiation of Tregs and immune tolerance,  thereby providing a potentially more effective immunotherapeutic strategy against  cancers that are resistant to current immune checkpoint inhibitors.
CANIT0001662	29467463	Basic research	Triple-negative breast cancer (cell lines and mice)	Triple-negative breast cancer	EFO:0005537	Breast	CTLA-4 (P16410); TUMOR-INFILTRATING TREGS (N/A); 	CTLA-4; TUMOR-INFILTRATING TREGS	A-CTLA4-TGFRIIecd	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); a-CTLA-4-TGFRIIecd (NCIT:C128036); 	A375 or patient-derived tumor xenograft (PDX)-bearing mice	A375 or patient-derived tumor xenograft (PDX)-bearing mice	Basic research	A-CTLA4-TGFRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab)	Immune tolerance	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2018 Feb 21	 Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously  disable TGFbeta enhance the efficacy of cancer immunotherapy.	 Nat Commun	 A majority of cancers fail to respond to immunotherapy with antibodies targeting   immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or  programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express  transforming growth factor-beta (TGFbeta), which drives immune dysfunction in the  tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting  CD8(+) and TH1 cells. To address this therapeutic challenge, we invent  bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting  CTLA-4 or PD-L1 fused to a TGFbeta receptor II ectodomain sequence that  simultaneously disables autocrine/paracrine TGFbeta in the target cell  microenvironment (a-CTLA4-TGFbetaRIIecd and a-PDL1-TGFbetaRIIecd).  a-CTLA4-TGFbetaRIIecd is more effective in reducing tumor-infiltrating Tregs and   inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab).  Likewise, a-PDL1-TGFbetaRIIecd exhibits superior antitumor efficacy compared with  PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps  counteract TGFbeta-mediated differentiation of Tregs and immune tolerance,  thereby providing a potentially more effective immunotherapeutic strategy against  cancers that are resistant to current immune checkpoint inhibitors.
CANIT0001663	29468713	Case report	Advanced glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Granulomatous and lichenoid dermatitis	Granulomatous and lichenoid dermatitis	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Granulomatous and lichenoid dermatitis after IgG4 anti-PD-1 monoclonal antibody  therapy for advanced cancer.	 J Cutan Pathol	 Nivolumab is a fully human IgG4 monoclonal antibody directed against programmed  cell death protein 1 (PD-1). PD-1 inhibition allows T-cell activation and  recruitment to destroy cancer cells. Checkpoint inhibitors have shown significant  survival advantage and relatively low side-effects in comparison with  conventional chemotherapy in several types of advanced cancer. Granulomatous  cutaneous reactions have been reported showing sarcoidal and panniculitic  morphology. Here we present a case of drug-induced lichenoid and granulomatous  dermatitis after checkpoint inhibitor therapy observed in a 63-year-old male  treated with nivolumab for advanced glioblastoma. This morphology has not been  previously reported. We documented a high number of CD8+ T-cells within the  lesions. Additionally, we review the side-effects observed with the use of  checkpoint inhibitors, with special focus on cutaneous manifestations.CI  - (c) 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001664	29469720	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Erythema multiforme major	N/A	N/A	N/A	N/A	N/A	 2017 Sep 15	 Erythema multiforme major in a patient with metastatic melanoma treated with  nivolumab.	 Dermatol Online J	 Nivolumab, a relatively novel immune checkpoint inhibitor with FDA approval in  2014, is gaining greater utilization due to its efficacy in treating metastatic  melanoma. Many of the cutaneous immune-related adverse events (irAEs) being  catalogued do not necessitate discontinuation of immunotherapy and are managed  with supportive therapy. We present a case of erythema multiforme major secondary  to nivolumab requiring hospitalization and discontinuation of treatment. This is   only the second reported case of nivolumab-induced erythema multiforme in the  literature we are aware of, and emphasizes the importance of oncologists working   in conjunction with dermatologists for prompt diagnosis and management.
CANIT0001665	29469753	Case report	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	De novo palmoplantar psoriasis with psoriatic arthritis and autoimmune hypothyroidism	N/A	N/A	N/A	N/A	N/A	 2017 Aug 15	 A case of de novo palmoplantar psoriasis with psoriatic arthritis and autoimmune   hypothyroidism after receiving nivolumab therapy.	 Dermatol Online J	 Nivolumab, a monoclonal antibody against the programmed cell death protein 1  (PD-1), has shown promising results in patients with advanced malignancies,  including melanoma, lung cancer, and renal cancer. Immune-related adverse events   (irAEs) have been reported, including both organ-specific toxicities and skin  toxicities. Herein, we report a case of predominantly palmoplantar psoriasis with  severe nail involvement, psoriatic arthritis, and autoimmune hypothyroidism after  receiving nivolumab treatment for lung cancer. We also summarize the case reports  that have been published previously. The knowledge of these irAEs in patients  undergoing anti-PD1 therapy is important since it will enable earlier recognition  and appropriate management, with the aim of maintaining effective dose without  disruption.
CANIT0001666	29470536	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	Liver and lung metastases and a poor performance status are independent predictors of nivolumab efficacy in patients with advanced non-small cell lung cancer.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	2018	 Metastatic site as a predictor of nivolumab efficacy in patients with advanced  non-small cell lung cancer: A retrospective multicenter trial.	 PLoS One	 PURPOSE: To conduct a retrospective multicenter trial to determine the  significance of metastatic site as a predictor of nivolumab efficacy in patients   with advanced non-small cell lung cancer. METHODS: This study was conducted  across three medical centers in Japan. We retrospectively reviewed all patients  who commenced nivolumab treatment at these centers between December 17, 2015 and   July 31, 2016. Clinical data were collected, including age, sex, smoking status,   Eastern Cooperative Oncology Group performance status, and metastatic site (lymph  nodes, liver, brain, bone, lungs [intrapulmonary metastasis], and malignant  pleural effusion) at the time of commencing nivolumab treatment. Patients were  followed-up until March 31, 2017. RESULTS: Two hundred and one patients were  enrolled. The median age at the time of commencing nivolumab treatment was 68  (range, 27-87) years. One hundred and thirty-five patients were male, 157  patients had a history of smoking, 153 patients had a performance status of 0-1,   and 42 patients had squamous cell carcinoma. The median progression-free survival  of all patients was 2.5 months. In the univariate analysis, a performance status   of >/=2 (hazard ratio [HR]: 1.89, 95.0% confidence interval [CI]: 1.33-2.69; p <   0.001) and liver (HR: 2.09, 95.0% CI: 1.35-3.25; p < 0.001) and lung (HR: 1.57,  95.0% CI: 1.14-2.16; p < 0.01) metastases correlated with a significantly shorter  progression-free survival in nivolumab-treated patients. In the multivariate  analysis, a performance status of >/=2 (HR: 1.54, 95.0% CI: 1.05-2.25; p < 0.05)   and liver (HR: 1.90, 95.0% CI: 1.21-2.98; p < 0.01) and lung (HR: 1.41, 95.0% CI:  1.00-1.99; p < 0.05) metastases were independently correlated with a  significantly shorter progression-free survival in nivolumab-treated patients.  CONCLUSION: Liver and lung metastases and a poor performance status are  independent predictors of nivolumab efficacy in patients with advanced non-small   cell lung cancer.
CANIT0001667	29470536	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	Liver and lung metastases and a poor performance status are independent predictors of nivolumab efficacy in patients with advanced non-small cell lung cancer.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Lung metastasis	Disease status	2018	 Metastatic site as a predictor of nivolumab efficacy in patients with advanced  non-small cell lung cancer: A retrospective multicenter trial.	 PLoS One	 PURPOSE: To conduct a retrospective multicenter trial to determine the  significance of metastatic site as a predictor of nivolumab efficacy in patients   with advanced non-small cell lung cancer. METHODS: This study was conducted  across three medical centers in Japan. We retrospectively reviewed all patients  who commenced nivolumab treatment at these centers between December 17, 2015 and   July 31, 2016. Clinical data were collected, including age, sex, smoking status,   Eastern Cooperative Oncology Group performance status, and metastatic site (lymph  nodes, liver, brain, bone, lungs [intrapulmonary metastasis], and malignant  pleural effusion) at the time of commencing nivolumab treatment. Patients were  followed-up until March 31, 2017. RESULTS: Two hundred and one patients were  enrolled. The median age at the time of commencing nivolumab treatment was 68  (range, 27-87) years. One hundred and thirty-five patients were male, 157  patients had a history of smoking, 153 patients had a performance status of 0-1,   and 42 patients had squamous cell carcinoma. The median progression-free survival  of all patients was 2.5 months. In the univariate analysis, a performance status   of >/=2 (hazard ratio [HR]: 1.89, 95.0% confidence interval [CI]: 1.33-2.69; p <   0.001) and liver (HR: 2.09, 95.0% CI: 1.35-3.25; p < 0.001) and lung (HR: 1.57,  95.0% CI: 1.14-2.16; p < 0.01) metastases correlated with a significantly shorter  progression-free survival in nivolumab-treated patients. In the multivariate  analysis, a performance status of >/=2 (HR: 1.54, 95.0% CI: 1.05-2.25; p < 0.05)   and liver (HR: 1.90, 95.0% CI: 1.21-2.98; p < 0.01) and lung (HR: 1.41, 95.0% CI:  1.00-1.99; p < 0.05) metastases were independently correlated with a  significantly shorter progression-free survival in nivolumab-treated patients.  CONCLUSION: Liver and lung metastases and a poor performance status are  independent predictors of nivolumab efficacy in patients with advanced non-small   cell lung cancer.
CANIT0001668	29470536	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	Liver and lung metastases and a poor performance status are independent predictors of nivolumab efficacy in patients with advanced non-small cell lung cancer.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	2018	 Metastatic site as a predictor of nivolumab efficacy in patients with advanced  non-small cell lung cancer: A retrospective multicenter trial.	 PLoS One	 PURPOSE: To conduct a retrospective multicenter trial to determine the  significance of metastatic site as a predictor of nivolumab efficacy in patients   with advanced non-small cell lung cancer. METHODS: This study was conducted  across three medical centers in Japan. We retrospectively reviewed all patients  who commenced nivolumab treatment at these centers between December 17, 2015 and   July 31, 2016. Clinical data were collected, including age, sex, smoking status,   Eastern Cooperative Oncology Group performance status, and metastatic site (lymph  nodes, liver, brain, bone, lungs [intrapulmonary metastasis], and malignant  pleural effusion) at the time of commencing nivolumab treatment. Patients were  followed-up until March 31, 2017. RESULTS: Two hundred and one patients were  enrolled. The median age at the time of commencing nivolumab treatment was 68  (range, 27-87) years. One hundred and thirty-five patients were male, 157  patients had a history of smoking, 153 patients had a performance status of 0-1,   and 42 patients had squamous cell carcinoma. The median progression-free survival  of all patients was 2.5 months. In the univariate analysis, a performance status   of >/=2 (hazard ratio [HR]: 1.89, 95.0% confidence interval [CI]: 1.33-2.69; p <   0.001) and liver (HR: 2.09, 95.0% CI: 1.35-3.25; p < 0.001) and lung (HR: 1.57,  95.0% CI: 1.14-2.16; p < 0.01) metastases correlated with a significantly shorter  progression-free survival in nivolumab-treated patients. In the multivariate  analysis, a performance status of >/=2 (HR: 1.54, 95.0% CI: 1.05-2.25; p < 0.05)   and liver (HR: 1.90, 95.0% CI: 1.21-2.98; p < 0.01) and lung (HR: 1.41, 95.0% CI:  1.00-1.99; p < 0.05) metastases were independently correlated with a  significantly shorter progression-free survival in nivolumab-treated patients.  CONCLUSION: Liver and lung metastases and a poor performance status are  independent predictors of nivolumab efficacy in patients with advanced non-small   cell lung cancer.
CANIT0001669	29475202	Case report	Vaginal melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); CTLA-4 (P16410); 	PD-1; CTLA-4	Biochemotherapy followed by ipilimumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Ipilimumab (DB06186); biochemotherapy (NCIT:C154330); 	1	N/A	Case	Non-surgical treatment was provided, with biochemotherapy followed by ipilimumab and nivolumab. The patient died one year later. Postpartum vaginal bleeding, even if late-onset, should be investigated, as it may be a pregnancy-associated malignant melanoma, which has a poor prognosis.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Postpartum Genital Melanoma - A Case Report.	 Rev Bras Ginecol Obstet	 Melanomas of the female genital tract may occur in the vulva, the vagina, the  ovary or the cervix. Pregnancy has been considered an aggravating factor in the  evolution and prognosis of melanoma. A 35-year-old female presented with vaginal   bleeding 2 months after a term cesarean delivery. An endovaginal ultrasound  revealed a lesion in the uterine cervix. The pathological report revealed a small  round-cell neoplasm, and the immunohistochemistry confirmed the diagnosis of  malignant melanoma. A positron emission tomography revealed an expansive  hypermetabolic lesion centered on the cervix, and hypermetabolic lesions in the  liver and right kidney. Non-surgical treatment was provided, with biochemotherapy  followed by ipilimumab and nivolumab. The patient died one year later. Postpartum  vaginal bleeding, even if late-onset, should be investigated, as it may be a  pregnancy-associated malignant melanoma, which has a poor prognosis.CI  - Thieme Revinter Publicacoes Ltda Rio de Janeiro, Brazil.
CANIT0001670	29475202	Case report	Vaginal melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); CTLA-4 (P16410); 	PD-1; CTLA-4	Biochemotherapy followed by nivolumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Nivolumab (DB09035); biochemotherapy (NCIT:C154330); 	1	N/A	Case	Non-surgical treatment was provided, with biochemotherapy followed by ipilimumab and nivolumab. The patient died one year later. Postpartum vaginal bleeding, even if late-onset, should be investigated, as it may be a pregnancy-associated malignant melanoma, which has a poor prognosis.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Postpartum Genital Melanoma - A Case Report.	 Rev Bras Ginecol Obstet	 Melanomas of the female genital tract may occur in the vulva, the vagina, the  ovary or the cervix. Pregnancy has been considered an aggravating factor in the  evolution and prognosis of melanoma. A 35-year-old female presented with vaginal   bleeding 2 months after a term cesarean delivery. An endovaginal ultrasound  revealed a lesion in the uterine cervix. The pathological report revealed a small  round-cell neoplasm, and the immunohistochemistry confirmed the diagnosis of  malignant melanoma. A positron emission tomography revealed an expansive  hypermetabolic lesion centered on the cervix, and hypermetabolic lesions in the  liver and right kidney. Non-surgical treatment was provided, with biochemotherapy  followed by ipilimumab and nivolumab. The patient died one year later. Postpartum  vaginal bleeding, even if late-onset, should be investigated, as it may be a  pregnancy-associated malignant melanoma, which has a poor prognosis.CI  - Thieme Revinter Publicacoes Ltda Rio de Janeiro, Brazil.
CANIT0001671	29477367	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Taken together, this case indicates, that well-tolerated ipilimumab of intermediate dose does not necessarily imply a good tolerability of high-dose therapy. This should be taken into account at treatment decisions and thoroughly discussed with the concerned patients.	Severe, life-threatening gastrointestinal toxicity to high-dose ipilimumab	N/A	N/A	N/A	N/A	N/A	 2018 May	 Dose-dependent toxicity of ipilimumab in metastatic melanoma.	 Eur J Cancer	Unable to provide
CANIT0001672	29477368	Case report	Metachronous metastatic primary adenosquamous-cell carcinoma of the prostate	Primary prostate adenosquamous cell carcinoma	EFO:1000073	Prostate	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Nivolumab (with or without pelvic irradiation) may represent a feasible treatment option in recurrent or metastatic ASCC of the prostate.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 May	 Concurrent radiotherapy and nivolumab in metachronous metastatic primary  adenosquamous-cell carcinoma of the prostate.	 Eur J Cancer	Unable to provide
CANIT0001673	29478412	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Remitting seronegative symmetrical synovitis with pitting edema	N/A	N/A	N/A	N/A	N/A	 2018 Feb 26	 Nivolumab induced remitting seronegative symmetrical synovitis with pitting edema  in a patient with melanoma: a case report.	 J Med Case Rep	 BACKGROUND: Novel immune checkpoint inhibitors have been often utilized for  different types of malignancies as salvage therapy with varying success. One  obstacle to immune checkpoint inhibitor use is the higher incidence of  immune-mediated side effects that can prompt discontinuation of therapy.  Remitting seronegative symmetrical synovitis with pitting edema has been  described with immune checkpoint inhibitors only once previously. We report a  case of a patient who developed remitting seronegative symmetrical synovitis with  pitting edema related to immune checkpoint inhibitor therapy and stress that  these symptoms can be managed without cessation of immune checkpoint inhibitor  therapy. CASE PRESENTATION: We present a 70-year-old white man who presented with  4 months of progressive inflammatory arthritis with pitting edema. He had been  started on nivolumab therapy for his metastatic melanoma with excellent response   prior to symptom onset. The symptoms started in his knees and subsequently  involved both hands and feet. On evaluation, he was wheelchair bound and  completely dependent for all activities of daily living. Evaluation revealed  negative serological testing and plain film imaging. Ultrasound demonstrated  diffuse flexor tenosynovitis and soft tissue swelling, and a diagnosis of  remitting seronegative symmetrical synovitis with pitting edema was made. He was   treated with orally administered corticosteroids (0.5 mg/kg per day) which  improved his symptoms significantly and allowed him to regain prior independent  functioning. His corticosteroids were tapered (0.15 mg/kg per day) but not  discontinued and his nivolumab treatment was not interrupted. In follow up he  continued to have stable control of his melanoma as well as his remitting  seronegative symmetrical synovitis with pitting edema. CONCLUSIONS: In conclusion  we present the first case of nivolumab-induced remitting seronegative symmetrical  synovitis with pitting edema that is controlled by maintenance low-dose orally  administered corticosteroids allowing for continuation of nivolumab therapy.  Clinicians who encounter mild-to-moderate immune checkpoint inhibitor  immune-mediated adverse effects can consider maintaining immune checkpoint  inhibitor therapy with concomitant low-dose corticosteroids rather than abrupt  cessation of the immune checkpoint inhibitor.
CANIT0001674	29478735	Clinical research	Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	218	N/A	A single-arm, open-label study	The benefit/risk profile of atezolizumab was consistent with that observed in previous studies, despite pretreatment and poor prognostic factors. These results suggest a potential role for atezolizumab in a broader patient range than typically eligible for phase 1-3 studies.	Treatment-related adverse events (mostly fatigue) occurred in 98 of 214 treated patients.	N/A	N/A	N/A	N/A	N/A	 2018 May	 Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial  Carcinoma: Clinical Experience from an Expanded Access Study in the United  States.	 Eur Urol	 BACKGROUND: Atezolizumab (anti-programmed death-ligand 1) was approved in the  USA, Europe, and elsewhere for treatment-naive and platinum-treated locally  advanced/metastatic urothelial carcinoma (mUC). OBJECTIVE: To report efficacy and  safety from an atezolizumab expanded access study. DESIGN, SETTING, AND  PARTICIPANTS: This single-arm, open-label study enrolled 218 patients at 36 US  sites. Key eligibility criteria included progression during/following >/=1  platinum-based chemotherapy for mUC or in perioperative setting (progression  within 12 mo) and Eastern Cooperative Oncology Group performance status (ECOG PS)  0-2. INTERVENTION: Patients received atezolizumab1200mg intravenously every 3 wk   until loss of clinical benefit, unacceptable toxicity, consent withdrawal,  decision to discontinue, death, atezolizumab commercial availability, or study  closure. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Key end points reported  herein included Response Evaluation Criteria in Solid Tumors v1.1 objective  response rate and duration, disease control rate (DCR; response or stable  disease), and safety. RESULTS AND LIMITATIONS: All patients received prior  systemic therapy (68% mUC; 27% adjuvant; and 26% neoadjuvant). At baseline, 57%  of 214 treated patients had ECOG PS >/=1, 19% had hemoglobin <10g/dl, and 25% had  liver metastases. Median treatment duration was 9 wk (interquartile range [IQR],   6-12 wk). Median follow-up duration was 2.3 mo (IQR, 1.6-3.4 mo) overall and 2.7   mo (IQR, 2.0-3.5 mo) in patients not known to have died. Seventeen of 114  evaluable patients (15%) had objective responses (16 ongoing at study  termination). DCR was 49%. Treatment-related adverse events (mostly fatigue)  occurred in 98 of 214 treated patients. CONCLUSIONS: The benefit/risk profile of   atezolizumab was consistent with that observed in previous studies, despite  pretreatment and poor prognostic factors. These results suggest a potential role   for atezolizumab in a broader patient range than typically eligible for phase 1-3  studies. PATIENT SUMMARY: In this expanded access study, atezolizumab was active   and tolerable in a range of patients with platinum-treated metastatic urothelial   carcinoma.CI  - Copyright (c) 2018 European Association of Urology. Published by Elsevier B.V.  All rights reserved.
CANIT0001675	29485070	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus high-dose radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); radiotherapy (NCIT:C15313); 	13	N/A	A phase I clinical trial 	Our findings suggest that the combination of ipilimumab and high-dose radiation therapy is feasible and safe.	Grade 3 or 4 ipilimumab-related adverse events occurred in 25% of patients. 	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Phase 1 Dose Escalation Trial of Ipilimumab and Stereotactic Body Radiation  Therapy in Metastatic Melanoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To report the results of a phase 1 trial evaluating the safety of the  ipilimumab/radiation therapy combination in patients with metastatic melanoma.  PATIENTS AND METHODS: Thirteen patients with metastatic melanoma were enrolled.  Trial treatment consisted of 4 cycles of ipilimumab in combination with  concurrent dose-escalated high-dose radiation therapy to 1 lesion administered  before the third cycle of ipilimumab. RESULTS: Grade 3 or 4 ipilimumab-related  adverse events occurred in 25% of patients. The maximum tolerated radiation  therapy dose was not reached. Local control of the irradiated lesions was  achieved in 11 of 12 irradiated patients (1 patient had progressive disease  before irradiation and dropped out of the trial). Evaluation of the nonirradiated  lesions demonstrated that 3 of 13 patients experienced clinical benefit, with 1  patient developing a partial response and 2 patients having confirmed stable  disease. Immunomonitoring data showed that in patients without clinical benefit,   factors linked to immunotolerance increased early after the initiation of  ipilimumab, suggesting that early initiation of radiation therapy might be more  effective if combined with ipilimumab. CONCLUSIONS: Our findings suggest that the  combination of ipilimumab and high-dose radiation therapy is feasible and safe.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001676	29485071	Clinical research	Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus SRS-SRT	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	260	N/A	A retrospective cohort study	Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.	Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of 3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337).	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain  Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To characterize the effect of concurrent stereotactic  radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint  inhibitors on patient outcomes and safety in patients with brain metastases  (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small   cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated  with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We  included SRS-SRT patients who were treated with anti-cytotoxic  T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death  protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune  checkpoint inhibitors on active or unreported clinical trials were excluded, and   concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2  weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent   ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall  survival (OS) were estimated using Kaplan-Meier survival curves, and Cox  proportional hazards models were used for multivariate analysis. Logistic  regression was used to identify predictors of acute neurologic toxicity,  immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were  treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT  alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with  concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased  rates of immune-related adverse events or acute neurologic toxicity and predicted  for a decreased likelihood of the development of >/=3 new BMs after SRS-SRT  (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT  with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5  months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated  with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69)  and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on  multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was  significant in comparison with patients treated with SRS-SRT before ICI (P=.002;   HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with  concurrent ICI may be associated with a decreased incidence of new BMs and  favorable survival outcomes without increased rates of adverse events.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001677	29485071	Clinical research	Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus SRS-SRT	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); stereotactic ablative radiotherapy (NCIT:C157991); 	260	N/A	A retrospective cohort study	Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.	Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of 3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337).	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain  Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To characterize the effect of concurrent stereotactic  radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint  inhibitors on patient outcomes and safety in patients with brain metastases  (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small   cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated  with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We  included SRS-SRT patients who were treated with anti-cytotoxic  T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death  protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune  checkpoint inhibitors on active or unreported clinical trials were excluded, and   concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2  weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent   ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall  survival (OS) were estimated using Kaplan-Meier survival curves, and Cox  proportional hazards models were used for multivariate analysis. Logistic  regression was used to identify predictors of acute neurologic toxicity,  immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were  treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT  alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with  concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased  rates of immune-related adverse events or acute neurologic toxicity and predicted  for a decreased likelihood of the development of >/=3 new BMs after SRS-SRT  (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT  with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5  months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated  with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69)  and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on  multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was  significant in comparison with patients treated with SRS-SRT before ICI (P=.002;   HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with  concurrent ICI may be associated with a decreased incidence of new BMs and  favorable survival outcomes without increased rates of adverse events.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001678	29485071	Clinical research	Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus SRS-SRT	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); stereotactic ablative radiotherapy (NCIT:C157991); 	260	N/A	A retrospective cohort study	Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.	Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of 3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337).	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain  Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To characterize the effect of concurrent stereotactic  radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint  inhibitors on patient outcomes and safety in patients with brain metastases  (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small   cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated  with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We  included SRS-SRT patients who were treated with anti-cytotoxic  T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death  protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune  checkpoint inhibitors on active or unreported clinical trials were excluded, and   concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2  weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent   ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall  survival (OS) were estimated using Kaplan-Meier survival curves, and Cox  proportional hazards models were used for multivariate analysis. Logistic  regression was used to identify predictors of acute neurologic toxicity,  immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were  treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT  alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with  concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased  rates of immune-related adverse events or acute neurologic toxicity and predicted  for a decreased likelihood of the development of >/=3 new BMs after SRS-SRT  (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT  with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5  months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated  with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69)  and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on  multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was  significant in comparison with patients treated with SRS-SRT before ICI (P=.002;   HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with  concurrent ICI may be associated with a decreased incidence of new BMs and  favorable survival outcomes without increased rates of adverse events.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001679	29485071	Clinical research	Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus SRS-SRT	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	260	N/A	A retrospective cohort study	Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.	Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of 3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337).	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain  Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To characterize the effect of concurrent stereotactic  radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint  inhibitors on patient outcomes and safety in patients with brain metastases  (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small   cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated  with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We  included SRS-SRT patients who were treated with anti-cytotoxic  T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death  protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune  checkpoint inhibitors on active or unreported clinical trials were excluded, and   concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2  weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent   ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall  survival (OS) were estimated using Kaplan-Meier survival curves, and Cox  proportional hazards models were used for multivariate analysis. Logistic  regression was used to identify predictors of acute neurologic toxicity,  immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were  treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT  alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with  concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased  rates of immune-related adverse events or acute neurologic toxicity and predicted  for a decreased likelihood of the development of >/=3 new BMs after SRS-SRT  (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT  with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5  months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated  with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69)  and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on  multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was  significant in comparison with patients treated with SRS-SRT before ICI (P=.002;   HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with  concurrent ICI may be associated with a decreased incidence of new BMs and  favorable survival outcomes without increased rates of adverse events.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001680	29485071	Clinical research	Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus SRS-SRT	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); stereotactic ablative radiotherapy (NCIT:C157991); 	260	N/A	A retrospective cohort study	Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.	Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of 3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337).	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain  Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To characterize the effect of concurrent stereotactic  radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint  inhibitors on patient outcomes and safety in patients with brain metastases  (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small   cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated  with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We  included SRS-SRT patients who were treated with anti-cytotoxic  T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death  protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune  checkpoint inhibitors on active or unreported clinical trials were excluded, and   concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2  weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent   ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall  survival (OS) were estimated using Kaplan-Meier survival curves, and Cox  proportional hazards models were used for multivariate analysis. Logistic  regression was used to identify predictors of acute neurologic toxicity,  immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were  treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT  alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with  concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased  rates of immune-related adverse events or acute neurologic toxicity and predicted  for a decreased likelihood of the development of >/=3 new BMs after SRS-SRT  (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT  with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5  months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated  with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69)  and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on  multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was  significant in comparison with patients treated with SRS-SRT before ICI (P=.002;   HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with  concurrent ICI may be associated with a decreased incidence of new BMs and  favorable survival outcomes without increased rates of adverse events.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001681	29485071	Clinical research	Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus SRS-SRT	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); stereotactic ablative radiotherapy (NCIT:C157991); 	260	N/A	A retrospective cohort study	Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.	Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of 3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337).	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain  Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To characterize the effect of concurrent stereotactic  radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint  inhibitors on patient outcomes and safety in patients with brain metastases  (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small   cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated  with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We  included SRS-SRT patients who were treated with anti-cytotoxic  T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death  protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune  checkpoint inhibitors on active or unreported clinical trials were excluded, and   concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2  weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent   ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall  survival (OS) were estimated using Kaplan-Meier survival curves, and Cox  proportional hazards models were used for multivariate analysis. Logistic  regression was used to identify predictors of acute neurologic toxicity,  immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were  treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT  alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with  concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased  rates of immune-related adverse events or acute neurologic toxicity and predicted  for a decreased likelihood of the development of >/=3 new BMs after SRS-SRT  (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT  with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5  months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated  with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69)  and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on  multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was  significant in comparison with patients treated with SRS-SRT before ICI (P=.002;   HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with  concurrent ICI may be associated with a decreased incidence of new BMs and  favorable survival outcomes without increased rates of adverse events.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001682	29485071	Clinical research	Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus SRS-SRT	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); 	260	N/A	A retrospective cohort study	Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.	Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of 3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337).	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain  Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To characterize the effect of concurrent stereotactic  radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint  inhibitors on patient outcomes and safety in patients with brain metastases  (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small   cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated  with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We  included SRS-SRT patients who were treated with anti-cytotoxic  T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death  protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune  checkpoint inhibitors on active or unreported clinical trials were excluded, and   concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2  weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent   ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall  survival (OS) were estimated using Kaplan-Meier survival curves, and Cox  proportional hazards models were used for multivariate analysis. Logistic  regression was used to identify predictors of acute neurologic toxicity,  immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were  treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT  alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with  concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased  rates of immune-related adverse events or acute neurologic toxicity and predicted  for a decreased likelihood of the development of >/=3 new BMs after SRS-SRT  (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT  with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5  months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated  with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69)  and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on  multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was  significant in comparison with patients treated with SRS-SRT before ICI (P=.002;   HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with  concurrent ICI may be associated with a decreased incidence of new BMs and  favorable survival outcomes without increased rates of adverse events.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001683	29485071	Clinical research	Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus SRS-SRT	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); stereotactic ablative radiotherapy (NCIT:C157991); 	260	N/A	A retrospective cohort study	Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.	Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of 3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337).	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain  Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To characterize the effect of concurrent stereotactic  radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint  inhibitors on patient outcomes and safety in patients with brain metastases  (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small   cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated  with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We  included SRS-SRT patients who were treated with anti-cytotoxic  T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death  protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune  checkpoint inhibitors on active or unreported clinical trials were excluded, and   concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2  weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent   ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall  survival (OS) were estimated using Kaplan-Meier survival curves, and Cox  proportional hazards models were used for multivariate analysis. Logistic  regression was used to identify predictors of acute neurologic toxicity,  immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were  treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT  alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with  concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased  rates of immune-related adverse events or acute neurologic toxicity and predicted  for a decreased likelihood of the development of >/=3 new BMs after SRS-SRT  (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT  with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5  months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated  with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69)  and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on  multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was  significant in comparison with patients treated with SRS-SRT before ICI (P=.002;   HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with  concurrent ICI may be associated with a decreased incidence of new BMs and  favorable survival outcomes without increased rates of adverse events.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001684	29485071	Clinical research	Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus SRS-SRT	N/A	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); stereotactic ablative radiotherapy (NCIT:C157991); 	260	N/A	A retrospective cohort study	Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events.	Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of 3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337).	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain  Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma.	 Int J Radiat Oncol Biol Phys	 PURPOSE: To characterize the effect of concurrent stereotactic  radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint  inhibitors on patient outcomes and safety in patients with brain metastases  (BMs). METHODS AND MATERIALS: We retrospectively identified metastatic non-small   cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated  with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We  included SRS-SRT patients who were treated with anti-cytotoxic  T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death  protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune  checkpoint inhibitors on active or unreported clinical trials were excluded, and   concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2  weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent   ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall  survival (OS) were estimated using Kaplan-Meier survival curves, and Cox  proportional hazards models were used for multivariate analysis. Logistic  regression was used to identify predictors of acute neurologic toxicity,  immune-related adverse events, and new BMs. RESULTS: A total of 260 patients were  treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT  alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with  concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased  rates of immune-related adverse events or acute neurologic toxicity and predicted  for a decreased likelihood of the development of >/=3 new BMs after SRS-SRT  (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT  with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5  months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated  with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69)  and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on  multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was  significant in comparison with patients treated with SRS-SRT before ICI (P=.002;   HR, 3.82) or after ICI (P=.021; HR, 2.64). CONCLUSIONS: Delivering SRS-SRT with  concurrent ICI may be associated with a decreased incidence of new BMs and  favorable survival outcomes without increased rates of adverse events.CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
CANIT0001685	29485550	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Dermatologists and oncologists need to be aware that fulminant type 1 diabetes may occur as a significant immune-related adverse drug reaction and should pay close attention to its occurrence. Moreover, prompt consultation with diabetologists would be important.	Fulminant type 1 diabetes	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Fulminant type 1 diabetes associated with nivolumab in a patient with metastatic   melanoma.	 Melanoma Res	Unable to provide
CANIT0001686	29486723	Clinical research	Nonsmall-cell lung cancers	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	34	N/A	N/A	Our results suggested that chemokine and immunosuppressive molecule expression profiles can be used to accurately predict clinical responses thus differentiating among patients who would and would not benefit from PD-1 or PD-L1 immunotherapies.	N/A	N/A	N/A	Immunosuppressive gene (NCIT:C40913); Chemokine (NCIT:C20466); 	Chemokine and immunosuppressive gene expression signatures	Gene expression signature on/in tumor cell	 2018 Feb 27	 Genomics of NSCLC patients both affirm PD-L1 expression and predict their  clinical responses to anti-PD-1 immunotherapy.	 BMC Cancer	 BACKGROUND: Programmed Death Ligand 1 (PD-L1) is a co-stimulatory and immune  checkpoint protein. PD-L1 expression in non-small cell lung cancers (NSCLC) is a   hallmark of adaptive resistance and its expression is often used to predict the  outcome of Programmed Death 1 (PD-1) and PD-L1 immunotherapy treatments. However,  clinical benefits do not occur in all patients and new approaches are needed to  assist in selecting patients for PD-1 or PD-L1 immunotherapies. Here, we  hypothesized that patient tumor cell genomics influenced cell signaling and  expression of PD-L1, chemokines, and immunosuppressive molecules and these  profiles could be used to predict patient clinical responses. METHODS: We used a   recent dataset from NSCLC patients treated with pembrolizumab. Deleterious gene  mutational profiles in patient exomes were identified and annotated into a cancer  network to create NSCLC patient-specific predictive computational simulation  models. Validation checks were performed on the cancer network, simulation model   predictions, and PD-1 match rates between patient-specific predicted and clinical  responses. RESULTS: Expression profiles of these 24 chemokines and  immunosuppressive molecules were used to identify patients who would or would not  respond to PD-1 immunotherapy. PD-L1 expression alone was not sufficient to  predict which patients would or would not respond to PD-1 immunotherapy. Adding  chemokine and immunosuppressive molecule expression profiles allowed patient  models to achieve a greater than 85.0% predictive correlation among predicted and  reported patient clinical responses. CONCLUSIONS: Our results suggested that  chemokine and immunosuppressive molecule expression profiles can be used to  accurately predict clinical responses thus differentiating among patients who  would and would not benefit from PD-1 or PD-L1 immunotherapies.
CANIT0001687	29486725	Case report	Stage IV non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy.	Kidney injury	N/A	N/A	N/A	N/A	N/A	 2018 Feb 27	 Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the  importance of recognizing concomitant medications known to cause acute  tubulointerstitial nephritis: a case report.	 BMC Nephrol	 BACKGROUND: Acute tubulointerstitial nephritis (ATIN) has been increasingly  recognized as an important manifestation of kidney injury associated with the use  of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact  pathophysiology remains unknown, corticosteroids are the mainstay of management.   CASE PRESENTATION: We describe a 67-year-old man with stage IV non-small-cell  lung cancer who developed kidney injury during treatment with the anti-PD-1  antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation.  Considering their mechanism of action, immune checkpoint inhibitors can alter  immunological tolerance to concomitant drugs that have been safely used for a  long time. For more than 4 years before the initiation of nivolumab therapy, the   patient had been receiving the proton pump inhibitor lansoprazole, known to cause  drug-induced ATIN, without significant adverse events including kidney injury. He  showed rapid improvement in kidney function in 3 days (creatinine decreased from   2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg  intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral  prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl.  Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive.  CONCLUSIONS: The rapid improvement of kidney function after discontinuation and  DLST positivity indicate that lansoprazole contributed to the development of ATIN  during nivolumab therapy. Considering the time course, it is plausible that  nivolumab altered the long-lasting immunological tolerance against lansoprazole  in this patient. To the best of our knowledge, this is the first case report of  DLST positivity for a drug that had been used safely before the initiation of an   immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the   recognition and discontinuation of concomitant drugs, especially those known to  induce ATIN, is necessary for the management of kidney injury associated with  anti-PD-1 therapy.
CANIT0001688	29488243	Case report	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); 	PD-1; BRAF	Nivolumab followed by dabrafenib,nivolumab followed by trametinib	N/A	Immune checkpoint therapy followed by Target therapy	Trametinib (DB08911); dabrafenib (DB08912); nivolumab (DB09035); 	2	N/A	Case	N/A	Interestingly, both cases had HLA-DRB1*04:05,  which is strongly associated with VKH disease, and achieved biologically complete  remission after the treatment for uveitis. Our cases suggest a possible  correlation between VKH-like uveitis as an AE and the clinical outcomes of  sequential administration of nivolumab and dabrafenib/trametinib therapy for the   treatment of advanced melanoma.	N/A	N/A	HLA (P04439); 	HLA-DRB1*04:05	Mutational status	 2018 Jun	 HLA-DRB1*04:05 in two cases of Vogt-Koyanagi-Harada disease-like uveitis  developing from an advanced melanoma patient treated by sequential administration  of nivolumab and dabrafenib/trametinib therapy.	 J Dermatol	 Although uveitis is reported as a rare adverse event (AE) associated with  dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is  extremely rare. We describe two cases of Vogt-Koyanagi-Harada (VKH)-like uveitis   developing after the sequential administration of nivolumab and  dabrafenib/trametinib therapy. Interestingly, both cases had HLA-DRB1*04:05,  which is strongly associated with VKH disease, and achieved biologically complete  remission after the treatment for uveitis. Our cases suggest a possible  correlation between VKH-like uveitis as an AE and the clinical outcomes of  sequential administration of nivolumab and dabrafenib/trametinib therapy for the   treatment of advanced melanoma.CI  - (c) 2018 Japanese Dermatological Association.
CANIT0001689	29489833	Basic research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	Agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	2018	 Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various  stages of rheumatoid arthritis disease progression.	 PLoS One	 Immune checkpoint blockade with therapeutic anti-cytotoxic T  lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death  (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown  remarkable efficacy in multiple cancer types, concomitant with immune-related  adverse events, including arthralgia and inflammatory arthritis (IA) in some  patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along  with transcriptomics of synovial tissue from multiple stages of rheumatoid  arthritis (RA) disease progression, we have interrogated the activity status of  PD-1 pathway during RA development. We demonstrate that the expression of PD-1  was increased in early and established RA synovial tissue compared to normal and   OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and  PD-L2, was increased at all the stages of RA disease progression, namely  arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further,   we show that RA patients expressed PD-1 on a majority of synovial tissue  infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene  signature was observed in IA and RA, indicating that the PD-1 pathway was  downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1   levels were increased in autoantibody positive early RA patients. Interestingly,   most of the early RA synovium tissue sections showed negative PD-L1 staining by  immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in  RA could be attributed to increased serum sPD-1 and decreased synovial tissue  PD-L1 levels. Taken together, these data suggest that agonistic PD1  antibody-based therapeutics may show efficacy in RA treatment and interception.
CANIT0001690	29491310	Case report	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	This case of F1DM highlights specific mechanisms underlying pancreatic beta cell immunity.	Fulminant Type 1 Diabetes mellitus accompanied by positive conversion of Anti-insulin antibody after the administration of Anti-CTLA-4 antibody following the discontinuation of Anti-PD-1 antibody.	N/A	N/A	N/A	N/A	N/A	 2018 Jul 15	 Fulminant Type 1 Diabetes Mellitus Accompanied by Positive Conversion of  Anti-insulin Antibody after the Administration of Anti-CTLA-4 Antibody Following   the Discontinuation of Anti-PD-1 Antibody.	 Intern Med	 An 80-year-old woman with malignant melanoma received 20 cycles of  anti-programmed death 1 (PD-1) antibody (nivolumab) treatment and showed normal  glucose tolerance. Three weeks after switching to anti-cytotoxic T-lymphocyte  associated antigen 4 (CTLA-4) antibody (ipilimumab), her plasma glucose level was  elevated to 639 mg/dL, her HbA1c was 7.7%, and her fastening serum C-peptide  immunoreactivity was undetectable. Anti-glutamic acid decarboxylase and  insulinoma-associated protein-2 antibodies were negative. She was diagnosed with   fulminant type 1 diabetes mellitus (F1DM). Remarkably, her anti-insulin antibody   was positively converted, and her Sialylated Carbohydrate Antigen, Krebs von den   Lungen-6 levels increased after ipilimumab therapy. She possessed  F1DM-susceptible Human Leukocyte Antigen-DR4. A fluorescence activated cell  sorting analysis showed an altered T-cell population. This case of F1DM  highlights specific mechanisms underlying pancreatic beta cell immunity.
CANIT0001691	29494816	Basic research	Colorectal cancer (murine CT26 syngeneic model)	Colorectal cancer	EFO:0005842	Intestines	IDO2 (Q6ZQW0); 	IDO2; 	4-Bromophenylhydrazinyl benzenesulfonylphenylureas	N/A	Immune checkpoint therapy	4-Bromophenylhydrazinyl benzenesulfonylphenylureas (NCIT:C141137); 	Cell lines/ animal models	N/A	Basic research	In the CT26 tumor model, 4-bromophenylhydrazinyl benzenesulfonylphenylurea 5k was found to slightly increase the percentage of CD3+ T cells and lymphocyte responsiveness, indicating that 4-bromophenylhydrazinyl benzenesulfonylphenylurea 5k may have potential in modulating anti-tumor immunity. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2018 Apr	 4-Bromophenylhydrazinyl benzenesulfonylphenylureas as indoleamine 2,3-dioxygenase  inhibitors with in vivo target inhibition and anti-tumor efficacy.	 Bioorg Chem	 Indoleamine 2,3-dioxygenase is a heme-containing enzyme implicated in the down  regulation of the anti-tumor immune response, and considered a promising  anti-cancer drug target. Several pharmaceutical companies, including Pfizer,  Merck, and Bristol-Myers Squibb, are known to be in pursuit of IDO inhibitors,  and Incyte recently reported good results in the phase II clinical trial of the  IDO inhibitor Epacadostat. In previous work, we developed a series of IDO  inhibitors based on a sulfonylhydrazide core structure, and explored how they  could serve as potent IDO inhibitors with good drug profiles. Herein, we disclose  the development of the 4-bromophenylhydrazinyl benzenesulfonylphenylurea 5k, a  potent IDO inhibitor which demonstrated 25% tumor growth inhibition in a murine  CT26 syngeneic model on day 18 with 100mg/kg oral administration twice daily, and  a 30% reduction in tumor weight. Pharmacodynamic testing of 5k found it to cause   a 25% and 21% reduction in kyn/trp ratio at the plasma and tumor, respectively.  In the CT26 tumor model, 5k was found to slightly increase the percentage of  CD3(+) T cells and lymphocyte responsiveness, indicating that 5k may have  potential in modulating anti-tumor immunity. These data suggest 5k to be worthy  of further investigation in the development of anti-tumor drugs.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001692	29496324	Case report	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Case	Surface marker profiles on lung lymphocytes may predict the mechanism of immune-mediated pneumonitis triggered by tumor-infiltrating lymphocytes in lung cancer patients treated with pembrolizumab.	N/A	N/A	N/A	Lymphocyte (NCIT:C12535); Surface marker gene (NCIT:C40700); 	Surface marker gene expression signatures on lung lymphocytes	Gene expression signature on/in immune cell	 2018 Apr	 Surface marker profiles on lung lymphocytes may predict the mechanism of  immune-mediated pneumonitis triggered by tumor-infiltrating lymphocytes in lung  cancer patients treated with pembrolizumab.	 Lung Cancer	Unable to provide
CANIT0001693	29498219	Case report	Small cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Transcatheter arterial chemoembolization (TACE)  with nivolumab can interfere with several steps of the cancer immunity cycle to enhance anti-tumor effect.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 May	 Combination nivolumab with transcatheter arterial chemoembolization for clinical   remission of small cell lung cancer: A case report.	 Thorac Cancer	 The outcome of small cell lung cancer (SCLC) patients is poor because rapid  metastasis develops after first-line chemotherapy and few drugs are available for  second-line chemotherapy. The median survival rate has not significantly changed   in recent years. In this report, we discuss the case of a 71-year-old Chinese  female non-smoker diagnosed with extensive-stage SCLC who was treated with  nivolumab for a short period and obtained a prolonged clinical benefit. We report  the clinical history, clinical features, potential mechanism, benefits, and the  best therapeutic window. The patient was treated with transcatheter arterial  chemoembolization because of liver metastasis and then with four doses of  nivolumab as third-line systemic treatment. There was no disease progression for   15 months. The lesions became larger than before, suggesting disease progression,  thus nivolumab treatment was ceased. Immunotherapy has the capacity to turn  combined therapy into a feature that may be exploited for clinical benefit.  Further research is required to evaluate whether combined treatment is beneficial  for patients, affecting the efficacy of immunotherapy, and to determine the best   therapeutic window for clinical treatment.CI  - (c) 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and   John Wiley & Sons Australia, Ltd.
CANIT0001694	29498788	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	15	N/A	N/A	In contrast to PD-L1, these results suggest that IDO-1 may be a more promising predictive biomarker for response to immune-based cancer therapy in mRCC.	N/A	N/A	N/A	IDO1 (P14902); 	IDO1 expression levels in tumor cells	Gene expression signature on/in tumor cell	 2018 May	 High IDO-1 expression in tumor endothelial cells is associated with response to  immunotherapy in metastatic renal cell carcinoma.	 Cancer Sci	 Nivolumab belongs to the standard therapy in the second-line setting of  metastatic renal cell carcinoma (mRCC). Although deep and long-lasting responses   are seen in some patients, the majority of patients will further progress. PD-L1   is still under critical evaluation as a predictive biomarker. Thus, more accurate  biomarkers are clearly warranted. Here, we investigated for the first time the  predictive role of IDO-1, a negative immune-regulatory molecule, on clear cell  RCC tissues of 15 patients undergoing nivolumab therapy. IDO-1 and other immune  inhibitory molecules (PD-L1, PD-L2, FOXP3) as well as immune cell subsets (CD3,  CD4 and CD8) were measured on formalin-fixed, paraffin-embedded sections of RCC  specimens by immunohistochemistry. IDO-1 was predominantly expressed in tumor  endothelial cells, and was totally absent from tumor cells itself. IDO-1  overexpression (>10%) could be detected more frequently in responders (100%, n =   6/6) compared to non-responders (33.3%, n = 3/9; P = .028), resulting in a better  progression-free survival during immunotherapy (IDO-1 </= 10% vs >10%, median:  3.5 vs not estimated (NE) months, P = .01 by log-rank test). In addition, IDO-1  was positively correlated with CD8(+) T cell expression (rs = .691, P = .006).  PD-L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients,  irrespective of therapeutic response (responders vs non-responders: 83.3% vs  88.9%). No differences were noticed in the PD-L1 expression on tumor-infiltrating  immune cells (PD-L1 < 1% in 66.7% of both responders and non-responders). In  contrast to PD-L1, these results suggest that IDO-1 may be a more promising  predictive biomarker for response to immune-based cancer therapy in mRCC.CI  - (c) 2018 The Authors. Cancer Science published by John Wiley & Sons Australia,  Ltd on behalf of Japanese Cancer Association.
CANIT0001695	29518553	Clinical research	Anaplastic Lymphoma kinase translocation - positive advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus crizotinib	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); crizotinib (DB08865); 	13	N/A	A single-arm, phase I/II Study, 	These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.	Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade 3 hepatic toxicities. Five patients (38%) had a partial response.	N/A	N/A	N/A	N/A	N/A	 2018 May	 Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for  the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation - Positive  Advanced Non-Small Cell Lung Cancer (CheckMate 370).	 J Thorac Oncol	 INTRODUCTION: Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a  first-line treatment for ALK translocation-positive advanced non-small cell lung   cancer (NSCLC); however, patients eventually progress. Immunotherapies, including  the programmed death-1 inhibitor nivolumab, have resulted in durable responses  and long-term overall survival in patients with NSCLC. We hypothesized that  combining targeted therapy with immunotherapy could result in more patients with   responses and/or more durable responses. Herein we report data from a study  assessing nivolumab plus crizotinib in patients with previously untreated  advanced ALK translocation-positive NSCLC. METHODS: Group E in CheckMate 370 was   a single-arm cohort designed to evaluate the safety of first-line nivolumab (240   mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK  translocation-positive NSCLC. The primary endpoint of safety would be met if  </=20% of patients discontinued treatment due to treatment-related adverse events  by week 17. Objective response rate was a secondary endpoint. A planned safety  review occurred in November 2016; the data cutoff was May 26, 2017. RESULTS: Of  the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed  severe hepatic toxicities leading to the discontinuation of the combination. Of  these, two patients died and the presence of severe hepatic toxicities may have  contributed to death. Enrollment was closed and combination treatment  discontinued due to observed grade >/=3 hepatic toxicities. Five patients (38%)  had a partial response. CONCLUSIONS: These findings do not support further  evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.CI  - Copyright (c) 2018 International Association for the Study of Lung Cancer.  Published by Elsevier Inc. All rights reserved.
CANIT0001696	29523604	Case report	Advanced lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We aim to highlight the importance of close monitoring for prompt identification and management of potentially fatal autoimmune haemolytic anaemia (AIHA) and immune-related adverse events of PD-1 inhibitors by holding immunotherapy and treating with high-dose steroids, particularly in subgroups which may be at increased risk.	Autoimmune haemolytic anaemia	N/A	N/A	N/A	N/A	N/A	 2018 Mar 9	 Autoimmune haemolytic anaemia in a patient with advanced lung adenocarcinoma and   chronic lymphocytic leukaemia receiving nivolumab and intravenous immunoglobulin.	 BMJ Case Rep	 We describe a rare case of severe autoimmune haemolytic anaemia (AIHA) in the  setting of underlying chronic lymphocytic leukaemia receiving intravenous  immunoglobulin, history of warm IgG autoantibody and treatment with nivolumab for  advanced non-small cell lung cancer. In this report, we describe AIHA as a  potential serious immune-related adverse event from immune checkpoint inhibitors,  discuss other potential contributing factors and review previously described  cases of AIHA in patients receiving programmed death 1 (PD-1) inhibitors. In the   era of immunotherapy, we hope to add literature to raise awareness of potential  immune-related sequelae such as AIHA. We aim to highlight the importance of close  monitoring for prompt identification and management of potentially fatal AIHA and  immune-related adverse events of PD-1 inhibitors by holding immunotherapy and  treating with high-dose steroids, particularly in subgroups which may be at  increased risk.CI  - (c) BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)  2018. All rights reserved. No commercial use is permitted unless otherwise  expressly granted.
CANIT0001697	29525239	Clinical research	Previously Treated Advanced Non-Small-Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Docetaxel 	Immune checkpoint therapy	Docetaxel (DB01248); atezolizumab (DB11595); 	103	101	A subgroup Analysis of the phase III OAK Study	Atezolizumab was effective and well tolerated in pretreated Japanese patients with NSCLC. Results are consistent with the primary analysis of OAK.	Atezolizumab was generally well tolerated, with no treatment-related deaths.	N/A	N/A	N/A	N/A	N/A	 2018 Jul	 Atezolizumab in Japanese Patients With Previously Treated Advanced Non-Small-Cell  Lung Cancer: A Subgroup Analysis of the Phase 3 OAK Study.	 Clin Lung Cancer	 INTRODUCTION: Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) agent, is  effective and well tolerated in patients with pretreated advanced non-small-cell   lung cancer (NSCLC). We assessed its efficacy and safety in Japanese patients  through subgroup analyses of the phase 3 OAK study (NCT02008227). PATIENTS AND  METHODS: Key eligibility criteria of this randomized, controlled, open-label,  international study include locally advanced/metastatic NSCLC, >/= 1 prior  platinum-based chemotherapy, age >/= 18 years, measurable disease (Response  Evaluation Criteria in Solid Tumors v1.1), and Eastern Cooperative Oncology Group  performance status 0 or 1. Atezolizumab 1200 mg or docetaxel 75 mg/m(2) was  provided intravenously every 3 weeks. Co-primary end points were overall survival  (OS) in the intention-to-treat (ITT) population and those with >/= 1% PD-L1  expression on tumor cells (TC) or tumor-infiltrating immune cells (IC; TC1/2/3 or  IC1/2/3). RESULTS: Sixty-four ITT patients were Japanese; 19 had TC1/2/3 or  IC1/2/3 status. In Japanese ITT patients, median OS in the atezolizumab arm (n =   36) was longer than the docetaxel arm (n = 28; 21.3 months [95% confidence  interval (CI), 11.0-not estimable (NE)] versus 17.0 months [95% CI, 12.5-NE],  respectively; hazard ratio 0.80 [95% CI, 0.41-1.57]). In the TC1/2/3 or IC1/2/3  population, median OS was 21.3 months (95% CI, 15.0-NE) and NE in the  atezolizumab (n = 11) and docetaxel (n = 8) groups, respectively (hazard ratio,  0.81 [95% CI, 0.22-3.05]). Atezolizumab was generally well tolerated, with no  treatment-related deaths. CONCLUSION: Atezolizumab was effective and well  tolerated in pretreated Japanese patients with NSCLC. Results are consistent with  the primary analysis of OAK.CI  - Copyright (c) 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
CANIT0001698	29526968	Case report	Advanced Lung Adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	It is important to consider drug-associated dermatomyositis in the differential diagnosis of patients presenting with skin lesions and muscle weakness after nivolumab treatment.	This patient was diagnosed with dermatomyositis due to the presence of proximal muscle weakness with abnormal electromyography and magnetic resonance imaging findings; skin lesions, such as heliotrope rash, shawl sign, and periungual erythema; and an elevated serum aldolase level after nivolumab administration.	N/A	N/A	N/A	N/A	N/A	 2018 Aug 1	 Advanced Lung Adenocarcinoma with Nivolumab-associated Dermatomyositis.	 Intern Med	 We herein report a 42-year-old man with advanced lung adenocarcinoma and  nivolumab-associated dermatomyositis. Nivolumab, an anticancer drug that is  classified as an immune checkpoint inhibitor, often induces immune-related  adverse events (irAEs). However, there have so far been no reports regarding  nivolumab-associated dermatomyositis. This patient was diagnosed with  dermatomyositis due to the presence of proximal muscle weakness with abnormal  electromyography and magnetic resonance imaging findings; skin lesions, such as  heliotrope rash, shawl sign, and periungual erythema; and an elevated serum  aldolase level after nivolumab administration. It is important to consider  drug-associated dermatomyositis in the differential diagnosis of patients  presenting with skin lesions and muscle weakness after nivolumab treatment.
CANIT0001699	29530667	Clinical research	Advanced clear-cell renal-cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab plus axitinib	N/A	Immune checkpoint therapy plus Target therapy	Axitinib (DB06626); avelumab (DB11945); 	55	N/A	An open-label, multicentre, dose-finding, and dose-expansion, phase Ib a study, done in 14 centres in the USA, UK, and Japan	The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy.	One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily.	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Preliminary results for avelumab plus axitinib as first-line therapy in patients   with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label,  dose-finding and dose-expansion, phase 1b trial.	 Lancet Oncol	 BACKGROUND: The combination of an immune checkpoint inhibitor and a VEGF pathway   inhibitor to treat patients with advanced renal-cell carcinoma might increase the  clinical benefit of these drugs compared with their use alone. Here, we report  preliminary results for the combination of avelumab, an IgG1 monoclonal antibody   against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF  receptor inhibitor approved for second-line treatment of advanced renal-cell  carcinoma, in treatment-naive patients with advanced renal-cell carcinoma.  METHODS: The JAVELIN Renal 100 study is an ongoing open-label, multicentre,  dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA,   UK, and Japan. Eligible patients were aged 18 years or older (>/=20 years in  Japan) and had histologically or cytologically confirmed advanced renal-cell  carcinoma with clear-cell component, life expectancy of at least 3 months, an  Eastern Cooperative Oncology Group performance status of 1 or less, received no  previous systemic treatment for advanced renal cell carcinoma, and had a resected  primary tumour. Patients enrolled into the dose-finding phase received 5 mg  axitinib orally twice daily for 7 days, followed by combination therapy with 10  mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily.   Based on the pharmacokinetic data from the dose-finding phase, ten additional  patients were enrolled into the dose-expansion phase and assigned to this  regimen. The other patients in the dose-expansion phase started taking  combination therapy directly. The primary endpoint was dose-limiting toxicities  in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib.  Safety and antitumour activity analyses were done in all patients who received at  least one dose of avelumab or axitinib. This trial is registered with  ClinicalTrials.gov, number NCT02493751. FINDINGS: Between Oct 30, 2015, and Sept   30, 2016, we enrolled six patients into the dose-finding phase and 49 into the  dose-expansion phase of the study. One dose-limiting toxicity of grade 3  proteinuria due to axitinib was reported among the six patients treated during  the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI  54-100) of six patients in the dose-finding phase and 26 (53%, 38-68) of 49  patients in the dose-expansion phase had confirmed objective responses (32 [58%,   44-71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse  treatment-related adverse events, the most frequent being hypertension in 16  (29%) patients and increased concentrations of alanine aminotransferase, amylase,  and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients  each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease   progression and one (2%) due to treatment-related autoimmune myocarditis. At the   end of the dose-finding phase, the maximum tolerated dose established for the  combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily.  INTERPRETATION: The safety profile of the combination avelumab plus axitinib in  treatment-naive patients with advanced renal-cell carcinoma seemed to be  manageable and consistent with that of each drug alone, and the preliminary data   on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and  axitinib compared with sunitinib monotherapy. FUNDING: Pfizer and Merck.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001700	29545095	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	444	N/A	An open-label, single-arm, phase II study	The clinical activity of durvalumab in patients with EGFR+ NSCLC with 25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted.	The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Apr	 Durvalumab as third-line or later treatment for advanced non-small-cell lung  cancer (ATLANTIC): an open-label, single-arm, phase 2 study.	 Lancet Oncol	 BACKGROUND: Immune checkpoint inhibitors are a new standard of care for patients   with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or   anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical  benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has  not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in  three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour  expression of PD-L1. METHODS: ATLANTIC is a phase 2, open-label, single-arm trial  at 139 study centres in Asia, Europe, and North America. Eligible patients had  advanced NSCLC with disease progression following at least two previous systemic   regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor  therapy if indicated); were aged 18 years or older; had a WHO performance status   score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid  Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell  lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1  antibody; and any previous grade 3 or worse immune-related adverse event while  receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with  at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients  in cohorts 2 and 3 had EGFR-/ALK- NSCLC; cohort 2 included patients with at least  25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3  included patients with at least 90% of tumour cells with PD-L1 expression.  Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion,   for up to 12 months. Retreatment was allowed for patients who benefited but then   progressed after completing 12 months. The primary endpoint was the proportion of  patients with increased tumour expression of PD-L1 (defined as >/=25% of tumour  cells in cohorts 1 and 2, and >/=90% of tumour cells in cohort 3) who achieved an  objective response, assessed in patients who were evaluable for response per  independent central review according to RECIST version 1.1. Safety was assessed  in all patients who received at least one dose of durvalumab and for whom any  post-dose data were available. The trial is ongoing, but is no longer open to  accrual, and is registered with ClinicalTrials.gov, number NCT02087423. FINDINGS:  Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received  durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients   with at least 25% of tumour cells expressing PD-L1 who were evaluable for  objective response per independent central review, an objective response was  achieved in 9 (12.2%, 95% CI 5.7-21.8) of 74 patients in cohort 1 and 24 (16.4%,   10.8-23.5) of 146 patients in cohort 2. In cohort 3, 21 (30.9%, 20.2-43.3) of 68   patients achieved an objective response. Grade 3 or 4 treatment-related adverse  events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in  cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most  common treatment-related grade 3 or 4 adverse events were pneumonitis (four  patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three   [1%]), infusion-related reaction (three [1%]), elevated aspartate  aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two  [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events  occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort   1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common  serious adverse events overall were pneumonitis (five patients [1%]), fatigue  (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events   were manageable with standard treatment guidelines. INTERPRETATION: In patients  with advanced and heavily pretreated NSCLC, the clinical activity and safety  profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1   agents. Responses were recorded in all cohorts; the proportion of patients with  EGFR-/ALK- NSCLC (cohorts 2 and 3) achieving a response was higher than the  proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical  activity of durvalumab in patients with EGFR+ NSCLC with >/=25% of tumour cells  expressing PD-L1 was encouraging, and further investigation of durvalumab in  patients with EGFR+/ALK+ NSCLC is warranted. FUNDING: AstraZeneca.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001701	29545095	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	444	N/A	An open-label, single-arm, phase II study	The proportion of patients with EGFR-/ALK- NSCLC (n=333) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (n=111) achieving a response. 	The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines.	N/A	N/A	EGFR/ALK (P00533); 	EGFR/ALK mutational status	Mutational status	 2018 Apr	 Durvalumab as third-line or later treatment for advanced non-small-cell lung  cancer (ATLANTIC): an open-label, single-arm, phase 2 study.	 Lancet Oncol	 BACKGROUND: Immune checkpoint inhibitors are a new standard of care for patients   with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or   anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical  benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has  not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in  three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour  expression of PD-L1. METHODS: ATLANTIC is a phase 2, open-label, single-arm trial  at 139 study centres in Asia, Europe, and North America. Eligible patients had  advanced NSCLC with disease progression following at least two previous systemic   regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor  therapy if indicated); were aged 18 years or older; had a WHO performance status   score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid  Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell  lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1  antibody; and any previous grade 3 or worse immune-related adverse event while  receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with  at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients  in cohorts 2 and 3 had EGFR-/ALK- NSCLC; cohort 2 included patients with at least  25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3  included patients with at least 90% of tumour cells with PD-L1 expression.  Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion,   for up to 12 months. Retreatment was allowed for patients who benefited but then   progressed after completing 12 months. The primary endpoint was the proportion of  patients with increased tumour expression of PD-L1 (defined as >/=25% of tumour  cells in cohorts 1 and 2, and >/=90% of tumour cells in cohort 3) who achieved an  objective response, assessed in patients who were evaluable for response per  independent central review according to RECIST version 1.1. Safety was assessed  in all patients who received at least one dose of durvalumab and for whom any  post-dose data were available. The trial is ongoing, but is no longer open to  accrual, and is registered with ClinicalTrials.gov, number NCT02087423. FINDINGS:  Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received  durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients   with at least 25% of tumour cells expressing PD-L1 who were evaluable for  objective response per independent central review, an objective response was  achieved in 9 (12.2%, 95% CI 5.7-21.8) of 74 patients in cohort 1 and 24 (16.4%,   10.8-23.5) of 146 patients in cohort 2. In cohort 3, 21 (30.9%, 20.2-43.3) of 68   patients achieved an objective response. Grade 3 or 4 treatment-related adverse  events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in  cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most  common treatment-related grade 3 or 4 adverse events were pneumonitis (four  patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three   [1%]), infusion-related reaction (three [1%]), elevated aspartate  aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two  [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events  occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort   1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common  serious adverse events overall were pneumonitis (five patients [1%]), fatigue  (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events   were manageable with standard treatment guidelines. INTERPRETATION: In patients  with advanced and heavily pretreated NSCLC, the clinical activity and safety  profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1   agents. Responses were recorded in all cohorts; the proportion of patients with  EGFR-/ALK- NSCLC (cohorts 2 and 3) achieving a response was higher than the  proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical  activity of durvalumab in patients with EGFR+ NSCLC with >/=25% of tumour cells  expressing PD-L1 was encouraging, and further investigation of durvalumab in  patients with EGFR+/ALK+ NSCLC is warranted. FUNDING: AstraZeneca.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001702	29545428	Case report	Metastatic primary pulmonary melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Pembrolizumab followed by ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); 	1	N/A	Case	The patient remains free of disease progression 2 years after treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Metastatic primary pulmonary melanoma successfully treated with checkpoint  inhibitors.	 BMJ Case Rep	 Our patient is a 69-year-old man who presented to the emergency department with  left-sided hemiparesis that started 4 hours prior to presentation. Brain CT  showed right basal ganglia and internal capsule haemorrhagic strokes. MRI  revealed multiple brain lesions suspicious for metastases. Further workup  revealed a 5 cm lung mass and a 1 cm pancreatic nodule. Biopsy of both pulmonary   and pancreatic lesions was consistent with melanoma and was similar  histologically. The patient underwent cyberknife stereotactic radiosurgery to the  brain metastases followed by immunotherapy with pembrolizumab, and then by  nivolumab and ipilimumab. The patient remains free of disease progression 2 years  after treatment.CI  - (c) BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)  2018. All rights reserved. No commercial use is permitted unless otherwise  expressly granted.
CANIT0001703	29545428	Case report	Metastatic primary pulmonary melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Pembrolizumab followed by nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); pembrolizumab (DB09037); 	1	N/A	Case	The patient remains free of disease progression 2 years after treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Mar 15	 Metastatic primary pulmonary melanoma successfully treated with checkpoint  inhibitors.	 BMJ Case Rep	 Our patient is a 69-year-old man who presented to the emergency department with  left-sided hemiparesis that started 4 hours prior to presentation. Brain CT  showed right basal ganglia and internal capsule haemorrhagic strokes. MRI  revealed multiple brain lesions suspicious for metastases. Further workup  revealed a 5 cm lung mass and a 1 cm pancreatic nodule. Biopsy of both pulmonary   and pancreatic lesions was consistent with melanoma and was similar  histologically. The patient underwent cyberknife stereotactic radiosurgery to the  brain metastases followed by immunotherapy with pembrolizumab, and then by  nivolumab and ipilimumab. The patient remains free of disease progression 2 years  after treatment.CI  - (c) BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)  2018. All rights reserved. No commercial use is permitted unless otherwise  expressly granted.
CANIT0001704	29548660	Case report	Recurrent squamous cell carcinoma of the head and neck	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Severe interstitial pneumonia	A 70-year-old Japanese man with recurrent squamous cell carcinoma of the head and neck presented with severe interstitial pneumonia associated with nivolumab, after talc slurry pleurodesis. Following the development of malignant pleural effusion, he underwent chest drainage and was administered intrathoracic talc as a pleurodesis. Two weeks later, we administered nivolumab (3mg/kg) to be repeated every 2 weeks. However, on day 12, chest computed tomography scan demonstrated diffuse non-segmental ground-glass opacity and mild bronchiectasis. We diagnosed interstitial pneumonia associated with nivolumab. Although corticosteroid pulse therapy was initiated, the patient died of respiratory failure on day 14.	N/A	N/A	N/A	N/A	N/A	 2018 Mar	 Severe interstitial pneumonia associated with anti-PD-1 immune checkpoint  antibody after talc slurry pleurodesis.	 Respir Investig	 A 70-year-old Japanese man with recurrent squamous cell carcinoma of the head and  neck presented with severe interstitial pneumonia associated with nivolumab,  after talc slurry pleurodesis. Following the development of malignant pleural  effusion, he underwent chest drainage and was administered intrathoracic talc as   a pleurodesis. Two weeks later, we administered nivolumab (3mg/kg) to be repeated  every 2 weeks. However, on day 12, chest computed tomography scan demonstrated  diffuse non-segmental ground-glass opacity and mild bronchiectasis. We diagnosed   interstitial pneumonia associated with nivolumab. Although corticosteroid pulse  therapy was initiated, the patient died of respiratory failure on day 14.CI  - Copyright (c) 2017 The Japanese Respiratory Society. Published by Elsevier B.V.  All rights reserved.
CANIT0001705	29554874	Case report	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Partial response	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Mar 20	 Re-challenging immune checkpoint inhibitor in a patient with advanced non-small  cell lung cancer: a case report.	 BMC Cancer	 BACKGROUND: Currently, immune checkpoint (ICP) inhibitors are essential drugs for  the treatment of non-small cell lung cancer (NSCLC). However, in patients  previously treated with ICP inhibitors, the efficacy and safety of re-challenging  the same or another ICP inhibitor remain unclear. CASE PRESENTATION: We present  the case of a patient treated with nivolumab for advanced NSCLC who was  previously treated with an ICP inhibitor as the first-line chemotherapy along  with heavy cytotoxic chemotherapy. After the failure of five lines of  chemotherapy, 3 cycles of nivolumab, as the ICP inhibitor re-challenge, the  patient achieved a partial response. CONCLUSIONS: This case might suggest that  re-challenging an ICP inhibitor could be clinically active in selected patients  with advanced NSCLC who progress after achieving an initial clinical benefit with  an ICP inhibitor.
CANIT0001706	29561296	Case report	Melanoma after disease progression on immune checkpoint inhibitors and BRAF inhibitors	Melanoma	EFO:0000756	Skin	N/A (N/A); 	N/A; 	Talimogene laherparepvec	N/A	Tumor vaccine	Talimogene laherparepvec (DB13896); 	2	N/A	Case	Feasible treatment option	Mild-to-moderate nausea and vomiting, which were managed using ondansetron, metoclopramide, and pantoprazole.	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Potential clinical and immunotherapeutic utility of talimogene laherparepvec for   patients with melanoma after disease progression on immune checkpoint inhibitors   and BRAF inhibitors.	 Melanoma Res	 Talimogene laherparepvec is a genetically modified herpes simplex virus type  1-based oncolytic immunotherapy for the local treatment of unresectable  subcutaneous and nodal tumors in patients with melanoma recurrent after initial  surgery. We report on two patients with melanoma who, after progression on  numerous systemic therapies, derived clinical benefit from talimogene  laherparepvec in an expanded-access protocol (ClinicalTrials.gov, NCT02147951).  Intralesional talimogene laherparepvec (day 1, </=4 ml 10 PFU/ml; after 3 weeks,   </=4 ml 10 PFU/ml every 2 weeks) was administered until complete response, no  injectable tumors, progressive disease, or intolerance occurred. Patient 1 was 71  years old, had stage IIIB disease, and had previously received  granulocyte-macrophage colony-stimulating factor, vemurafenib, metformin,  ipilimumab, dabrafenib, trametinib, and pembrolizumab. Patient 2 was 45 years  old, had stage IIIC disease, and had previously received nivolumab/ipilimumab  combination therapy. There were marked reductions in the number and size of  melanoma lesions during treatment with talimogene laherparepvec. Both patients  experienced mild-to-moderate nausea and vomiting, which were managed using  ondansetron, metoclopramide, and pantoprazole. Both patients completed treatment   with talimogene laherparepvec in the expanded-access protocol on 24 November  2015, but received talimogene laherparepvec in clinical practice. Patient 1  continues to receive therapy (>60 weeks); patient 2 experienced a complete  response at 23 weeks. Immunohistochemistry of a biopsied dermal metastasis from  patient 1 showed a marked infiltration of CD4 and CD8 T cells after 1 year of  treatment. Talimogene laherparepvec was active in patients with advanced melanoma  with disease progression following multiple previous systemic therapies; no new  safety signals were identified.
CANIT0001707	29572003	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	319	N/A	N/A	POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.	N/A	N/A	N/A	POLE (Q07864); 	POLE 697fs	Mutational status	 2018 Apr	 Clinicopathological characteristics of POLE mutation in patients with  non-small-cell lung cancer.	 Lung Cancer	 BACKGROUND: Mutations in polymerase epsilon (POLE), a DNA polymerase involved in   DNA replication and repair, have been investigated in endometrial cancers and  response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1)  immunotherapy. However, the frequency of POLE gene mutation in patients with  non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS:   We assessed POLE mutation in 319 patients with NSCLC by next-generation  sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA  mismatch repair proteins (MMR), and the abundance of CD8-positive tumor  infiltrating lymphocytes (TILs) were assayed by immunohistochemistry.  Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and  compared among groups using log-rank tests. RESULTS: Nine of the 319 patients  (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor  mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without  POLE mutation, respectively (P=0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and  PMS2), and CD8-positive TILs were evaluated in all nine patients. No  microsatellite instability was detected, but seven patients had high levels of  CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient  receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a  PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in  NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients  with mutant compared with wild-type POLE. POLE mutation may thus represent a  candidate biomarker for response to immunotherapy in patients with NSCLC.CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
CANIT0001708	29572003	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	319	N/A	N/A	POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.	N/A	N/A	N/A	POLE (Q07864); 	POLE E648K mutation	Mutational status	 2018 Apr	 Clinicopathological characteristics of POLE mutation in patients with  non-small-cell lung cancer.	 Lung Cancer	 BACKGROUND: Mutations in polymerase epsilon (POLE), a DNA polymerase involved in   DNA replication and repair, have been investigated in endometrial cancers and  response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1)  immunotherapy. However, the frequency of POLE gene mutation in patients with  non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS:   We assessed POLE mutation in 319 patients with NSCLC by next-generation  sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA  mismatch repair proteins (MMR), and the abundance of CD8-positive tumor  infiltrating lymphocytes (TILs) were assayed by immunohistochemistry.  Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and  compared among groups using log-rank tests. RESULTS: Nine of the 319 patients  (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor  mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without  POLE mutation, respectively (P=0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and  PMS2), and CD8-positive TILs were evaluated in all nine patients. No  microsatellite instability was detected, but seven patients had high levels of  CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient  receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a  PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in  NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients  with mutant compared with wild-type POLE. POLE mutation may thus represent a  candidate biomarker for response to immunotherapy in patients with NSCLC.CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
CANIT0001709	29572003	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	319	N/A	N/A	POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.	N/A	N/A	N/A	POLE (Q07864); 	POLE G1628R mutation	Mutational status	 2018 Apr	 Clinicopathological characteristics of POLE mutation in patients with  non-small-cell lung cancer.	 Lung Cancer	 BACKGROUND: Mutations in polymerase epsilon (POLE), a DNA polymerase involved in   DNA replication and repair, have been investigated in endometrial cancers and  response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1)  immunotherapy. However, the frequency of POLE gene mutation in patients with  non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS:   We assessed POLE mutation in 319 patients with NSCLC by next-generation  sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA  mismatch repair proteins (MMR), and the abundance of CD8-positive tumor  infiltrating lymphocytes (TILs) were assayed by immunohistochemistry.  Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and  compared among groups using log-rank tests. RESULTS: Nine of the 319 patients  (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor  mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without  POLE mutation, respectively (P=0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and  PMS2), and CD8-positive TILs were evaluated in all nine patients. No  microsatellite instability was detected, but seven patients had high levels of  CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient  receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a  PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in  NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients  with mutant compared with wild-type POLE. POLE mutation may thus represent a  candidate biomarker for response to immunotherapy in patients with NSCLC.CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
CANIT0001710	29572003	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	319	N/A	N/A	POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.	N/A	N/A	N/A	POLE (Q07864); 	POLE M1T mutation	Mutational status	 2018 Apr	 Clinicopathological characteristics of POLE mutation in patients with  non-small-cell lung cancer.	 Lung Cancer	 BACKGROUND: Mutations in polymerase epsilon (POLE), a DNA polymerase involved in   DNA replication and repair, have been investigated in endometrial cancers and  response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1)  immunotherapy. However, the frequency of POLE gene mutation in patients with  non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS:   We assessed POLE mutation in 319 patients with NSCLC by next-generation  sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA  mismatch repair proteins (MMR), and the abundance of CD8-positive tumor  infiltrating lymphocytes (TILs) were assayed by immunohistochemistry.  Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and  compared among groups using log-rank tests. RESULTS: Nine of the 319 patients  (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor  mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without  POLE mutation, respectively (P=0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and  PMS2), and CD8-positive TILs were evaluated in all nine patients. No  microsatellite instability was detected, but seven patients had high levels of  CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient  receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a  PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in  NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients  with mutant compared with wild-type POLE. POLE mutation may thus represent a  candidate biomarker for response to immunotherapy in patients with NSCLC.CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
CANIT0001711	29572003	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	319	N/A	N/A	POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.	N/A	N/A	N/A	POLE (Q07864); 	POLE P1779L mutation	Mutational status	 2018 Apr	 Clinicopathological characteristics of POLE mutation in patients with  non-small-cell lung cancer.	 Lung Cancer	 BACKGROUND: Mutations in polymerase epsilon (POLE), a DNA polymerase involved in   DNA replication and repair, have been investigated in endometrial cancers and  response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1)  immunotherapy. However, the frequency of POLE gene mutation in patients with  non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS:   We assessed POLE mutation in 319 patients with NSCLC by next-generation  sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA  mismatch repair proteins (MMR), and the abundance of CD8-positive tumor  infiltrating lymphocytes (TILs) were assayed by immunohistochemistry.  Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and  compared among groups using log-rank tests. RESULTS: Nine of the 319 patients  (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor  mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without  POLE mutation, respectively (P=0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and  PMS2), and CD8-positive TILs were evaluated in all nine patients. No  microsatellite instability was detected, but seven patients had high levels of  CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient  receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a  PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in  NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients  with mutant compared with wild-type POLE. POLE mutation may thus represent a  candidate biomarker for response to immunotherapy in patients with NSCLC.CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
CANIT0001712	29572003	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	319	N/A	N/A	POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.	N/A	N/A	N/A	POLE (Q07864); 	POLE P441L mutation	Mutational status	 2018 Apr	 Clinicopathological characteristics of POLE mutation in patients with  non-small-cell lung cancer.	 Lung Cancer	 BACKGROUND: Mutations in polymerase epsilon (POLE), a DNA polymerase involved in   DNA replication and repair, have been investigated in endometrial cancers and  response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1)  immunotherapy. However, the frequency of POLE gene mutation in patients with  non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS:   We assessed POLE mutation in 319 patients with NSCLC by next-generation  sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA  mismatch repair proteins (MMR), and the abundance of CD8-positive tumor  infiltrating lymphocytes (TILs) were assayed by immunohistochemistry.  Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and  compared among groups using log-rank tests. RESULTS: Nine of the 319 patients  (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor  mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without  POLE mutation, respectively (P=0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and  PMS2), and CD8-positive TILs were evaluated in all nine patients. No  microsatellite instability was detected, but seven patients had high levels of  CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient  receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a  PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in  NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients  with mutant compared with wild-type POLE. POLE mutation may thus represent a  candidate biomarker for response to immunotherapy in patients with NSCLC.CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
CANIT0001713	29572003	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	319	N/A	N/A	POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.	N/A	N/A	N/A	POLE (Q07864); 	POLE R1037H mutation	Mutational status	 2018 Apr	 Clinicopathological characteristics of POLE mutation in patients with  non-small-cell lung cancer.	 Lung Cancer	 BACKGROUND: Mutations in polymerase epsilon (POLE), a DNA polymerase involved in   DNA replication and repair, have been investigated in endometrial cancers and  response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1)  immunotherapy. However, the frequency of POLE gene mutation in patients with  non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS:   We assessed POLE mutation in 319 patients with NSCLC by next-generation  sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA  mismatch repair proteins (MMR), and the abundance of CD8-positive tumor  infiltrating lymphocytes (TILs) were assayed by immunohistochemistry.  Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and  compared among groups using log-rank tests. RESULTS: Nine of the 319 patients  (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor  mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without  POLE mutation, respectively (P=0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and  PMS2), and CD8-positive TILs were evaluated in all nine patients. No  microsatellite instability was detected, but seven patients had high levels of  CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient  receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a  PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in  NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients  with mutant compared with wild-type POLE. POLE mutation may thus represent a  candidate biomarker for response to immunotherapy in patients with NSCLC.CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
CANIT0001714	29572003	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	319	N/A	N/A	POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.	N/A	N/A	N/A	POLE (Q07864); 	POLE R1382H mutation	Mutational status	 2018 Apr	 Clinicopathological characteristics of POLE mutation in patients with  non-small-cell lung cancer.	 Lung Cancer	 BACKGROUND: Mutations in polymerase epsilon (POLE), a DNA polymerase involved in   DNA replication and repair, have been investigated in endometrial cancers and  response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1)  immunotherapy. However, the frequency of POLE gene mutation in patients with  non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS:   We assessed POLE mutation in 319 patients with NSCLC by next-generation  sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA  mismatch repair proteins (MMR), and the abundance of CD8-positive tumor  infiltrating lymphocytes (TILs) were assayed by immunohistochemistry.  Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and  compared among groups using log-rank tests. RESULTS: Nine of the 319 patients  (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor  mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without  POLE mutation, respectively (P=0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and  PMS2), and CD8-positive TILs were evaluated in all nine patients. No  microsatellite instability was detected, but seven patients had high levels of  CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient  receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a  PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in  NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients  with mutant compared with wild-type POLE. POLE mutation may thus represent a  candidate biomarker for response to immunotherapy in patients with NSCLC.CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
CANIT0001715	29572003	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	319	N/A	N/A	POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.	N/A	N/A	N/A	POLE (Q07864); 	POLE R1932C mutation	Mutational status	 2018 Apr	 Clinicopathological characteristics of POLE mutation in patients with  non-small-cell lung cancer.	 Lung Cancer	 BACKGROUND: Mutations in polymerase epsilon (POLE), a DNA polymerase involved in   DNA replication and repair, have been investigated in endometrial cancers and  response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1)  immunotherapy. However, the frequency of POLE gene mutation in patients with  non-small cell lung cancer (NSCLC) has not been reported. MATERIALS AND METHODS:   We assessed POLE mutation in 319 patients with NSCLC by next-generation  sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA  mismatch repair proteins (MMR), and the abundance of CD8-positive tumor  infiltrating lymphocytes (TILs) were assayed by immunohistochemistry.  Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and  compared among groups using log-rank tests. RESULTS: Nine of the 319 patients  (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor  mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without  POLE mutation, respectively (P=0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and  PMS2), and CD8-positive TILs were evaluated in all nine patients. No  microsatellite instability was detected, but seven patients had high levels of  CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient  receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a  PFS of >8 months. CONCLUSION: POLE mutation represents an uncommon phenotype in  NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients  with mutant compared with wild-type POLE. POLE mutation may thus represent a  candidate biomarker for response to immunotherapy in patients with NSCLC.CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
CANIT0001716	29581417	Case report	Non-Small Cell Lung Cancer with stage IV adenocarcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Oral cyclosporine treatment can be a third-line therapy for enterocolitis associated with immune-related adverse events.	Enterocolitis	N/A	N/A	N/A	N/A	N/A	 2018 Mar 27	 Resolution of Infliximab-Refractory Nivolumab-Induced Acute Severe Enterocolitis   After Cyclosporine Treatment in a Patient with Non-Small Cell Lung Cancer.	 Am J Case Rep	 BACKGROUND Enterocolitis is an immune-related adverse event associated with  nivolumab treatment. Although intravenous corticosteroids and infliximab are  recommended as a first-line and second-line therapy, respectively, there is no  established treatment for severe enterocolitis that is refractory to these drugs.  CASE REPORT A 62-year-old male with non-small cell lung cancer, with multiple  brain metastasis, received nivolumab as the eighth-line chemotherapy for his  disease. A few days after nivolumab administration, grade 2-3 enterocolitis  developed in the patient. The enterocolitis improved to grade 1 after careful  observation; however, it was aggravated to grade 3 after resuming nivolumab  treatment. After cessation of nivolumab, 3.3 mg of intravenous dexamethasone and   40 mg of methylprednisolone were administered for 16 days and subsequently 30-60   mg of oral prednisolone was administered for 50 days, with little improvement in   the patient's colitis. A second-line treatment with 5 mg/kg of infliximab was  twice attempted, but the patient had persistent diarrhea. Therefore, 50 mg of  oral cyclosporine was started as a third-line therapy. Three days after the start  of cyclosporine, the number of diarrhea events decreased, with resolution 2 weeks  after cyclosporine administration. CONCLUSIONS Oral cyclosporine treatment can be  a third-line therapy for enterocolitis associated with immune-related adverse  events.
CANIT0001717	29602646	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	36	43	A multicentre randomised phase II study	Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.	Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred.	N/A	N/A	N/A	N/A	N/A	 2018 May	 Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain  metastases: a multicentre randomised phase 2 study.	 Lancet Oncol	 BACKGROUND: Nivolumab monotherapy and combination nivolumab plus ipilimumab  increase proportions of patients achieving a response and survival versus  ipilimumab in patients with metastatic melanoma; however, efficacy in active  brain metastases is unknown. We aimed to establish the efficacy and safety of  nivolumab alone or in combination with ipilimumab in patients with active  melanoma brain metastases. METHODS: This multicentre open-label randomised phase   2 trial was done at four sites in Australia, in three cohorts of  immunotherapy-naive patients aged 18 years or older with melanoma brain  metastases. Patients with asymptomatic brain metastases with no previous local  brain therapy were randomly assigned using the biased coin minimisation method,  stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to  cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain  metastases in whom local therapy had failed, or who had neurological symptoms, or  leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab).  Patients in cohort A received intravenous nivolumab 1 mg/kg combined with  ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2  weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg  every 2 weeks. The primary endpoint was intracranial response from week 12.  Primary and safety analyses were done on an intention-to-treat basis in all  patients who received at least one dose of the study drug. This trial is  registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the  final survival analysis. FINDINGS: Between Nov 4, 2014, and April 21, 2017, 79  patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One  patient in cohort A and two in cohort B were found to be ineligible and excluded   from the study before receiving the study drug. At the data cutoff (Aug 28,  2017), with a median follow up of 17 months (IQR 8-25), intracranial responses  were achieved by 16 (46%; 95% CI 29-63) of 35 patients in cohort A, five (20%;  7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial  complete responses occurred in six (17%) patients in cohort A, three (12%) in  cohort B, and none in cohort C. Treatment-related adverse events occurred in 34  (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of   16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19  (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No  treatment-related deaths occurred. INTERPRETATION: Nivolumab combined with  ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A  high proportion of patients achieved an intracranial response with the  combination. Thus, nivolumab combined with ipilimumab should be considered as a  first-line therapy for patients with asymptomatic untreated brain metastases.  FUNDING: Melanoma Institute Australia and Bristol-Myers Squibb.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001718	29616914	Clinical research	Metastatic Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	108	N/A	A retrospective cohort study	For patients with metastatic melanoma treated with nivolumab or pembrolizumab, higher neutrophil counts are associated with higher risk of progression. For these patients, we recommend more frequent assessment for progression and closer follow-up, especially for patients with substantial comorbidities or poor physical performance.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	2018	 Association of Inflammatory Markers with Disease Progression in Patients with  Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.	 Perm J	 INTRODUCTION: We investigated the effect of inflammatory biomarkers (neutrophil,   platelet, and lymphocyte counts) on risk of progression in patients with  metastatic melanoma treated with an immune checkpoint inhibitor targeting  programmed cell death protein-1 (PD-1). METHODS: This retrospective cohort study   included 108 patients with malignant melanoma treated with an anti-PD-1  checkpoint inhibitor from August 2014 through December 2015. The outcome was  disease progression noted on imaging or clinical examination. Follow-up began on   the date of initiation of anti-PD-1 therapy and ended on the date of progression,  disenrollment, death of causes other than malignant melanoma, or the end of the  study in February 2017. RESULTS: The median time from initiating therapy with an   anti-PD-1 checkpoint inhibitor (nivolumab or pembrolizumab) to the end of  follow-up was 118 days. After adjustment, baseline neutrophil and platelet counts  were associated with progression. The hazard ratio (HR) for neutrophil counts >/=  5501/muL vs </= 3900/muL was 2.3 (95% confidence interval [CI] = 1.2-4.6, p <  0.05). For platelet counts >/= 304,000 vs </= 215,000/muL, the HR was 2.0 (CI =  1.0-3.9, p < 0.05). For lymphocyte counts >/= 1716/muL vs </= 1120/muL, the HR  was 0.5 (CI = 0.2-1.0, p = 0.05). CONCLUSION: For patients with metastatic  melanoma treated with nivolumab or pembrolizumab, higher neutrophil or platelet  counts, or lower lymphocyte counts, are associated with higher risk of  progression. For these patients, we recommend more frequent assessment for  progression and closer follow-up, especially for patients with substantial  comorbidities or poor physical performance.
CANIT0001719	29616914	Clinical research	Metastatic Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	108	N/A	A retrospective cohort study	For patients with metastatic melanoma treated with nivolumab or pembrolizumab, higher neutrophil counts are associated with higher risk of progression. For these patients, we recommend more frequent assessment for progression and closer follow-up, especially for patients with substantial comorbidities or poor physical performance.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	2018	 Association of Inflammatory Markers with Disease Progression in Patients with  Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.	 Perm J	 INTRODUCTION: We investigated the effect of inflammatory biomarkers (neutrophil,   platelet, and lymphocyte counts) on risk of progression in patients with  metastatic melanoma treated with an immune checkpoint inhibitor targeting  programmed cell death protein-1 (PD-1). METHODS: This retrospective cohort study   included 108 patients with malignant melanoma treated with an anti-PD-1  checkpoint inhibitor from August 2014 through December 2015. The outcome was  disease progression noted on imaging or clinical examination. Follow-up began on   the date of initiation of anti-PD-1 therapy and ended on the date of progression,  disenrollment, death of causes other than malignant melanoma, or the end of the  study in February 2017. RESULTS: The median time from initiating therapy with an   anti-PD-1 checkpoint inhibitor (nivolumab or pembrolizumab) to the end of  follow-up was 118 days. After adjustment, baseline neutrophil and platelet counts  were associated with progression. The hazard ratio (HR) for neutrophil counts >/=  5501/muL vs </= 3900/muL was 2.3 (95% confidence interval [CI] = 1.2-4.6, p <  0.05). For platelet counts >/= 304,000 vs </= 215,000/muL, the HR was 2.0 (CI =  1.0-3.9, p < 0.05). For lymphocyte counts >/= 1716/muL vs </= 1120/muL, the HR  was 0.5 (CI = 0.2-1.0, p = 0.05). CONCLUSION: For patients with metastatic  melanoma treated with nivolumab or pembrolizumab, higher neutrophil or platelet  counts, or lower lymphocyte counts, are associated with higher risk of  progression. For these patients, we recommend more frequent assessment for  progression and closer follow-up, especially for patients with substantial  comorbidities or poor physical performance.
CANIT0001720	29616914	Clinical research	Metastatic Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	108	N/A	A retrospective cohort study	For patients with metastatic melanoma treated with nivolumab or pembrolizumab, higher platelet counts are associated with higher risk of progression. For these patients, we recommend more frequent assessment for progression and closer follow-up, especially for patients with substantial comorbidities or poor physical performance.	N/A	N/A	N/A	Platelet counts (NCIT:C12520); 	Platelet counts	Cell percentage/counts in blood	2018	 Association of Inflammatory Markers with Disease Progression in Patients with  Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.	 Perm J	 INTRODUCTION: We investigated the effect of inflammatory biomarkers (neutrophil,   platelet, and lymphocyte counts) on risk of progression in patients with  metastatic melanoma treated with an immune checkpoint inhibitor targeting  programmed cell death protein-1 (PD-1). METHODS: This retrospective cohort study   included 108 patients with malignant melanoma treated with an anti-PD-1  checkpoint inhibitor from August 2014 through December 2015. The outcome was  disease progression noted on imaging or clinical examination. Follow-up began on   the date of initiation of anti-PD-1 therapy and ended on the date of progression,  disenrollment, death of causes other than malignant melanoma, or the end of the  study in February 2017. RESULTS: The median time from initiating therapy with an   anti-PD-1 checkpoint inhibitor (nivolumab or pembrolizumab) to the end of  follow-up was 118 days. After adjustment, baseline neutrophil and platelet counts  were associated with progression. The hazard ratio (HR) for neutrophil counts >/=  5501/muL vs </= 3900/muL was 2.3 (95% confidence interval [CI] = 1.2-4.6, p <  0.05). For platelet counts >/= 304,000 vs </= 215,000/muL, the HR was 2.0 (CI =  1.0-3.9, p < 0.05). For lymphocyte counts >/= 1716/muL vs </= 1120/muL, the HR  was 0.5 (CI = 0.2-1.0, p = 0.05). CONCLUSION: For patients with metastatic  melanoma treated with nivolumab or pembrolizumab, higher neutrophil or platelet  counts, or lower lymphocyte counts, are associated with higher risk of  progression. For these patients, we recommend more frequent assessment for  progression and closer follow-up, especially for patients with substantial  comorbidities or poor physical performance.
CANIT0001721	29616914	Clinical research	Metastatic Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	108	N/A	A retrospective cohort study	For patients with metastatic melanoma treated with nivolumab or pembrolizumab, higher platelet counts are associated with higher risk of progression. For these patients, we recommend more frequent assessment for progression and closer follow-up, especially for patients with substantial comorbidities or poor physical performance.	N/A	N/A	N/A	Platelet counts (NCIT:C12520); 	Platelet counts	Cell percentage/counts in blood	2018	 Association of Inflammatory Markers with Disease Progression in Patients with  Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.	 Perm J	 INTRODUCTION: We investigated the effect of inflammatory biomarkers (neutrophil,   platelet, and lymphocyte counts) on risk of progression in patients with  metastatic melanoma treated with an immune checkpoint inhibitor targeting  programmed cell death protein-1 (PD-1). METHODS: This retrospective cohort study   included 108 patients with malignant melanoma treated with an anti-PD-1  checkpoint inhibitor from August 2014 through December 2015. The outcome was  disease progression noted on imaging or clinical examination. Follow-up began on   the date of initiation of anti-PD-1 therapy and ended on the date of progression,  disenrollment, death of causes other than malignant melanoma, or the end of the  study in February 2017. RESULTS: The median time from initiating therapy with an   anti-PD-1 checkpoint inhibitor (nivolumab or pembrolizumab) to the end of  follow-up was 118 days. After adjustment, baseline neutrophil and platelet counts  were associated with progression. The hazard ratio (HR) for neutrophil counts >/=  5501/muL vs </= 3900/muL was 2.3 (95% confidence interval [CI] = 1.2-4.6, p <  0.05). For platelet counts >/= 304,000 vs </= 215,000/muL, the HR was 2.0 (CI =  1.0-3.9, p < 0.05). For lymphocyte counts >/= 1716/muL vs </= 1120/muL, the HR  was 0.5 (CI = 0.2-1.0, p = 0.05). CONCLUSION: For patients with metastatic  melanoma treated with nivolumab or pembrolizumab, higher neutrophil or platelet  counts, or lower lymphocyte counts, are associated with higher risk of  progression. For these patients, we recommend more frequent assessment for  progression and closer follow-up, especially for patients with substantial  comorbidities or poor physical performance.
CANIT0001722	29616914	Clinical research	Metastatic Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	108	N/A	A retrospective cohort study	For patients with metastatic melanoma treated with nivolumab or pembrolizumab, lower lymphocyte counts, are associated with higher risk of progression. For these patients, we recommend more frequent assessment for progression and closer follow-up, especially for patients with substantial comorbidities or poor physical performance.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	2018	 Association of Inflammatory Markers with Disease Progression in Patients with  Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.	 Perm J	 INTRODUCTION: We investigated the effect of inflammatory biomarkers (neutrophil,   platelet, and lymphocyte counts) on risk of progression in patients with  metastatic melanoma treated with an immune checkpoint inhibitor targeting  programmed cell death protein-1 (PD-1). METHODS: This retrospective cohort study   included 108 patients with malignant melanoma treated with an anti-PD-1  checkpoint inhibitor from August 2014 through December 2015. The outcome was  disease progression noted on imaging or clinical examination. Follow-up began on   the date of initiation of anti-PD-1 therapy and ended on the date of progression,  disenrollment, death of causes other than malignant melanoma, or the end of the  study in February 2017. RESULTS: The median time from initiating therapy with an   anti-PD-1 checkpoint inhibitor (nivolumab or pembrolizumab) to the end of  follow-up was 118 days. After adjustment, baseline neutrophil and platelet counts  were associated with progression. The hazard ratio (HR) for neutrophil counts >/=  5501/muL vs </= 3900/muL was 2.3 (95% confidence interval [CI] = 1.2-4.6, p <  0.05). For platelet counts >/= 304,000 vs </= 215,000/muL, the HR was 2.0 (CI =  1.0-3.9, p < 0.05). For lymphocyte counts >/= 1716/muL vs </= 1120/muL, the HR  was 0.5 (CI = 0.2-1.0, p = 0.05). CONCLUSION: For patients with metastatic  melanoma treated with nivolumab or pembrolizumab, higher neutrophil or platelet  counts, or lower lymphocyte counts, are associated with higher risk of  progression. For these patients, we recommend more frequent assessment for  progression and closer follow-up, especially for patients with substantial  comorbidities or poor physical performance.
CANIT0001723	29616914	Clinical research	Metastatic Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	108	N/A	A retrospective cohort study	For patients with metastatic melanoma treated with nivolumab or pembrolizumab, lower lymphocyte counts, are associated with higher risk of progression. For these patients, we recommend more frequent assessment for progression and closer follow-up, especially for patients with substantial comorbidities or poor physical performance.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	2018	 Association of Inflammatory Markers with Disease Progression in Patients with  Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.	 Perm J	 INTRODUCTION: We investigated the effect of inflammatory biomarkers (neutrophil,   platelet, and lymphocyte counts) on risk of progression in patients with  metastatic melanoma treated with an immune checkpoint inhibitor targeting  programmed cell death protein-1 (PD-1). METHODS: This retrospective cohort study   included 108 patients with malignant melanoma treated with an anti-PD-1  checkpoint inhibitor from August 2014 through December 2015. The outcome was  disease progression noted on imaging or clinical examination. Follow-up began on   the date of initiation of anti-PD-1 therapy and ended on the date of progression,  disenrollment, death of causes other than malignant melanoma, or the end of the  study in February 2017. RESULTS: The median time from initiating therapy with an   anti-PD-1 checkpoint inhibitor (nivolumab or pembrolizumab) to the end of  follow-up was 118 days. After adjustment, baseline neutrophil and platelet counts  were associated with progression. The hazard ratio (HR) for neutrophil counts >/=  5501/muL vs </= 3900/muL was 2.3 (95% confidence interval [CI] = 1.2-4.6, p <  0.05). For platelet counts >/= 304,000 vs </= 215,000/muL, the HR was 2.0 (CI =  1.0-3.9, p < 0.05). For lymphocyte counts >/= 1716/muL vs </= 1120/muL, the HR  was 0.5 (CI = 0.2-1.0, p = 0.05). CONCLUSION: For patients with metastatic  melanoma treated with nivolumab or pembrolizumab, higher neutrophil or platelet  counts, or lower lymphocyte counts, are associated with higher risk of  progression. For these patients, we recommend more frequent assessment for  progression and closer follow-up, especially for patients with substantial  comorbidities or poor physical performance.
CANIT0001724	29622100	Case report	Metastatic hepatocellular carcinoma	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Nivolumab-induced neurotoxicity can be both life-threatening and reversible with the appropriate treatment. Although the exact mechanism of nivolumab-induced cranial neuropathy is unknown, this case suggests that treatment with corticosteroids alone may be insufficient, at least in severe cases, and that the addition of plasmapheresis and intravenous immunoglobulin can lead to sustained recovery.	Multiple cranial neuropathies	N/A	N/A	N/A	N/A	N/A	 2018 Apr	 Multiple Cranial Neuropathies From Nivolumab in a Patient With Metastatic  Hepatocellular Carcinoma.	 Mayo Clin Proc	Unable to provide
CANIT0001725	29623482	Case report	Gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Prompt administration of high-dose corticosteroid is thus recommended after diagnosis of this adverse event of nivolumab treatment by kidney biopsy.	Acute granulomatous tubulointerstitial nephritis	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Nivolumab-induced acute granulomatous tubulointerstitial nephritis in a patient  with gastric cancer.	 Invest New Drugs	 We here report a case of nivolumab-induced acute granulomatous tubulointerstitial  nephritis in a patient with gastric cancer. A 68-year-old woman with recurrent  gastric cancer developed acute kidney injury associated with kidney enlargement  and urinary leukocytes after 38 cycles of nivolumab treatment. A diagnosis of  acute granulomatous tubulointerstitial nephritis was made based on kidney biopsy   findings. Immunohistochemistry revealed expression of programmed cell  death-ligand 1 (PD-L1) in degenerated epithelial cells of collecting tubules.  Among infiltrating immune cells, aggregation of T cells was more extensive than  that of B cells, with CD4(+) T cells outnumbering CD8(+) T cells, consistent with  the relative numbers of these cells in the circulation. Treatment with  methylprednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function  and reduction in the number of circulating CD4(+) T cells. Prompt administration   of high-dose corticosteroid is thus recommended after diagnosis of this adverse  event of nivolumab treatment by kidney biopsy.
CANIT0001726	29624748	Case report	Relapsed primary central nervous system lymphoma	Central nervous system lymphoma	EFO:1000157	Nervous system	PD-1 (Q15116); 	PD-1; 	Autologous stem cell transplantation followed by nivolumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Nivolumab (DB09035); autologous stem cell transplantation (NCIT:C16039); 	1	N/A	Case	Long-term remission	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jul	 Nivolumab maintenance after salvage autologous stem cell transplantation results   in long-term remission in multiple relapsed primary CNS lymphoma.	 Eur J Haematol	 Recurrence of primary central nervous system lymphoma (PCNSL) after high-dose  chemotherapy with autologous stem cell transplantation (ASCT) usually has a poor   overall prognosis with limited treatment options. Data on repeated ASCT are  sparse. Checkpoint inhibitor maintenance therapy has also not been reported in  PCNSL. Here, we report the first documented case of a successful third ASCT in  second relapse of PCNSL. Whole-exome sequencing identified a hypermutated tumor  genotype. Additionally, immunohistochemistry on pretreatment tumor tissue  revealed infiltrates of PD-1(+) cytolytic T cells. These alterations provided a  rationale for subsequent nivolumab maintenance treatment. Therapy led to a  long-term, ongoing complete remission. In eligible patients with recurrent  MTX-sensitive PCNSL, multiple long-term remissions can be induced by repetition  of high-dose MTX-based chemotherapy followed by autologous retransplantation.  Subsequent immune checkpoint inhibitor maintenance therapy might be able to  prolong or maintain remission.CI  - (c) 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001727	29625593	Case report	Recurrent nasopharyngeal carcinoma	Nasopharyngeal squamous cell carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	Cell lines	N/A	Case	Demonstrating distinct signs of immunostimulation as well as excellent tumor response in a heavily pretreated patient progressing under anti-PD-1 immunotherapy, the case adds to the rising paradigm of an immunostimulatory effect of radiotherapy in patients undergoing treatment with immune checkpoint inhibitors.	Immunotherapy with pembrolizumab was reinitiated, with re- staging showing excellent response with regression of all tumorous lesions. At the time of this report, following near complete recovery of inflammatory symptoms, the patient remains in excellent condition and free from recurrence under treatment with pembrolizumab.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2018 Apr 6	 Radiotherapy-induced anti-tumor immune response and immune-related adverse events  in a case of recurrent nasopharyngeal carcinoma undergoing anti-PD-1  immunotherapy.	 BMC Cancer	 BACKGROUND: Treatment of recurrent nasopharyngeal carcinoma is a challenging  clinical problem. We report the case of a 46 year old male showing excellent  response and signs of immunostimulation following re-re-irradiation for recurrent  nasopharyngeal carcinoma under systemic treatment with pembrolizumab. CASE  PRESENTATION: Patient was first diagnosed with locoregionally advanced,  non-keratinizing nasopharyngeal carcinoma in 2010. After achieving complete  remission following induction chemotherapy and concurrent curative  chemoradiation, the patient subsequently developed distant and locoregionally  recurrent disease. He received various treatments (neck dissection, radiotherapy   to a bony metastasis, palliative chemotherapy, stereotactic re-irradiation of  local recurrence) before initiation of anti- PD-1 immunotherapy with  pembrolizumab in January of 2016. Following marked local progression 6 months  thereafter, we performed re-re-irradiation of the recurrent tumor after careful  evaluation and treatment planning. While treatment was well tolerated, the  patient subsequently developed marked clinical and radiological signs of  immunostimulation with mucosal irritation and swelling of lacrimal and salivary  glands as described in the report. Immunotherapy with pembrolizumab was  reinitiated, with re- staging showing excellent response with regression of all  tumorous lesions. At the time of this report, following near complete recovery of  inflammatory symptoms, the patient remains in excellent condition and free from  recurrence under treatment with pembrolizumab. CONCLUSIONS: To our knowledge, we   report the first observation of a combined effect of immunotherapy and  radiotherapy in a patient with recurrent nasopharyngeal carcinoma. Demonstrating   distinct signs of immunostimulation as well as excellent tumor response in a  heavily pretreated patient progressing under anti-PD-1 immunotherapy, the case  adds to the rising paradigm of an immunostimulatory effect of radiotherapy in  patients undergoing treatment with immune checkpoint inhibitors.
CANIT0001728	29628312	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); IL15R (P40933); 	PD-1; IL15R	Nivolumab plus ALT-803	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ALT-803 (NCIT:C107503); 	21	N/A	A non-randomised, open-label, phase 1b  trial	ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC.	The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. 	N/A	N/A	N/A	N/A	N/A	 2018 May	 ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with  metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b  trial.	 Lancet Oncol	 BACKGROUND: Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response   in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and   many of those who do initially respond then develop resistance to treatment.  Agonists that target the shared interleukin-2 (IL-2) and IL-15Rbetagamma pathway   have induced complete and durable responses in some cancers, but no studies have   been done to assess the safety or efficacy of these agonists in combination with   anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and  activity of this drug combination in patients with NSCLC. METHODS: In this  non-randomised, open-label, phase 1b trial, we enrolled patients (aged >/=18  years) with previously treated histologically or cytologically confirmed stage  IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility  criteria included measurable disease, eligibility to receive anti-PD-1  immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0   or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously  at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved  dosing changed) every 14 days (either as new treatment or continued treatment at   the time of disease progression) and the IL-15 superagonist ALT-803  subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months.  ALT-803 was administered at one of four escalating dose concentrations: 6, 10,  15, or 20 mug/kg. The primary endpoint was to define safety and tolerability and   to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab.  Analyses were per-protocol and included any patients who received at least one  dose of study treatment. This trial is registered with ClinicalTrials.gov, number  NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS: Between Jan 18,   2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four  dose levels of ALT-803 in combination with nivolumab. Two patients did not  receive treatment because of the development of inter-current illness during  enrolment, one patient due to leucopenia and one patient due to pulmonary  dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated   dose was not reached. The most common adverse events were injection-site  reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most  common grade 3 adverse events, occurring in two patients each, were  lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one  patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2  dose of ALT-803 is 20 mug/kg given once per week subcutaneously in combination  with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION: ALT-803 in  combination with nivolumab can be safely administered in an outpatient setting.  The promising clinical activity observed with the addition of ALT-803 to the  regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease  shows evidence of anti-tumour activity for a new class of agents in NSCLC.  FUNDING: Altor BioScience (a NantWorks company), National Institutes of Health,  and Medical University of South Carolina Hollings Cancer Center.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001729	29631966	Clinical research	Advanced Non-Small-Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	N/A	Two patients with MET exon 14 mutation and high PD-L1 expression failed to respond to pembrolizumab.	N/A	N/A	N/A	MET (P08581); 	MET exon 14 mutation	Mutational status	 2018 Jul	 MET Expression in Advanced Non-Small-Cell Lung Cancer: Effect on Clinical  Outcomes of Chemotherapy, Targeted Therapy, and Immunotherapy.	 Clin Lung Cancer	 BACKGROUND: The receptor tyrosine kinase MET is implicated in malignant  transformation, tumor progression, metastasis, and acquired treatment resistance.  We conducted an analysis of the effect of MET expression and MET genomic  aberrations on the outcome of patients with advanced or metastatic pulmonary  adenocarcinomas prospectively enrolled in an institutional precision oncology  program. PATIENTS AND METHODS: Standardized immunohistochemistry (IHC) analyses  of MET and markers of pathway activation were available in 384 patients, and  next-generation sequencing-based MET hotspot mutation analyses were available  from 892 patients. Clinical data were retrieved with a median follow-up from  initial diagnosis of 37 months. RESULTS: High MET expression, defined as MET IHC   3+ or MET H-Score in the upper quartile, was observed in 102 of 384 patients  (26.6%). MET exon 14 mutations were only detected in 7 of 892 patients (0.78%).  High MET expression correlated with activation markers of the mitogen-activated  protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B  (PI3K/AKT) pathways only in cases without Kirsten rat sarcoma viral oncogene  homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma  viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and  proto-oncogene tyrosine-protein kinase ROS (ROS1) aberrations. There was no  association of MET expression with outcome during chemotherapy. High MET  expression negatively affected the outcome during EGFR-targeting therapy but was   associated with more favorable results with programmed death 1/programmed death  ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1  expression or KRAS mutation. Two patients with MET exon 14 mutation and high  PD-L1 expression failed to respond to pembrolizumab. CONCLUSION: MET expression  affects the outcomes of targeted therapies in non-small-cell lung cancer, thus  supporting the development of biomarker-informed combination strategies. The  interaction of MET expression and MET mutation with immune checkpoint inhibitor  therapy is novel and merits further investigation.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001730	29631966	Clinical research	Advanced Non-Small-Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	N/A	Two patients with MET exon 14 mutation and high PD-L1 expression failed to respond to pembrolizumab.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Jul	 MET Expression in Advanced Non-Small-Cell Lung Cancer: Effect on Clinical  Outcomes of Chemotherapy, Targeted Therapy, and Immunotherapy.	 Clin Lung Cancer	 BACKGROUND: The receptor tyrosine kinase MET is implicated in malignant  transformation, tumor progression, metastasis, and acquired treatment resistance.  We conducted an analysis of the effect of MET expression and MET genomic  aberrations on the outcome of patients with advanced or metastatic pulmonary  adenocarcinomas prospectively enrolled in an institutional precision oncology  program. PATIENTS AND METHODS: Standardized immunohistochemistry (IHC) analyses  of MET and markers of pathway activation were available in 384 patients, and  next-generation sequencing-based MET hotspot mutation analyses were available  from 892 patients. Clinical data were retrieved with a median follow-up from  initial diagnosis of 37 months. RESULTS: High MET expression, defined as MET IHC   3+ or MET H-Score in the upper quartile, was observed in 102 of 384 patients  (26.6%). MET exon 14 mutations were only detected in 7 of 892 patients (0.78%).  High MET expression correlated with activation markers of the mitogen-activated  protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B  (PI3K/AKT) pathways only in cases without Kirsten rat sarcoma viral oncogene  homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma  viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and  proto-oncogene tyrosine-protein kinase ROS (ROS1) aberrations. There was no  association of MET expression with outcome during chemotherapy. High MET  expression negatively affected the outcome during EGFR-targeting therapy but was   associated with more favorable results with programmed death 1/programmed death  ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1  expression or KRAS mutation. Two patients with MET exon 14 mutation and high  PD-L1 expression failed to respond to pembrolizumab. CONCLUSION: MET expression  affects the outcomes of targeted therapies in non-small-cell lung cancer, thus  supporting the development of biomarker-informed combination strategies. The  interaction of MET expression and MET mutation with immune checkpoint inhibitor  therapy is novel and merits further investigation.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001731	29631966	Clinical research	Advanced Non-Small-Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	384	N/A	N/A	High MET expression was associated with more favorable results with programmed death 1/programmed death ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1 expression or KRAS mutation. 	N/A	N/A	N/A	MET (P08581); 	MET expression levels in tumor cells	Gene expression signature on/in tumor cell	 2018 Jul	 MET Expression in Advanced Non-Small-Cell Lung Cancer: Effect on Clinical  Outcomes of Chemotherapy, Targeted Therapy, and Immunotherapy.	 Clin Lung Cancer	 BACKGROUND: The receptor tyrosine kinase MET is implicated in malignant  transformation, tumor progression, metastasis, and acquired treatment resistance.  We conducted an analysis of the effect of MET expression and MET genomic  aberrations on the outcome of patients with advanced or metastatic pulmonary  adenocarcinomas prospectively enrolled in an institutional precision oncology  program. PATIENTS AND METHODS: Standardized immunohistochemistry (IHC) analyses  of MET and markers of pathway activation were available in 384 patients, and  next-generation sequencing-based MET hotspot mutation analyses were available  from 892 patients. Clinical data were retrieved with a median follow-up from  initial diagnosis of 37 months. RESULTS: High MET expression, defined as MET IHC   3+ or MET H-Score in the upper quartile, was observed in 102 of 384 patients  (26.6%). MET exon 14 mutations were only detected in 7 of 892 patients (0.78%).  High MET expression correlated with activation markers of the mitogen-activated  protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B  (PI3K/AKT) pathways only in cases without Kirsten rat sarcoma viral oncogene  homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma  viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and  proto-oncogene tyrosine-protein kinase ROS (ROS1) aberrations. There was no  association of MET expression with outcome during chemotherapy. High MET  expression negatively affected the outcome during EGFR-targeting therapy but was   associated with more favorable results with programmed death 1/programmed death  ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1  expression or KRAS mutation. Two patients with MET exon 14 mutation and high  PD-L1 expression failed to respond to pembrolizumab. CONCLUSION: MET expression  affects the outcomes of targeted therapies in non-small-cell lung cancer, thus  supporting the development of biomarker-informed combination strategies. The  interaction of MET expression and MET mutation with immune checkpoint inhibitor  therapy is novel and merits further investigation.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001732	29633300	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); ipilimumab (DB06186); 	1	N/A	Case	Patient did not require cessation of immunotherapy for these lesions, which subsequently remained stable, while the patient's melanoma remained controlled. 	Here we describe a patient treated with combination immunotherapy of ipilimumab and pembrolizumab, who developed asymptomatic erythematous patches on both legs. Histopathologic examination revealed a cutaneous interstitial granulomatous dermatitis. Notably, our patient did not require cessation of immunotherapy for these lesions, which subsequently remained stable, while the patient's melanoma remained controlled.	N/A	N/A	N/A	N/A	N/A	 2018 Jul	 Dermatologic toxicity from immune checkpoint blockade therapy with an  interstitial granulomatous pattern.	 J Cutan Pathol	 Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)  and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have  showed significant therapeutic benefit in patients with clinically advanced solid  malignancies, including melanoma. However, immune-related adverse events (irAE)  are common, and novel dermatologic toxicities continue to emerge as more patients  are treated with immunotherapy. Here we describe a patient treated with  combination immunotherapy of ipilimumab and pembrolizumab, who developed  asymptomatic erythematous patches on both legs. Histopathologic examination  revealed a cutaneous interstitial granulomatous dermatitis. Notably, our patient   did not require cessation of immunotherapy for these lesions, which subsequently   remained stable, while the patient's melanoma remained controlled. This case  expands the dermatologic toxicity profile of immune checkpoint blockade, as  recognition of such toxicities is critical to optimal patient management.CI  - (c) 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001733	29634634	Case report	Metastatic cutaneous melanoma to the eye	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	The clinical diagnosis was of cutaneous melanoma metastatic to the vitreous, ciliary body and iris. Enucleation was performed for symptom control, with histopathology confirming the clinical diagnosis. The immune privilege of the eye may preclude ocular metastasis control with immunotherapy. Ocular symptoms in such patients merit referral to an ophthalmologist.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Immune privilege: failure of immunotherapy in controlling metastatic cutaneous  melanoma to the eye.	 Melanoma Res	 This report concerns a 49-year-old female with cutaneous malignant melanoma and  systemic metastases. These resolved following combination immunotherapy with  ipilimumab and nivolumab. She subsequently experienced unilateral floaters, an  increase in iris pigmentation and pigmentary glaucoma. The eye progressively lost  vision and became painful due to iris neovascularization. The clinical diagnosis   was of cutaneous melanoma metastatic to the vitreous, ciliary body and iris.  Enucleation was performed for symptom control, with histopathology confirming the  clinical diagnosis. The immune privilege of the eye may preclude ocular  metastasis control with immunotherapy. Ocular symptoms in such patients merit  referral to an ophthalmologist.
CANIT0001734	29658848	Clinical research	Resectable non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	21	N/A	A single-group study	Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. Responses occurred in both PD-L1-positive and PD-L1-negative tumors.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 May 24	 Neoadjuvant PD-1 Blockade in Resectable Lung Cancer.	 N Engl J Med	 BACKGROUND: Antibodies that block programmed death 1 (PD-1) protein improve  survival in patients with advanced non-small-cell lung cancer (NSCLC) but have  not been tested in resectable NSCLC, a condition in which little progress has  been made during the past decade. METHODS: In this pilot study, we administered  two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated,  surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of  3 mg per kilogram of body weight) was administered intravenously every 2 weeks,  with surgery planned approximately 4 weeks after the first dose. The primary end   points of the study were safety and feasibility. We also evaluated the tumor  pathological response, expression of programmed death ligand 1 (PD-L1),  mutational burden, and mutation-associated, neoantigen-specific T-cell responses.  RESULTS: Neoadjuvant nivolumab had an acceptable side-effect profile and was not   associated with delays in surgery. Of the 21 tumors that were removed, 20 were  completely resected. A major pathological response occurred in 9 of 20 resected  tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative  tumors. There was a significant correlation between the pathological response and  the pretreatment tumor mutational burden. The number of T-cell clones that were  found in both the tumor and peripheral blood increased systemically after PD-1  blockade in eight of nine patients who were evaluated. Mutation-associated,  neoantigen-specific T-cell clones from a primary tumor with a complete response  on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks  after treatment; some of these clones were not detected before the administration  of nivolumab. CONCLUSIONS: Neoadjuvant nivolumab was associated with few side  effects, did not delay surgery, and induced a major pathological response in 45%   of resected tumors. The tumor mutational burden was predictive of the  pathological response to PD-1 blockade. Treatment induced expansion of  mutation-associated, neoantigen-specific T-cell clones in peripheral blood.  (Funded by Cancer Research Institute-Stand Up 2 Cancer and others;  ClinicalTrials.gov number, NCT02259621 .).
CANIT0001735	29658848	Clinical research	Resectable non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	21	N/A	A single-group study	Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade.	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2018 May 24	 Neoadjuvant PD-1 Blockade in Resectable Lung Cancer.	 N Engl J Med	 BACKGROUND: Antibodies that block programmed death 1 (PD-1) protein improve  survival in patients with advanced non-small-cell lung cancer (NSCLC) but have  not been tested in resectable NSCLC, a condition in which little progress has  been made during the past decade. METHODS: In this pilot study, we administered  two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated,  surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of  3 mg per kilogram of body weight) was administered intravenously every 2 weeks,  with surgery planned approximately 4 weeks after the first dose. The primary end   points of the study were safety and feasibility. We also evaluated the tumor  pathological response, expression of programmed death ligand 1 (PD-L1),  mutational burden, and mutation-associated, neoantigen-specific T-cell responses.  RESULTS: Neoadjuvant nivolumab had an acceptable side-effect profile and was not   associated with delays in surgery. Of the 21 tumors that were removed, 20 were  completely resected. A major pathological response occurred in 9 of 20 resected  tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative  tumors. There was a significant correlation between the pathological response and  the pretreatment tumor mutational burden. The number of T-cell clones that were  found in both the tumor and peripheral blood increased systemically after PD-1  blockade in eight of nine patients who were evaluated. Mutation-associated,  neoantigen-specific T-cell clones from a primary tumor with a complete response  on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks  after treatment; some of these clones were not detected before the administration  of nivolumab. CONCLUSIONS: Neoadjuvant nivolumab was associated with few side  effects, did not delay surgery, and induced a major pathological response in 45%   of resected tumors. The tumor mutational burden was predictive of the  pathological response to PD-1 blockade. Treatment induced expansion of  mutation-associated, neoantigen-specific T-cell clones in peripheral blood.  (Funded by Cancer Research Institute-Stand Up 2 Cancer and others;  ClinicalTrials.gov number, NCT02259621 .).
CANIT0001736	29658856	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	Chemotherapy plus placebo	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	410	206	A double-blind, phase III	Better outcome in patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations	Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.	N/A	N/A	N/A	N/A	N/A	 2018 May 31	 Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.	 N Engl J Med	 BACKGROUND: First-line therapy for advanced non-small-cell lung cancer (NSCLC)  that lacks targetable mutations is platinum-based chemotherapy. Among patients  with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or  greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line  treatment of choice. The addition of pembrolizumab to chemotherapy resulted in  significantly higher rates of response and longer progression-free survival than   chemotherapy alone in a phase 2 trial. METHODS: In this double-blind, phase 3  trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic  nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no  previous treatment for metastatic disease to receive pemetrexed and a  platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks   for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles  plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was  permitted among the patients in the placebo-combination group who had verified  disease progression. The primary end points were overall survival and  progression-free survival, as assessed by blinded, independent central radiologic  review. RESULTS: After a median follow-up of 10.5 months, the estimated rate of  overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to  73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2)   in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to  0.64; P<0.001). Improvement in overall survival was seen across all PD-L1  categories that were evaluated. Median progression-free survival was 8.8 months  (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95%  CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease  progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of  grade 3 or higher occurred in 67.2% of the patients in the  pembrolizumab-combination group and in 65.8% of those in the placebo-combination   group. CONCLUSIONS: In patients with previously untreated metastatic nonsquamous   NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard  chemotherapy of pemetrexed and a platinum-based drug resulted in significantly  longer overall survival and progression-free survival than chemotherapy alone.  (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).
CANIT0001737	29659371	Clinical research	Metastatic cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	807	N/A	A phase II clinical trial	An elevated lactate dehydrogenase level (hazard ratio: 2.25 and 1.70 in treatment-naive and previously-treated patients, respectively) and American Joint Committee on Cancer M1c-stage disease (hazard ratio: 1.81 and 1.83, respectively) were negatively associated with overall survival. 	Grade 3 and 4 immune-related adverse events occurred in 29% of treatment-naive patients and 21% of previously-treated patients. No treatment-related deaths occurred. 	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2018 Jul	 Real-world use, safety, and survival of ipilimumab in metastatic cutaneous  melanoma in The Netherlands.	 Anticancer Drugs	 Phase III trials with ipilimumab showed an improved survival in patients with  metastatic melanoma. We evaluated the use and safety of ipilimumab, and the  survival of all patients with metastatic cutaneous melanoma (N=807) receiving  ipilimumab in real-world clinical practice in The Netherlands using data from the  Dutch Melanoma Treatment Registry. Patients who were registered between July 2012  and July 2015 were included and analyzed according to their treatment status:  treatment-naive (N=344) versus previously-treated (N=463). Overall, 70% of  treatment-naive patients and 62% of previously-treated patients received all four  planned doses of ipilimumab. Grade 3 and 4 immune-related adverse events occurred  in 29% of treatment-naive patients and 21% of previously-treated patients. No  treatment-related deaths occurred. Median time to first event was 5.4 months [95%  confidence interval (CI): 4.7-6.5 months] in treatment-naive patients and 4.4  months (95% CI: 4.0-4.7 months) in previously-treated patients. Median overall  survival was 14.3 months (95% CI: 11.6-16.7 months) in treatment-naive patients  and 8.7 months (95% CI: 7.6-9.6 months) in previously-treated patients. In both  patient groups, an elevated lactate dehydrogenase level (hazard ratio: 2.25 and  1.70 in treatment-naive and previously-treated patients, respectively) and  American Joint Committee on Cancer M1c-stage disease (hazard ratio: 1.81 and  1.83, respectively) were negatively associated with overall survival. These  real-world outcomes of ipilimumab slightly differed from outcomes in phase III  trials. Although phase III trials are crucial for establishing efficacy,  real-world data are of great added value enhancing the generalizability of  outcomes of ipilimumab in clinical practice.
CANIT0001738	29659371	Clinical research	Metastatic cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	807	N/A	A phase II clinical trial	An elevated lactate dehydrogenase level (hazard ratio: 2.25 and 1.70 in treatment-naive and previously-treated patients, respectively) and American Joint Committee on Cancer M1c-stage disease (hazard ratio: 1.81 and 1.83, respectively) were negatively associated with overall survival. 	Grade 3 and 4 immune-related adverse events occurred in 29% of treatment-naive patients and 21% of previously-treated patients. No treatment-related deaths occurred. 	N/A	N/A	M1c-stage disease (NCIT:C48703); 	M1c-stage disease	Disease status	 2018 Jul	 Real-world use, safety, and survival of ipilimumab in metastatic cutaneous  melanoma in The Netherlands.	 Anticancer Drugs	 Phase III trials with ipilimumab showed an improved survival in patients with  metastatic melanoma. We evaluated the use and safety of ipilimumab, and the  survival of all patients with metastatic cutaneous melanoma (N=807) receiving  ipilimumab in real-world clinical practice in The Netherlands using data from the  Dutch Melanoma Treatment Registry. Patients who were registered between July 2012  and July 2015 were included and analyzed according to their treatment status:  treatment-naive (N=344) versus previously-treated (N=463). Overall, 70% of  treatment-naive patients and 62% of previously-treated patients received all four  planned doses of ipilimumab. Grade 3 and 4 immune-related adverse events occurred  in 29% of treatment-naive patients and 21% of previously-treated patients. No  treatment-related deaths occurred. Median time to first event was 5.4 months [95%  confidence interval (CI): 4.7-6.5 months] in treatment-naive patients and 4.4  months (95% CI: 4.0-4.7 months) in previously-treated patients. Median overall  survival was 14.3 months (95% CI: 11.6-16.7 months) in treatment-naive patients  and 8.7 months (95% CI: 7.6-9.6 months) in previously-treated patients. In both  patient groups, an elevated lactate dehydrogenase level (hazard ratio: 2.25 and  1.70 in treatment-naive and previously-treated patients, respectively) and  American Joint Committee on Cancer M1c-stage disease (hazard ratio: 1.81 and  1.83, respectively) were negatively associated with overall survival. These  real-world outcomes of ipilimumab slightly differed from outcomes in phase III  trials. Although phase III trials are crucial for establishing efficacy,  real-world data are of great added value enhancing the generalizability of  outcomes of ipilimumab in clinical practice.
CANIT0001739	29665030	Case report	Stage IIIC melanoma of the right calf and inguinal lymph nodes	Melanoma	EFO:0000756	Skin	DENDRITIC CELL (N/A); 	DENDRITIC CELL; 	Antimicrobial peptide LL-37	N/A	Tumor vaccine	Antimicrobial peptide LL-37 (NCIT:C118292); 	1	N/A	Case	This case highlights adverse dermatological manifestations of LL-37 therapy, similar to the consequences of other novel therapies.	We report dermatologic toxicity in a 63-year-old woman with stage IIIC melanoma of the right calf and inguinal lymph nodes. She was previously treated with nivolumab and combination chemotherapy (cisplatin, vinblastine and dacarbazine) and subsequently treated with LL-37 injections upon progression of both prior regimens. She received a total of 8 weekly LL-37 injections, with interval clinical shrinkage of injected lesions. However, approximately 45 days after initiation of this therapy, she presented with multiple verrucous papules and a vesiculo-bullous lesion on the trunk and extremities. Clinically, most of these lesions were thought to be either squamous cell carcinoma or inflamed seborrheic keratosis. Histologically, 11 of the total 12 skin biopsies showed similar histopathologic features, with a prominent lichenoid inflammatory infiltrate admixed with eosinophils and an overlying atypical squamous epithelial proliferation with verrucous and keratoacanthoma-like features and varying degrees of keratinocytic atypia. Interestingly, a majority of the lesions did not show spongiosis (11/12). All lesions resolved within 2 months of cessation of LL-37 injection therapy.	N/A	N/A	N/A	N/A	N/A	 2018 Jul	 Dermatologic toxicity from novel therapy using antimicrobial peptide LL-37 in  melanoma: A detailed examination of the clinicopathologic features.	 J Cutan Pathol	 LL-37 is a naturally occurring 37-amino-acid peptide that is part of the innate  immune system in human skin. Preclinical studies have showed that intra-tumoral  injections of LL-37 stimulate the innate immune system by activation of  plasmacytoid dendritic cells, which mediate tumor destruction. LL-37  intra-tumoral injections have been utilized in a phase 1 clinical trial for  melanoma patients with cutaneous metastases. We report dermatologic toxicity in a  63-year-old woman with stage IIIC melanoma of the right calf and inguinal lymph  nodes. She was previously treated with nivolumab and combination chemotherapy  (cisplatin, vinblastine and dacarbazine) and subsequently treated with LL-37  injections upon progression of both prior regimens. She received a total of 8  weekly LL-37 injections, with interval clinical shrinkage of injected lesions.  However, approximately 45 days after initiation of this therapy, she presented  with multiple verrucous papules and a vesiculo-bullous lesion on the trunk and  extremities. Clinically, most of these lesions were thought to be either squamous  cell carcinoma or inflamed seborrheic keratosis. Histologically, 11 of the total   12 skin biopsies showed similar histopathologic features, with a prominent  lichenoid inflammatory infiltrate admixed with eosinophils and an overlying  atypical squamous epithelial proliferation with verrucous and  keratoacanthoma-like features and varying degrees of keratinocytic atypia.  Interestingly, a majority of the lesions did not show spongiosis (11/12). All  lesions resolved within 2 months of cessation of LL-37 injection therapy. This  case highlights adverse dermatological manifestations of LL-37 therapy, similar  to the consequences of other novel therapies.CI  - (c) 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001740	29667757	Case report	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Successful treatment with nivolumab for lung cancer with low expression of PD-L1 and prominent tumor-infiltrating B cells and immunoglobulin G. Pre-existing humoral immunity may be worth considering as a candidate therapeutic biomarker of nivolumab in some lung cancer patients.	N/A	N/A	N/A	B-Lymphocyte (NCIT:C12474); 	Tumor-infiltrating B-cells	Tumor-infiltrating immune cell	 2018 Jun	 Successful treatment with nivolumab for lung cancer with low expression of PD-L1   and prominent tumor-infiltrating B cells and immunoglobulin G.	 Thorac Cancer	 Little is known about the anti-tumor activity of humoral immunity in lung cancer   patients treated with nivolumab, an immune checkpoint inhibitor. Herein, we  report a case of lung cancer with 5% expression of PD-L1, in which a partial  response to nivolumab was sustained for > 7 months. Immunohistochemical analysis   of the metastatic lymph node biopsy specimen showed prominent accumulation of  plasma cells and immunoglobulin G. These findings suggest that pre-existing  humoral immunity may be worth considering as a candidate therapeutic biomarker of  nivolumab in some lung cancer patients.CI  - (c) 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and   John Wiley & Sons Australia, Ltd.
CANIT0001741	29667757	Case report	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Successful treatment with nivolumab for lung cancer with low expression of PD-L1 and prominent tumor-infiltrating B cells and immunoglobulin G. Pre-existing humoral immunity may be worth considering as a candidate therapeutic biomarker of nivolumab in some lung cancer patients.	N/A	N/A	N/A	Immunoglobulin G (P59901); 	Serum immunoglobulin G levels	Gene expression signature in serum	 2018 Jun	 Successful treatment with nivolumab for lung cancer with low expression of PD-L1   and prominent tumor-infiltrating B cells and immunoglobulin G.	 Thorac Cancer	 Little is known about the anti-tumor activity of humoral immunity in lung cancer   patients treated with nivolumab, an immune checkpoint inhibitor. Herein, we  report a case of lung cancer with 5% expression of PD-L1, in which a partial  response to nivolumab was sustained for > 7 months. Immunohistochemical analysis   of the metastatic lymph node biopsy specimen showed prominent accumulation of  plasma cells and immunoglobulin G. These findings suggest that pre-existing  humoral immunity may be worth considering as a candidate therapeutic biomarker of  nivolumab in some lung cancer patients.CI  - (c) 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and   John Wiley & Sons Australia, Ltd.
CANIT0001742	29669553	Case report	Metastatic chromophobe renal cell carcinoma with sarcomatoid differentiation	Chromophobe renal cell carcinoma	EFO:0000335	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Significant response	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Apr 18	 Significant response to nivolumab for metastatic chromophobe renal cell carcinoma  with sarcomatoid differentiation: a case report.	 BMC Urol	 BACKGROUND: The treatment of advanced or metastatic renal cell carcinoma (RCC)  has drastically changed since the approval of immune checkpoint therapy.  Nivolumab is a treatment option for patients with metastatic RCC, previously  treated with targeted antiangiogenic therapy. The efficacy of nivolumab for  patients with RCC was established by the Checkmate 025 clinical trial.  Chromophobe RCC (CRCC) represents around 5% of RCC cases, but non-clear cell RCC   (non-ccRCC) subtypes were excluded from the Checkmate 025 clinical trial. We  report a case in which the use of nivolumab as the seventh-line therapy elicited   a significant response in the treatment of metastatic CRCC with sarcomatoid  differentiation. CASE PRESENTATION: We report a case of a 41-year-old woman with   metastatic CRCC with sarcomatoid differentiation. She was treated with sunitinib,  pazopanib, everolimus, sorafenib, axtinib, and temsirolimus, but treatment was  discontinued because of disease progression or strong adverse events.  Seventh-line treatment with nivolumab was initiated and significant clinical  improvement was noted after 4 cycles. The treatment was well-tolerated with no  significant side effects and the patient continues with nivolumab treatment at  present. CONCLUSIONS: Nivolumab may be an attractive treatment option for  non-ccRCC patients with sarcomatoid differentiation that exhibited aggressive  characteristics and poor prognosis. Further investigation is warranted.
CANIT0001743	29669775	Case report	Metastatic lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Autoimmune haemolytic anaemia	Autoimmune haemolytic anaemia after 39 cycles of nivolumab	N/A	N/A	N/A	N/A	N/A	 2018 Apr 18	 A case of autoimmune haemolytic anaemia after 39 cycles of nivolumab.	 BMJ Case Rep	 With growing use of nivolumab, rare but serious side effects have surfaced in  some patients. We present a case of autoimmune haemolytic anaemia that developed   after 39 cycles of nivolumab. A 78-year-old man with metastatic lung  adenocarcinoma, refractory to multiple lines of chemotherapy was switched to  nivolumab. After around 2 years of stable course on nivolumab, he developed  transfusion-dependent anaemia with haemoglobin of 8.6 g/dL. Nivolumab was held  immediately. Bone marrow biopsy findings were inconclusive of myelodysplastic  syndrome. Further testing was suggestive of haemolysis with haptoglobin <10  mg/dL, elevated reticulocyte count and identification of immunoglobulin G  antibody. Haemoglobin improved significantly with initiation of 1 mg/kg  prednisone in addition to rituximab weekly x four doses. The development of  transfusion-dependent anaemia with the exposure to cytotoxic chemotherapy usually  raises the question for myelodysplastic syndrome. In contradiction, our patient  was diagnosed to have a haematological autoimmune complication related to  immunotherapy.CI  - (c) BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)  2018. All rights reserved. No commercial use is permitted unless otherwise  expressly granted.
CANIT0001744	29678530	Clinical research	Lung Cancer Patients With Brain Metastases	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus stereotactic radiosurgery	Stereotactic radiosurgery before or after nivolumab	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); stereotactic ablative radiotherapy (NCIT:C157991); 	37	N/A	A retrospective cohort study	Concurrent treatment with SRS and PD-1 pathway inhibitors was associated with favorable OS and locoregional disease control. This combination of therapy was well tolerated and merits further evaluation in larger cohorts in a prospective setting.	Four patients required steroids for SRS-associated toxicity. No patient experienced grade  4 toxicity.	N/A	N/A	N/A	N/A	N/A	 2018 Jul 1	 Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1  Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With  Brain Metastases.	 Int J Radiat Oncol Biol Phys	 PURPOSE: Despite the emerging role of programmed cell death-1 (PD-1) pathway  inhibitors for patients with advanced lung cancer, a paucity of data are  available on the activity of these agents among patients with brain metastases.  We investigated the outcomes of PD-1 pathway inhibitors and stereotactic  radiosurgery (SRS) for the treatment of patients with brain metastases from lung   cancer. METHODS AND MATERIALS: We retrospectively reviewed the medical records of  non-small-cell lung cancer patients with brain metastases consecutively treated  with PD-1 pathway inhibitors and SRS at our institution from 2012 to 2017.  Overall survival (OS), distant brain failure (DBF), and local control (LC) were  assessed using Kaplan-Meier estimates and Cox regression models. RESULTS: We  identified 37 patients treated with SRS to 85 lesions (90.6% intact and 9.4%  resected) and a median total of 7 doses of PD-1 pathway inhibitors (83.8%  nivolumab, 10.8% atezolizumab, 5.4% pembrolizumab). Most lesions were treated  with 18 Gy in a single fraction (n = 61; 71.8%). Patients treated with concurrent  SRS and PD-1 pathway inhibitors had longer OS and reduced rates of DBF compared  with patients treated with SRS before or after PD-1 pathway inhibitor therapy  (1-year OS, 87.3% vs 70.0% vs 0%, P = .008; 1-year DBF, 38.5% vs 65.8% vs 100%, P  = .042). LC was favorable among lesions treated with SRS concurrent with or after  PD-1 pathway inhibitor therapy compared with before PD-1 pathway inhibitor  therapy (1-year LC, 100% vs 72.3%, P = .016). Three lesions transiently enlarged   after SRS and then had partially or completely resolved on follow-up imaging.  Four patients required steroids for SRS-associated toxicity. No patient  experienced grade >/= 4 toxicity. CONCLUSIONS: Concurrent treatment with SRS and   PD-1 pathway inhibitors was associated with favorable OS and locoregional disease  control. This combination of therapy was well tolerated and merits further  evaluation in larger cohorts in a prospective setting.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001745	29678530	Clinical research	Lung Cancer Patients With Brain Metastases	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus stereotactic radiosurgery	Stereotactic radiosurgery before or after pembrolizumab	Immune checkpoint therapy plus Radiotherapy	Pembrolizumab (DB09037); stereotactic ablative radiotherapy (NCIT:C157991); 	37	N/A	A retrospective cohort study	Concurrent treatment with SRS and PD-1 pathway inhibitors was associated with favorable OS and locoregional disease control. This combination of therapy was well tolerated and merits further evaluation in larger cohorts in a prospective setting.	Four patients required steroids for SRS-associated toxicity. No patient experienced grade  4 toxicity.	N/A	N/A	N/A	N/A	N/A	 2018 Jul 1	 Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1  Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With  Brain Metastases.	 Int J Radiat Oncol Biol Phys	 PURPOSE: Despite the emerging role of programmed cell death-1 (PD-1) pathway  inhibitors for patients with advanced lung cancer, a paucity of data are  available on the activity of these agents among patients with brain metastases.  We investigated the outcomes of PD-1 pathway inhibitors and stereotactic  radiosurgery (SRS) for the treatment of patients with brain metastases from lung   cancer. METHODS AND MATERIALS: We retrospectively reviewed the medical records of  non-small-cell lung cancer patients with brain metastases consecutively treated  with PD-1 pathway inhibitors and SRS at our institution from 2012 to 2017.  Overall survival (OS), distant brain failure (DBF), and local control (LC) were  assessed using Kaplan-Meier estimates and Cox regression models. RESULTS: We  identified 37 patients treated with SRS to 85 lesions (90.6% intact and 9.4%  resected) and a median total of 7 doses of PD-1 pathway inhibitors (83.8%  nivolumab, 10.8% atezolizumab, 5.4% pembrolizumab). Most lesions were treated  with 18 Gy in a single fraction (n = 61; 71.8%). Patients treated with concurrent  SRS and PD-1 pathway inhibitors had longer OS and reduced rates of DBF compared  with patients treated with SRS before or after PD-1 pathway inhibitor therapy  (1-year OS, 87.3% vs 70.0% vs 0%, P = .008; 1-year DBF, 38.5% vs 65.8% vs 100%, P  = .042). LC was favorable among lesions treated with SRS concurrent with or after  PD-1 pathway inhibitor therapy compared with before PD-1 pathway inhibitor  therapy (1-year LC, 100% vs 72.3%, P = .016). Three lesions transiently enlarged   after SRS and then had partially or completely resolved on follow-up imaging.  Four patients required steroids for SRS-associated toxicity. No patient  experienced grade >/= 4 toxicity. CONCLUSIONS: Concurrent treatment with SRS and   PD-1 pathway inhibitors was associated with favorable OS and locoregional disease  control. This combination of therapy was well tolerated and merits further  evaluation in larger cohorts in a prospective setting.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001746	29678530	Clinical research	Lung Cancer Patients With Brain Metastases	Lung carcinoma	EFO:0001071	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab plus stereotactic radiosurgery	Stereotactic radiosurgery before or after atezolizumab	Immune checkpoint therapy plus Radiotherapy	Atezolizumab (DB11595); stereotactic ablative radiotherapy (NCIT:C157991); 	37	N/A	A retrospective cohort study	Concurrent treatment with SRS and PD-1 pathway inhibitors was associated with favorable OS and locoregional disease control. This combination of therapy was well tolerated and merits further evaluation in larger cohorts in a prospective setting.	Four patients required steroids for SRS-associated toxicity. No patient experienced grade  4 toxicity.	N/A	N/A	N/A	N/A	N/A	 2018 Jul 1	 Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1  Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With  Brain Metastases.	 Int J Radiat Oncol Biol Phys	 PURPOSE: Despite the emerging role of programmed cell death-1 (PD-1) pathway  inhibitors for patients with advanced lung cancer, a paucity of data are  available on the activity of these agents among patients with brain metastases.  We investigated the outcomes of PD-1 pathway inhibitors and stereotactic  radiosurgery (SRS) for the treatment of patients with brain metastases from lung   cancer. METHODS AND MATERIALS: We retrospectively reviewed the medical records of  non-small-cell lung cancer patients with brain metastases consecutively treated  with PD-1 pathway inhibitors and SRS at our institution from 2012 to 2017.  Overall survival (OS), distant brain failure (DBF), and local control (LC) were  assessed using Kaplan-Meier estimates and Cox regression models. RESULTS: We  identified 37 patients treated with SRS to 85 lesions (90.6% intact and 9.4%  resected) and a median total of 7 doses of PD-1 pathway inhibitors (83.8%  nivolumab, 10.8% atezolizumab, 5.4% pembrolizumab). Most lesions were treated  with 18 Gy in a single fraction (n = 61; 71.8%). Patients treated with concurrent  SRS and PD-1 pathway inhibitors had longer OS and reduced rates of DBF compared  with patients treated with SRS before or after PD-1 pathway inhibitor therapy  (1-year OS, 87.3% vs 70.0% vs 0%, P = .008; 1-year DBF, 38.5% vs 65.8% vs 100%, P  = .042). LC was favorable among lesions treated with SRS concurrent with or after  PD-1 pathway inhibitor therapy compared with before PD-1 pathway inhibitor  therapy (1-year LC, 100% vs 72.3%, P = .016). Three lesions transiently enlarged   after SRS and then had partially or completely resolved on follow-up imaging.  Four patients required steroids for SRS-associated toxicity. No patient  experienced grade >/= 4 toxicity. CONCLUSIONS: Concurrent treatment with SRS and   PD-1 pathway inhibitors was associated with favorable OS and locoregional disease  control. This combination of therapy was well tolerated and merits further  evaluation in larger cohorts in a prospective setting.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001747	29680230	Case report	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Percutaneous ablative cryoimmunotherapy for micrometastaic abscopal effect: No  complications.	 Cryobiology	 Recent studies have shown efficacy of nivolumab, a monoclonal antibody specific  for an immunoregulatory protein termed programmed death 1 (PD-1), against  metastatic renal cell carcinoma. PD-1 is a transmembrane protein expressed on T  cells that suppresses activation upon binding to its ligands, which may be  secreted paraneoplastically by various cancers. Inhibition of PD-1 signaling via   nivolumab may sensitize tumor-specific T lymphocytes in the immunosuppressive  tumor microenvironment. Systemic elimination of micrometastases requires robust  activation and proliferation of tumor antigen stimulated T cells. Cryoablation  lyses tumor cell membranes but leaves intracellular tumor antigens intact for  recognition by effectors systemically, while eliminating permissive T cell  subtypes locally. This single case report describes CT-guided percutaneous  cryoablation of a metastatic renal cell carcinoma with local administration of  nivolumab to simultaneously debulk the primary tumor, sensitize effector T cells   against tumor antigens, and augment the systemic immune response elicited against  established metastases. One month follow up PET scan revealed decreased uptake in  the two smaller metastatic bone lesions with the smallest lesion completely  eliminated. The largest metastatic bone lesion was slightly decreased in size and  exhibited slightly increased uptake. The patient's presenting complaint of hip  pain was abrogated, allowing her to resume independent ambulation. CT-guided  percutaneous cryoablation is minimally invasive and preserves tumor antigens,  which are subsequently presented to tumor-specific T cells; their differentiation  into cytotoxic T cells may be guided and their proliferation may be augmented by   local administration of immunostimulatory pharmacotherapy at the time of the  procedure.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001748	29681240	Case report	Lung adenocarcinoma (T1bN3M1b)  with human immunodeficiency virus	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Pembrolizumab combined with SBRT therapy for patients with human immunodeficiency virus infection and non-small cell lung cancer may lead to serious immune-related adverse events and more clinical trials are needed.	Serious immune-related adverse events 	N/A	N/A	N/A	N/A	N/A	 2018 Apr 23	 Pembrolizumab combined with stereotactic body radiotherapy in a patient with  human immunodeficiency virus and advanced non-small cell lung cancer: a case  report.	 J Med Case Rep	 BACKGROUND: Pembrolizumab has significantly improved outcomes in patients with  advanced non-small cell lung cancer. Combining programmed death-1 inhibitor with   stereotactic body radiotherapy showed a slight toxicity and good benefits in  recent clinical trials. However, patients infected with human immunodeficiency  virus were excluded from most trials because it was assumed that their anti-tumor  immunity was compromised compared with immunocompetent patients. CASE  PRESENTATION: In June 2016, a 52-year-old Chinese man presented with human  immunodeficiency virus and lung adenocarcinoma (T1bN3M1b). From November 2016 to   December 2016, systemic chemotherapy and palliative radiotherapy for bone  metastasis of femoral neck were carried out, but the tumor progressed. In January  2017, after immunochemistry detection of programmed death-1 and programmed  death-ligand 1 expression (both > 50%), pembrolizumab was started. Three weeks  after pembrolizumab, we combined stereotactic body radiotherapy for the primary  lung tumor. He received no comfort and his CD4 lymphocyte count was stable. Human  immunodeficiency virus-ribonucleic acid remained below the limits of detection.  In March 2017, after three cycles of pembrolizumab and 5 weeks of stereotactic  body radiotherapy therapy, he suddenly presented with palpitations. Emergency  computed tomography scanning showed massive pericardial effusion and interstitial  pneumonia. So we interrupted the pembrolizumab use and initiated treatment with  prednisolone 1 mg/kg; however, the tumor progressed. Then, his CD4 lymphocyte  count declined. Finally he died in June 2017 due to dyscrasia. CONCLUSIONS:  Pembrolizumab combined with SBRT therapy for patients with human immunodeficiency  virus infection and non-small cell lung cancer may lead to serious immune-related  adverse events and more clinical trials are needed.
CANIT0001749	29683761	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	N/A	In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.	N/A	N/A	N/A	Hsa-miR-215-5p (); 	MiR-215-5p expression on tumor cells	Gene expression signature on/in tumor cell	 2018 Sep	 Circulating microRNAs associated with prolonged overall survival in lung cancer  patients treated with nivolumab.	 Acta Oncol	 BACKGROUND: The introduction of immune check-point inhibition in non-small cell  lung cancer (NSCLC) therapy represents improved prospects for the patients. The  response rates to check-point inhibitors are approximately 20% in unselected  NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with  higher response rates. However, patients with low PD-L1 levels may also have  durable responses, and improved strategies for patient stratification are needed.  MATERIAL AND METHODS: In this study, we investigated circulating microRNAs aiming  to identify circulating predictive biomarkers associated with increased overall  survival after immune check-point treatment. Using next generation sequencing, we  performed microRNA profiling in serum from NSCLC patients (n = 20) treated with  nivolumab. Serum samples from 31 patients were used for validation using qPCR  assays. Serum samples were collected prior to immune therapy initiation. RESULTS:  Based on multivariate regression analysis, we identified a signature of seven  microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p,  miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) >   6 months in discovery cohort (p = .0003). We further validated this in another  similar set of samples (n = 31) and the model was significantly associated with  overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of  71% and 90%, respectively. CONCLUSIONS: In this study of circulating microRNAs,  we have identified a 7-miR signature associated with survival in  nivolumab-treated NSCLC patients. This signature may lead to better treatment  options for patients with NSCLC, but a validation in an independent cohort is  needed to confirm the predicted potential.
CANIT0001750	29683761	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	N/A	In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.	N/A	N/A	N/A	Hsa-miR-411-3p (); 	MiR-411-3p expression on tumor cells	Gene expression signature on/in tumor cell	 2018 Sep	 Circulating microRNAs associated with prolonged overall survival in lung cancer  patients treated with nivolumab.	 Acta Oncol	 BACKGROUND: The introduction of immune check-point inhibition in non-small cell  lung cancer (NSCLC) therapy represents improved prospects for the patients. The  response rates to check-point inhibitors are approximately 20% in unselected  NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with  higher response rates. However, patients with low PD-L1 levels may also have  durable responses, and improved strategies for patient stratification are needed.  MATERIAL AND METHODS: In this study, we investigated circulating microRNAs aiming  to identify circulating predictive biomarkers associated with increased overall  survival after immune check-point treatment. Using next generation sequencing, we  performed microRNA profiling in serum from NSCLC patients (n = 20) treated with  nivolumab. Serum samples from 31 patients were used for validation using qPCR  assays. Serum samples were collected prior to immune therapy initiation. RESULTS:  Based on multivariate regression analysis, we identified a signature of seven  microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p,  miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) >   6 months in discovery cohort (p = .0003). We further validated this in another  similar set of samples (n = 31) and the model was significantly associated with  overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of  71% and 90%, respectively. CONCLUSIONS: In this study of circulating microRNAs,  we have identified a 7-miR signature associated with survival in  nivolumab-treated NSCLC patients. This signature may lead to better treatment  options for patients with NSCLC, but a validation in an independent cohort is  needed to confirm the predicted potential.
CANIT0001751	29683761	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	N/A	In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.	N/A	N/A	N/A	Hsa-miR-493-5p (); 	MiR-493-5p expression on tumor cells	Gene expression signature on/in tumor cell	 2018 Sep	 Circulating microRNAs associated with prolonged overall survival in lung cancer  patients treated with nivolumab.	 Acta Oncol	 BACKGROUND: The introduction of immune check-point inhibition in non-small cell  lung cancer (NSCLC) therapy represents improved prospects for the patients. The  response rates to check-point inhibitors are approximately 20% in unselected  NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with  higher response rates. However, patients with low PD-L1 levels may also have  durable responses, and improved strategies for patient stratification are needed.  MATERIAL AND METHODS: In this study, we investigated circulating microRNAs aiming  to identify circulating predictive biomarkers associated with increased overall  survival after immune check-point treatment. Using next generation sequencing, we  performed microRNA profiling in serum from NSCLC patients (n = 20) treated with  nivolumab. Serum samples from 31 patients were used for validation using qPCR  assays. Serum samples were collected prior to immune therapy initiation. RESULTS:  Based on multivariate regression analysis, we identified a signature of seven  microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p,  miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) >   6 months in discovery cohort (p = .0003). We further validated this in another  similar set of samples (n = 31) and the model was significantly associated with  overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of  71% and 90%, respectively. CONCLUSIONS: In this study of circulating microRNAs,  we have identified a 7-miR signature associated with survival in  nivolumab-treated NSCLC patients. This signature may lead to better treatment  options for patients with NSCLC, but a validation in an independent cohort is  needed to confirm the predicted potential.
CANIT0001752	29683761	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	N/A	In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.	N/A	N/A	N/A	Hsa-miR-494-3p (); 	MiR-494-3p expression on tumor cells	Gene expression signature on/in tumor cell	 2018 Sep	 Circulating microRNAs associated with prolonged overall survival in lung cancer  patients treated with nivolumab.	 Acta Oncol	 BACKGROUND: The introduction of immune check-point inhibition in non-small cell  lung cancer (NSCLC) therapy represents improved prospects for the patients. The  response rates to check-point inhibitors are approximately 20% in unselected  NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with  higher response rates. However, patients with low PD-L1 levels may also have  durable responses, and improved strategies for patient stratification are needed.  MATERIAL AND METHODS: In this study, we investigated circulating microRNAs aiming  to identify circulating predictive biomarkers associated with increased overall  survival after immune check-point treatment. Using next generation sequencing, we  performed microRNA profiling in serum from NSCLC patients (n = 20) treated with  nivolumab. Serum samples from 31 patients were used for validation using qPCR  assays. Serum samples were collected prior to immune therapy initiation. RESULTS:  Based on multivariate regression analysis, we identified a signature of seven  microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p,  miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) >   6 months in discovery cohort (p = .0003). We further validated this in another  similar set of samples (n = 31) and the model was significantly associated with  overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of  71% and 90%, respectively. CONCLUSIONS: In this study of circulating microRNAs,  we have identified a 7-miR signature associated with survival in  nivolumab-treated NSCLC patients. This signature may lead to better treatment  options for patients with NSCLC, but a validation in an independent cohort is  needed to confirm the predicted potential.
CANIT0001753	29683761	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	N/A	In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.	N/A	N/A	N/A	Hsa-miR-495-3p (); 	MiR-495-3p expression on tumor cells	Gene expression signature on/in tumor cell	 2018 Sep	 Circulating microRNAs associated with prolonged overall survival in lung cancer  patients treated with nivolumab.	 Acta Oncol	 BACKGROUND: The introduction of immune check-point inhibition in non-small cell  lung cancer (NSCLC) therapy represents improved prospects for the patients. The  response rates to check-point inhibitors are approximately 20% in unselected  NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with  higher response rates. However, patients with low PD-L1 levels may also have  durable responses, and improved strategies for patient stratification are needed.  MATERIAL AND METHODS: In this study, we investigated circulating microRNAs aiming  to identify circulating predictive biomarkers associated with increased overall  survival after immune check-point treatment. Using next generation sequencing, we  performed microRNA profiling in serum from NSCLC patients (n = 20) treated with  nivolumab. Serum samples from 31 patients were used for validation using qPCR  assays. Serum samples were collected prior to immune therapy initiation. RESULTS:  Based on multivariate regression analysis, we identified a signature of seven  microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p,  miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) >   6 months in discovery cohort (p = .0003). We further validated this in another  similar set of samples (n = 31) and the model was significantly associated with  overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of  71% and 90%, respectively. CONCLUSIONS: In this study of circulating microRNAs,  we have identified a 7-miR signature associated with survival in  nivolumab-treated NSCLC patients. This signature may lead to better treatment  options for patients with NSCLC, but a validation in an independent cohort is  needed to confirm the predicted potential.
CANIT0001754	29683761	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	N/A	In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.	N/A	N/A	N/A	Hsa-miR-548j-5p (); 	MiR-548j-5p expression on tumor cells	Gene expression signature on/in tumor cell	 2018 Sep	 Circulating microRNAs associated with prolonged overall survival in lung cancer  patients treated with nivolumab.	 Acta Oncol	 BACKGROUND: The introduction of immune check-point inhibition in non-small cell  lung cancer (NSCLC) therapy represents improved prospects for the patients. The  response rates to check-point inhibitors are approximately 20% in unselected  NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with  higher response rates. However, patients with low PD-L1 levels may also have  durable responses, and improved strategies for patient stratification are needed.  MATERIAL AND METHODS: In this study, we investigated circulating microRNAs aiming  to identify circulating predictive biomarkers associated with increased overall  survival after immune check-point treatment. Using next generation sequencing, we  performed microRNA profiling in serum from NSCLC patients (n = 20) treated with  nivolumab. Serum samples from 31 patients were used for validation using qPCR  assays. Serum samples were collected prior to immune therapy initiation. RESULTS:  Based on multivariate regression analysis, we identified a signature of seven  microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p,  miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) >   6 months in discovery cohort (p = .0003). We further validated this in another  similar set of samples (n = 31) and the model was significantly associated with  overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of  71% and 90%, respectively. CONCLUSIONS: In this study of circulating microRNAs,  we have identified a 7-miR signature associated with survival in  nivolumab-treated NSCLC patients. This signature may lead to better treatment  options for patients with NSCLC, but a validation in an independent cohort is  needed to confirm the predicted potential.
CANIT0001755	29683761	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	N/A	In this study of circulating microRNAs, we have identified a 7-miR signature associated with survival in nivolumab-treated NSCLC patients. This signature may lead to better treatment options for patients with NSCLC, but a validation in an independent cohort is needed to confirm the predicted potential.	N/A	N/A	N/A	Hsa-miR-93-3p (); 	MiR-93-3p expression on tumor cells	Gene expression signature on/in tumor cell	 2018 Sep	 Circulating microRNAs associated with prolonged overall survival in lung cancer  patients treated with nivolumab.	 Acta Oncol	 BACKGROUND: The introduction of immune check-point inhibition in non-small cell  lung cancer (NSCLC) therapy represents improved prospects for the patients. The  response rates to check-point inhibitors are approximately 20% in unselected  NSCLC patients. Increasing levels of tumor PD-L1 expression are associated with  higher response rates. However, patients with low PD-L1 levels may also have  durable responses, and improved strategies for patient stratification are needed.  MATERIAL AND METHODS: In this study, we investigated circulating microRNAs aiming  to identify circulating predictive biomarkers associated with increased overall  survival after immune check-point treatment. Using next generation sequencing, we  performed microRNA profiling in serum from NSCLC patients (n = 20) treated with  nivolumab. Serum samples from 31 patients were used for validation using qPCR  assays. Serum samples were collected prior to immune therapy initiation. RESULTS:  Based on multivariate regression analysis, we identified a signature of seven  microRNAs (miR-215-5p, miR-411-3p, miR-493-5p, miR-494-3p, miR-495-3p,  miR-548j-5p and miR-93-3p) significantly associated with overall survival (OS) >   6 months in discovery cohort (p = .0003). We further validated this in another  similar set of samples (n = 31) and the model was significantly associated with  overall survival (OS) > 6 months (p = .001) with sensitivity and specificity of  71% and 90%, respectively. CONCLUSIONS: In this study of circulating microRNAs,  we have identified a 7-miR signature associated with survival in  nivolumab-treated NSCLC patients. This signature may lead to better treatment  options for patients with NSCLC, but a validation in an independent cohort is  needed to confirm the predicted potential.
CANIT0001756	29684049	Clinical research	Advanced non-small-cell lung cancers	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	67	N/A	A phase II clinical trial	Our results suggest that nivolumab is not beneficial or safe for patients with PS 2 and symptomatic brain metastases.	Treatment-related adverse events occurred in 47 patients (70%), symptomatic brain metastasis being significantly associated with Grade 3 toxicity (OR = 8.13, 95% CI 1.21-55.56, p = 0.031). Age and nutritional status were not associated with response, PFS, OS or toxicity.	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	2018	 Clinical factors associated with early progression and grade 3-4 toxicity in  patients with advanced non-small-cell lung cancers treated with nivolumab.	 PLoS One	 INTRODUCTION: The prognosis of advanced non-small-cell lung cancer (NSCLC) has  been improved by development of immune checkpoint inhibitors (ICIs) such as  nivolumab for second-line treatment. As phase III trials include only selected  patients, we here investigated the clinical factors associated with efficacy and   safety of nivolumab in 'real life' patients with advanced NSCLC. METHODS:  Clinical and histological characteristics, therapies and survival data of all  consecutive patients with advanced NSCLC included prospectively and treated by  nivolumab in two French academic hospitals between February 2015 and December  2016 were examined. RESULTS: Sixty-seven patients were included, mostly male  (69%), current or former smokers (87%) with PS <2 (73%). Median age was 68.5  years and 42% were aged >/=70 years. According to uni- and multi-variate  analyses, only PS 2 (OR = 0.17, 95% CI 0.03-0.99, p = 0.049) and number of  previous treatment lines (OR = 0.33, 95% CI 0.13-0.85, p = 0.022) were  significantly negatively associated with tumor control. Worse progression-free  survival (PFS) was significantly associated with PS 2 (HR = 5.17, 95% CI  1.99-13.43, p = 0.001) and use of steroids (HR = 3.27, 95% CI 1.39-7.69, p =  0.006). Worse overall survival was associated with symptomatic brain metastasis  (HR = 3.15, 95% CI 1.23-8.85, p = 0.029). Treatment-related adverse events  occurred in 47 patients (70%), symptomatic brain metastasis being significantly  associated with Grade >/=3 toxicity (OR = 8.13, 95% CI 1.21-55.56, p = 0.031).  Age and nutritional status were not associated with response, PFS, OS or  toxicity. CONCLUSION: Our results suggest that nivolumab is not beneficial or  safe for patients with PS 2 and symptomatic brain metastases.
CANIT0001757	29684049	Clinical research	Advanced non-small-cell lung cancers	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	67	N/A	A phase II clinical trial	Our results suggest that nivolumab is not beneficial or safe for patients with PS 2 and symptomatic brain metastases.	Treatment-related adverse events occurred in 47 patients (70%), symptomatic brain metastasis being significantly associated with Grade 3 toxicity (OR = 8.13, 95% CI 1.21-55.56, p = 0.031). Age and nutritional status were not associated with response, PFS, OS or toxicity.	N/A	N/A	Steroid use status (NCIT:C135483); 	Steroid use	Exposure factors/status	2018	 Clinical factors associated with early progression and grade 3-4 toxicity in  patients with advanced non-small-cell lung cancers treated with nivolumab.	 PLoS One	 INTRODUCTION: The prognosis of advanced non-small-cell lung cancer (NSCLC) has  been improved by development of immune checkpoint inhibitors (ICIs) such as  nivolumab for second-line treatment. As phase III trials include only selected  patients, we here investigated the clinical factors associated with efficacy and   safety of nivolumab in 'real life' patients with advanced NSCLC. METHODS:  Clinical and histological characteristics, therapies and survival data of all  consecutive patients with advanced NSCLC included prospectively and treated by  nivolumab in two French academic hospitals between February 2015 and December  2016 were examined. RESULTS: Sixty-seven patients were included, mostly male  (69%), current or former smokers (87%) with PS <2 (73%). Median age was 68.5  years and 42% were aged >/=70 years. According to uni- and multi-variate  analyses, only PS 2 (OR = 0.17, 95% CI 0.03-0.99, p = 0.049) and number of  previous treatment lines (OR = 0.33, 95% CI 0.13-0.85, p = 0.022) were  significantly negatively associated with tumor control. Worse progression-free  survival (PFS) was significantly associated with PS 2 (HR = 5.17, 95% CI  1.99-13.43, p = 0.001) and use of steroids (HR = 3.27, 95% CI 1.39-7.69, p =  0.006). Worse overall survival was associated with symptomatic brain metastasis  (HR = 3.15, 95% CI 1.23-8.85, p = 0.029). Treatment-related adverse events  occurred in 47 patients (70%), symptomatic brain metastasis being significantly  associated with Grade >/=3 toxicity (OR = 8.13, 95% CI 1.21-55.56, p = 0.031).  Age and nutritional status were not associated with response, PFS, OS or  toxicity. CONCLUSION: Our results suggest that nivolumab is not beneficial or  safe for patients with PS 2 and symptomatic brain metastases.
CANIT0001758	29684049	Clinical research	Advanced non-small-cell lung cancers	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	67	N/A	A phase II clinical trial	Our results suggest that nivolumab is not beneficial or safe for patients with PS 2 and symptomatic brain metastases.	Treatment-related adverse events occurred in 47 patients (70%), symptomatic brain metastasis being significantly associated with Grade 3 toxicity (OR = 8.13, 95% CI 1.21-55.56, p = 0.031). Age and nutritional status were not associated with response, PFS, OS or toxicity.	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	2018	 Clinical factors associated with early progression and grade 3-4 toxicity in  patients with advanced non-small-cell lung cancers treated with nivolumab.	 PLoS One	 INTRODUCTION: The prognosis of advanced non-small-cell lung cancer (NSCLC) has  been improved by development of immune checkpoint inhibitors (ICIs) such as  nivolumab for second-line treatment. As phase III trials include only selected  patients, we here investigated the clinical factors associated with efficacy and   safety of nivolumab in 'real life' patients with advanced NSCLC. METHODS:  Clinical and histological characteristics, therapies and survival data of all  consecutive patients with advanced NSCLC included prospectively and treated by  nivolumab in two French academic hospitals between February 2015 and December  2016 were examined. RESULTS: Sixty-seven patients were included, mostly male  (69%), current or former smokers (87%) with PS <2 (73%). Median age was 68.5  years and 42% were aged >/=70 years. According to uni- and multi-variate  analyses, only PS 2 (OR = 0.17, 95% CI 0.03-0.99, p = 0.049) and number of  previous treatment lines (OR = 0.33, 95% CI 0.13-0.85, p = 0.022) were  significantly negatively associated with tumor control. Worse progression-free  survival (PFS) was significantly associated with PS 2 (HR = 5.17, 95% CI  1.99-13.43, p = 0.001) and use of steroids (HR = 3.27, 95% CI 1.39-7.69, p =  0.006). Worse overall survival was associated with symptomatic brain metastasis  (HR = 3.15, 95% CI 1.23-8.85, p = 0.029). Treatment-related adverse events  occurred in 47 patients (70%), symptomatic brain metastasis being significantly  associated with Grade >/=3 toxicity (OR = 8.13, 95% CI 1.21-55.56, p = 0.031).  Age and nutritional status were not associated with response, PFS, OS or  toxicity. CONCLUSION: Our results suggest that nivolumab is not beneficial or  safe for patients with PS 2 and symptomatic brain metastases.
CANIT0001759	29693280	Case report	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Complete response	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Case of complete response to neoadjuvant therapy using nivolumab in a patient  with metastatic renal cell carcinoma.	 Int J Urol	 Here, we report a case of a 68-year-old woman with cT4N0M1 (liver invasion and  multiple lung metastases) metastatic renal cell carcinoma. We could carry out  less invasive nephrectomy with partial hepatectomy because nivolumab  administration as second-line therapy reduced the primary tumor remarkably. To  the best of our knowledge, this is the first report of the use of nivolumab  before carrying out surgery, and histological findings showed a pathological  complete response.CI  - (c) 2018 The Japanese Urological Association.
CANIT0001760	29696531	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic radiosurgery	Stereotactic radiosurgery	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); stereotactic ablative radiotherapy (NCIT:C157991); 	40	51	A retrospective cohort study	Patients who received ipilimumab had improved OS even after adjusting for prognostic factors. Ipilimumab did not appear to increase risk for acute toxicity. The majority of radiation necrosis  events, however, occurred in patients who received ipilimumab. Our results support the continued use of SRS and ipilimumab as clinically appropriate.	The incidence of radiation necrosis was 5%, with most events occurring in patients who received ipilimumab.	N/A	N/A	N/A	N/A	N/A	 2018 Sep	 Stereotactic radiosurgery and ipilimumab for patients with melanoma brain  metastases: clinical outcomes and toxicity.	 J Neurooncol	 INTRODUCTION: There is evidence that the combination of ipilimumab and  stereotactic radiosurgery (SRS) for brain metastases improves outcomes. We  investigated clinical outcomes, radiation toxicity, and impact of ipilimumab  timing in patients treated with SRS for melanoma brain metastases. METHODS: We  retrospectively identified 91 patients treated with SRS at our institution for  melanoma brain metastases from 2006 to 2015. Concurrent ipilimumab administration  was defined as within +/- 4 weeks of SRS procedure. Acute and late toxicities  were graded with CTCAE v4.03. Overall survival (OS), local failure, distant brain  failure, and failure-free survival were analyzed with the Kaplan-Meier method. OS  was analyzed with Cox regression. RESULTS: Twenty-three patients received  ipilimumab concurrent with SRS, 28 patients non-concurrently, and 40 patients did  not receive ipilimumab. The median age was 62 years and 91% had KPS >/= 80. The  median follow-up time was 7.4 months. Patients who received ipilimumab had a  median OS of 15.1 months compared to 7.8 months in patients who did not (p =  0.02). In multivariate analysis, ipilimumab (p = 0.02) and diagnosis-specific  graded prognostic assessment (p = 0.02) were associated with OS. There were no  differences in intracranial control by ipilimumab administration or timing. The  incidence of radiation necrosis was 5%, with most events occurring in patients  who received ipilimumab. CONCLUSIONS: Patients who received ipilimumab had  improved OS even after adjusting for prognostic factors. Ipilimumab did not  appear to increase risk for acute toxicity. The majority of radiation necrosis  events, however, occurred in patients who received ipilimumab. Our results  support the continued use of SRS and ipilimumab as clinically appropriate.
CANIT0001761	29722744	Case report	Choroidal melanoma with known liver metastases	Choroidal melanoma	EFO:0009093	Eye	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	2	N/A	Case	N/A	Neurological Complications	N/A	N/A	N/A	N/A	N/A	 2018 May	 The Mayo Clinic Experience With the Neurological Complications of the CTLA-4  Inhibitor Ipilimumab.	 Neurologist	 Neurological complications are an increasingly recognized complication of the use  of the immune checkpoint inhibitors in the treatment of solid tumors. Ipilimumab   is a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, an immune  checkpoint inhibitor that suppresses T-cell effector function. The clinical  spectrum of ipilimumab-associated neurological complications and optimum  treatment approach is not established. We describe our institution's experience  with ipilimumab and illustrate 2 cases of presumed autoimmune neurological  phenomenon resulting from its use.
CANIT0001762	29728723	Case report	Conventional clear cell renal cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The patient unexpectedly improved and went on to achieve a durable tumor response. The case is illustrative of an extreme manifestation of pseudoprogression, and impels us to probe the assumptions and controversies surrounding this phenomenon.	Extreme pseudoprogression	N/A	N/A	N/A	N/A	N/A	 2018 Jul	 Pushing the limits of immune-related response: a case of extreme  pseudoprogression.	 Cancer Immunol Immunother	 The advent of immune checkpoint targeted immunotherapy has seen a spectrum of  immune-related phenomena in both tumor responses and toxicities. We describe a  case of pseudoprogression that pushes the limits of immune-related response  criteria and challenges the boundaries and definitions set by trial protocols. A   middle-aged man with conventional clear cell renal cell carcinoma (RCC) had  received multiple prior systemic treatments including vascular endothelial growth  factor receptor tyrosine kinase inhibitors, as well as multiple surgeries and  radiotherapy treatments. He was eventually started on nivolumab-the  anti-programmed death receptor-1 monoclonal antibody approved for the treatment  of advanced RCC. Clinical deterioration was observed soon after a 100 mg dose of   nivolumab, with onset of acute renal failure and declining performance status.  Radiologic progression was documented in multiple sites including worsening tumor  infiltration of his residual kidney. The patient was on palliative treatment and   visited by the home hospice team in an end-of-life situation. The patient  unexpectedly improved and went on to achieve a durable tumor response. The case  is illustrative of an extreme manifestation of pseudoprogression, and impels us  to probe the assumptions and controversies surrounding this phenomenon.
CANIT0001763	29731394	Clinical research	Small-Cell Lung Cancer	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	156	245	N/A	Efficacy of nivolumab +/- ipilimumab was enhanced in patients with high tumor mutational burden. Nivolumab plus ipilimumab appeared to provide a greater clinical benefit than nivolumab monotherapy in the   high tumor mutational burden tertile.	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2018 May 14	 Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination   with Ipilimumab in Small-Cell Lung Cancer.	 Cancer Cell	 Durable responses and encouraging survival have been demonstrated with immune  checkpoint inhibitors in small-cell lung cancer (SCLC), but predictive markers  are unknown. We used whole exome sequencing to evaluate the impact of tumor  mutational burden on efficacy of nivolumab monotherapy or combined with  ipilimumab in patients with SCLC from the nonrandomized or randomized cohorts of   CheckMate 032. Patients received nivolumab (3 mg/kg every 2 weeks) or nivolumab  plus ipilimumab (1 mg/kg plus 3 mg/kg every 3 weeks for four cycles, followed by   nivolumab 3 mg/kg every 2 weeks). Efficacy of nivolumab +/- ipilimumab was  enhanced in patients with high tumor mutational burden. Nivolumab plus ipilimumab  appeared to provide a greater clinical benefit than nivolumab monotherapy in the   high tumor mutational burden tertile.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001764	29735504	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	Cell lines	N/A	Case	A serious adverse effect of pneumonitis	His treatment was continued with a weaning course of high-dose oral steroids, and he was discharged with a persistent oxygen requirement. The patient maintained a requirement for high doses of oral steroids and continued to deteriorate. He was referred to palliative care for symptom management and died a month following hospital discharge, as a result of pneumonitis due to pembrolizumab.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2018 May 7	 Pneumonitis: a serious adverse effect of PD-L1 inhibitors including  pembrolizumab.	 BMJ Case Rep	 A 70-year-old man presented with breathlessness, cough and fever while receiving   pembrolizumab for melanoma. A CT pulmonary angiogram demonstrated small bilateral  upper lobe segmental pulmonary emboli with patchy ground-glass opacities and  basal perilobular consolidation, in keeping with organising pneumonia. He was  treated for community-acquired pneumonia and pulmonary emboli but rapidly  deteriorated, with increasing hypoxia and dyspnoea. He was admitted to the  intensive care unit for support with continuous positive airway pressure and high  flow nasal oxygen. His clinical condition improved once he received high-dose  intravenous methylprednisolone to treat pneumonitis. His treatment was continued   with a weaning course of high-dose oral steroids, and he was discharged with a  persistent oxygen requirement. The patient maintained a requirement for high  doses of oral steroids and continued to deteriorate. He was referred to  palliative care for symptom management and died a month following hospital  discharge, as a result of pneumonitis due to pembrolizumab.CI  - (c) BMJ Publishing Group Ltd (unless otherwise stated in the text of the article)  2018. All rights reserved. No commercial use is permitted unless otherwise  expressly granted.
CANIT0001765	29740855	Case report	Oligometastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We report a case of scleroderma-like skin changes induced by checkpoint inhibitor therapy.  After discontinuation of nivolumab and initiation of steroid therapy, the patient's symptoms significantly improved. 	Scleroderma-like skin changes	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Scleroderma-like skin changes induced by checkpoint inhibitor therapy.	 J Cutan Pathol	 Checkpoint inhibitors have emerged as beneficial therapies in many different  types of malignancy. The most common toxicities of checkpoint inhibitors are  immune-related adverse events (irAEs). As clinical experience with these agents  increases, more irAEs have been described. We report a case of scleroderma-like  skin changes induced by checkpoint inhibitor therapy. A 61-year-old man was  treated with nivolumab for oligometastatic renal cell carcinoma. He initially  tolerated the therapy well, but after 16 treatments he began experiencing skin  thickening and edema of the abdominal wall, which progressed down the trunk and  legs. A punch biopsy revealed epidermal attenuation overlying thickened dermal  collagen with entrapment and displacement of the eccrine coils and loss of  periadnexal adipose tissue. Focally increased plasma cells were present near the   junction of the dermis and subcutaneous adipose tissue. Loss of CD34 staining was  seen throughout the dermis. These findings were consistent with a diagnosis of  scleroderma. After discontinuation of nivolumab and initiation of steroid  therapy, the patient's symptoms significantly improved. This case is among the  first reports of scleroderma-like changes induced by a checkpoint inhibitor.CI  - (c) 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
CANIT0001766	29742974	Case report	Anaplastic Thyroid Carcinoma	Anaplastic thyroid carcinoma	EFO:1000595	Thyroid	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	This novel neoadjuvant approach to BRAF-mutated ATC should be studied in further in clinical trials.	N/A	N/A	N/A	BRAF (P15056); 	BRAF amplification	Mutational status	 2018 Jul	 Neoadjuvant BRAF- and Immune-Directed Therapy for Anaplastic Thyroid Carcinoma.	 Thyroid	 Anaplastic thyroid cancer (ATC) is a devastating disease with a dismal prognosis.  Patients who have disease confined to the thyroid and who are able to undergo  complete surgery and chemoradiation stand the best chance for survival.  Unfortunately, nearly 50% of patients have distant metastases at diagnosis, and  most present with locally advanced, unresectable tumors. Nevertheless,  BRAF-mutated ATC patients represent a subset of cases who can benefit from a  combination therapy with BRAF and MEK inhibitors. Here, a patient is presented  with end-stage, locally advanced, unresectable ATC who was treated with this  combination. Immunotherapy with pembrolizumab was added at the first sign of  progression after which he achieved a partial response to therapy, enabling a  complete surgical resection followed by postoperative chemoradiation to be  undertaken. This novel neoadjuvant approach to BRAF-mutated ATC should be studied  in further in clinical trials.
CANIT0001767	29742974	Case report	Anaplastic Thyroid Carcinoma	Anaplastic thyroid carcinoma	EFO:1000595	Thyroid	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	This novel neoadjuvant approach to BRAF-mutated ATC should be studied in further in clinical trials.	N/A	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2018 Jul	 Neoadjuvant BRAF- and Immune-Directed Therapy for Anaplastic Thyroid Carcinoma.	 Thyroid	 Anaplastic thyroid cancer (ATC) is a devastating disease with a dismal prognosis.  Patients who have disease confined to the thyroid and who are able to undergo  complete surgery and chemoradiation stand the best chance for survival.  Unfortunately, nearly 50% of patients have distant metastases at diagnosis, and  most present with locally advanced, unresectable tumors. Nevertheless,  BRAF-mutated ATC patients represent a subset of cases who can benefit from a  combination therapy with BRAF and MEK inhibitors. Here, a patient is presented  with end-stage, locally advanced, unresectable ATC who was treated with this  combination. Immunotherapy with pembrolizumab was added at the first sign of  progression after which he achieved a partial response to therapy, enabling a  complete surgical resection followed by postoperative chemoradiation to be  undertaken. This novel neoadjuvant approach to BRAF-mutated ATC should be studied  in further in clinical trials.
CANIT0001768	29743138	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	173	N/A	N/A	Genotyping for CTLA-4 -1661A>G SNV might be relevant to identify MM patients prone to develop endo-immune-related adverse events during IPI therapy.	N/A	N/A	N/A	CTLA-4 (P16410); 	CTLA-4 1661A>G mutation	Mutational status	 2018 Jul	 CTLA-4 gene variant -1661A>G may predict the onset of endocrine adverse events in  metastatic melanoma patients treated with ipilimumab.	 Eur J Cancer	Unable to provide
CANIT0001769	29750753	Clinical research	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus denosumab	Ipilimumab or pembrolizumab	Immune checkpoint therapy plus Target therapy	Denosumab (DB06643); ipilimumab (DB06186); 	11	26	A retrospective cohort study	A combination therapy with denosumab and immune checkpoint inhibitors may have a beneficial effect on survival and progression as in our study; the patients receiving combination therapy did not behave poorly despite having poor prognostic features.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune   checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with  anti-RANKL denosumuab in malignant melanoma: a retrospective analysis at a  tertiary care center.	 Melanoma Res	 Denosumab is a monoclonal antibody against RANK ligand with a role in the  prevention of skeletal-related events and is also known to possess antitumor  properties. In this retrospective review, we aim to evaluate the synergist effect  of a combination therapy with immune checkpoint inhibitors and denosumab in  malignant melanoma patients. Patients of 18 years of age or older with a  diagnosis of malignant melanoma who have received immune checkpoint inhibitors  and denosumab between June 2015 and May 2017 were divided into two cohorts:  cohort A (immune checkpoint inhibitors only) and cohort B (immune checkpoint  inhibitors and denosumab). Overall survival, progression-free survival, objective  response rate, and safety analysis were performed. Stratified analysis based on  metastatic (M) status was performed as well. Eleven (29.72%) out of 37 patients  received immune checkpoint inhibitors and denosumab combination. Median overall  survival in cohort B was 57 months compared with 22.8 months in cohort A and 22  months in M1c patients from cohort A. Median progression-free survival was 4.15  months in cohort B compared with 11.6 months in cohort A and 5.12 months in M1c  patients from cohort A. The mean number of distant sites involved in metastasis  were significantly higher in cohort B (3.54 vs. 2.23, P=0.0015). Cohort B also  had more patients with more than two distant metastatic sites (90.9 vs. 30.8%,  P=0.001). A combination therapy with denosumab and immune checkpoint inhibitors  may have a beneficial effect on survival and progression as in our study; the  patients receiving combination therapy did not behave poorly despite having poor   prognostic features.
CANIT0001770	29750753	Clinical research	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	Ipilimumab or pembrolizumab	Immune checkpoint therapy plus Target therapy	Denosumab (DB06643); pembrolizumab (DB09037); 	11	26	A retrospective cohort study	A combination therapy with denosumab and immune checkpoint inhibitors may have a beneficial effect on survival and progression as in our study; the patients receiving combination therapy did not behave poorly despite having poor prognostic features.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune   checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with  anti-RANKL denosumuab in malignant melanoma: a retrospective analysis at a  tertiary care center.	 Melanoma Res	 Denosumab is a monoclonal antibody against RANK ligand with a role in the  prevention of skeletal-related events and is also known to possess antitumor  properties. In this retrospective review, we aim to evaluate the synergist effect  of a combination therapy with immune checkpoint inhibitors and denosumab in  malignant melanoma patients. Patients of 18 years of age or older with a  diagnosis of malignant melanoma who have received immune checkpoint inhibitors  and denosumab between June 2015 and May 2017 were divided into two cohorts:  cohort A (immune checkpoint inhibitors only) and cohort B (immune checkpoint  inhibitors and denosumab). Overall survival, progression-free survival, objective  response rate, and safety analysis were performed. Stratified analysis based on  metastatic (M) status was performed as well. Eleven (29.72%) out of 37 patients  received immune checkpoint inhibitors and denosumab combination. Median overall  survival in cohort B was 57 months compared with 22.8 months in cohort A and 22  months in M1c patients from cohort A. Median progression-free survival was 4.15  months in cohort B compared with 11.6 months in cohort A and 5.12 months in M1c  patients from cohort A. The mean number of distant sites involved in metastasis  were significantly higher in cohort B (3.54 vs. 2.23, P=0.0015). Cohort B also  had more patients with more than two distant metastatic sites (90.9 vs. 30.8%,  P=0.001). A combination therapy with denosumab and immune checkpoint inhibitors  may have a beneficial effect on survival and progression as in our study; the  patients receiving combination therapy did not behave poorly despite having poor   prognostic features.
CANIT0001771	29750753	Clinical research	Malignant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); TNF11 (O14788); 	CTLA-4 ;  PD-1 ;  TNF11 	Nivolumab plus denosumab	Ipilimumab or pembrolizumab	Immune checkpoint therapy plus Target therapy	Denosumab (DB06643); nivolumab (DB09035); 	11	26	A retrospective cohort study	A combination therapy with denosumab and immune checkpoint inhibitors may have a beneficial effect on survival and progression as in our study; the patients receiving combination therapy did not behave poorly despite having poor prognostic features.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune   checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with  anti-RANKL denosumuab in malignant melanoma: a retrospective analysis at a  tertiary care center.	 Melanoma Res	 Denosumab is a monoclonal antibody against RANK ligand with a role in the  prevention of skeletal-related events and is also known to possess antitumor  properties. In this retrospective review, we aim to evaluate the synergist effect  of a combination therapy with immune checkpoint inhibitors and denosumab in  malignant melanoma patients. Patients of 18 years of age or older with a  diagnosis of malignant melanoma who have received immune checkpoint inhibitors  and denosumab between June 2015 and May 2017 were divided into two cohorts:  cohort A (immune checkpoint inhibitors only) and cohort B (immune checkpoint  inhibitors and denosumab). Overall survival, progression-free survival, objective  response rate, and safety analysis were performed. Stratified analysis based on  metastatic (M) status was performed as well. Eleven (29.72%) out of 37 patients  received immune checkpoint inhibitors and denosumab combination. Median overall  survival in cohort B was 57 months compared with 22.8 months in cohort A and 22  months in M1c patients from cohort A. Median progression-free survival was 4.15  months in cohort B compared with 11.6 months in cohort A and 5.12 months in M1c  patients from cohort A. The mean number of distant sites involved in metastasis  were significantly higher in cohort B (3.54 vs. 2.23, P=0.0015). Cohort B also  had more patients with more than two distant metastatic sites (90.9 vs. 30.8%,  P=0.001). A combination therapy with denosumab and immune checkpoint inhibitors  may have a beneficial effect on survival and progression as in our study; the  patients receiving combination therapy did not behave poorly despite having poor   prognostic features.
CANIT0001772	29755082	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Nivolumab following carboplatin, gemcitabine plus bevacizumab	N/A	Immune checkpoint therapy followed by Chemotherapy	Nivolumab (DB09035); bevacizumab (DB00112); gemcitabine (DB00441); carboplatin (DB00958); 	1	N/A	Case	A good partial response is continuing 2 years and 5 months after confirming recurrence	N/A	N/A	N/A	N/A	N/A	N/A	 2018 May	 [Pulmonary Pleomorphic Carcinoma Relapsed after Surgery Surviving Long-term by  Chemotherapy and Nivolumab].	 Kyobu Geka	 A 60'-year-old man was referred to our hospital because of nodular shadow found  at mass screening. We diagnosed the tumor as non-small cell lung cancer by  transbronchial biopsy. Chest computed tomography showed a tumor shadow of 3 cm in  diameter with cavity. Right middle lobectomy was performed and the pathological  diagnosis was pleomorphic carcinoma of the lung. The tumor recurrence was found  at 10 months after surgery, and was treated with cisplatin, docetaxel plus  bevacizumab for 6 cycles. A complete remission was achieved, but regrowth at 5  months after chemotherapy was noted. The patient was treated with nivolumab  following carboplatin, gemcitabine plus bevacizumab 3 cycles. A good partial  response is continuing 2 years and 5 months after confirming recurrence.
CANIT0001773	29758930	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	N/A	The circulating immune cell ratios and plasma tumor marker levels could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.	N/A	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	Percentage of CD4(+) T-cell 	Gene expression signature on/in immune cell	2018	 The potential predictive value of circulating immune cell ratio and tumor marker   in atezolizumab treated advanced non-small cell lung cancer patients.	 Cancer Biomark	 BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in  patients with advanced non-small cell lung cancer. But the predictive marker of  clinical benefit has not been identified. OBJECTIVE: This study aimed to search  for potential predictive factors in circulating blood of patients receiving  atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung  cancer were enrolled in this open-label observing study. Circulating immune cells  and plasma tumor markers were examined in peripheral blood from these patients  before and after atezolizumab treatment respectively. Relation between changes in  circulating factors and anti-tumor efficacy were analyzed. RESULTS: Blood routine  test showed that atezolizumab therapy induced slightly elevation of white blood  cells count generally. The lymphocyte ratio was increased slightly in disease  controlled patients but decreased prominently in disease progressed patients in  response to atezolizumab therapy. Flow cytometric analysis revealed changes in  percentage of various immune cell types, including CD4+ T cell, CD8+ T cell,  myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell  after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also   altered after anti-PD-L1 therapy. In comparison with baseline, the disease  progressed patients showed sharp increase in tumor marker levels, while those  disease controlled patients were seen with decreased regulatory T cell and  myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell   ratios and plasma tumor marker levels were related with clinical efficacy of  atezolizumab therapy. These factors could be potential predictive marker for  anti-PD-L1 therapy in advanced non-small cell lung cancer.
CANIT0001774	29758930	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	N/A	The circulating immune cell ratios and plasma tumor marker levels could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Percentage of CD8(+) T-cell 	Gene expression signature on/in immune cell	2018	 The potential predictive value of circulating immune cell ratio and tumor marker   in atezolizumab treated advanced non-small cell lung cancer patients.	 Cancer Biomark	 BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in  patients with advanced non-small cell lung cancer. But the predictive marker of  clinical benefit has not been identified. OBJECTIVE: This study aimed to search  for potential predictive factors in circulating blood of patients receiving  atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung  cancer were enrolled in this open-label observing study. Circulating immune cells  and plasma tumor markers were examined in peripheral blood from these patients  before and after atezolizumab treatment respectively. Relation between changes in  circulating factors and anti-tumor efficacy were analyzed. RESULTS: Blood routine  test showed that atezolizumab therapy induced slightly elevation of white blood  cells count generally. The lymphocyte ratio was increased slightly in disease  controlled patients but decreased prominently in disease progressed patients in  response to atezolizumab therapy. Flow cytometric analysis revealed changes in  percentage of various immune cell types, including CD4+ T cell, CD8+ T cell,  myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell  after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also   altered after anti-PD-L1 therapy. In comparison with baseline, the disease  progressed patients showed sharp increase in tumor marker levels, while those  disease controlled patients were seen with decreased regulatory T cell and  myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell   ratios and plasma tumor marker levels were related with clinical efficacy of  atezolizumab therapy. These factors could be potential predictive marker for  anti-PD-L1 therapy in advanced non-small cell lung cancer.
CANIT0001775	29758930	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	N/A	The circulating immune cell ratios and plasma tumor marker levels could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.	N/A	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); T-Lymphocyte (NCIT:C12476); 	Percentage of monocytic myeloid-derived suppressor cells	Cell percentage/counts in blood	2018	 The potential predictive value of circulating immune cell ratio and tumor marker   in atezolizumab treated advanced non-small cell lung cancer patients.	 Cancer Biomark	 BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in  patients with advanced non-small cell lung cancer. But the predictive marker of  clinical benefit has not been identified. OBJECTIVE: This study aimed to search  for potential predictive factors in circulating blood of patients receiving  atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung  cancer were enrolled in this open-label observing study. Circulating immune cells  and plasma tumor markers were examined in peripheral blood from these patients  before and after atezolizumab treatment respectively. Relation between changes in  circulating factors and anti-tumor efficacy were analyzed. RESULTS: Blood routine  test showed that atezolizumab therapy induced slightly elevation of white blood  cells count generally. The lymphocyte ratio was increased slightly in disease  controlled patients but decreased prominently in disease progressed patients in  response to atezolizumab therapy. Flow cytometric analysis revealed changes in  percentage of various immune cell types, including CD4+ T cell, CD8+ T cell,  myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell  after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also   altered after anti-PD-L1 therapy. In comparison with baseline, the disease  progressed patients showed sharp increase in tumor marker levels, while those  disease controlled patients were seen with decreased regulatory T cell and  myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell   ratios and plasma tumor marker levels were related with clinical efficacy of  atezolizumab therapy. These factors could be potential predictive marker for  anti-PD-L1 therapy in advanced non-small cell lung cancer.
CANIT0001776	29758930	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	N/A	The circulating immune cell ratios and plasma tumor marker levels could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.	N/A	N/A	N/A	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	Percentage of PD-1 expressing T-cell 	Gene expression signature on/in immune cell	2018	 The potential predictive value of circulating immune cell ratio and tumor marker   in atezolizumab treated advanced non-small cell lung cancer patients.	 Cancer Biomark	 BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in  patients with advanced non-small cell lung cancer. But the predictive marker of  clinical benefit has not been identified. OBJECTIVE: This study aimed to search  for potential predictive factors in circulating blood of patients receiving  atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung  cancer were enrolled in this open-label observing study. Circulating immune cells  and plasma tumor markers were examined in peripheral blood from these patients  before and after atezolizumab treatment respectively. Relation between changes in  circulating factors and anti-tumor efficacy were analyzed. RESULTS: Blood routine  test showed that atezolizumab therapy induced slightly elevation of white blood  cells count generally. The lymphocyte ratio was increased slightly in disease  controlled patients but decreased prominently in disease progressed patients in  response to atezolizumab therapy. Flow cytometric analysis revealed changes in  percentage of various immune cell types, including CD4+ T cell, CD8+ T cell,  myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell  after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also   altered after anti-PD-L1 therapy. In comparison with baseline, the disease  progressed patients showed sharp increase in tumor marker levels, while those  disease controlled patients were seen with decreased regulatory T cell and  myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell   ratios and plasma tumor marker levels were related with clinical efficacy of  atezolizumab therapy. These factors could be potential predictive marker for  anti-PD-L1 therapy in advanced non-small cell lung cancer.
CANIT0001777	29758930	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	N/A	The circulating immune cell ratios and plasma tumor marker levels could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.	N/A	N/A	N/A	CEA (P06731); 	Serum CEA levels	Gene expression signature in serum	2018	 The potential predictive value of circulating immune cell ratio and tumor marker   in atezolizumab treated advanced non-small cell lung cancer patients.	 Cancer Biomark	 BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in  patients with advanced non-small cell lung cancer. But the predictive marker of  clinical benefit has not been identified. OBJECTIVE: This study aimed to search  for potential predictive factors in circulating blood of patients receiving  atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung  cancer were enrolled in this open-label observing study. Circulating immune cells  and plasma tumor markers were examined in peripheral blood from these patients  before and after atezolizumab treatment respectively. Relation between changes in  circulating factors and anti-tumor efficacy were analyzed. RESULTS: Blood routine  test showed that atezolizumab therapy induced slightly elevation of white blood  cells count generally. The lymphocyte ratio was increased slightly in disease  controlled patients but decreased prominently in disease progressed patients in  response to atezolizumab therapy. Flow cytometric analysis revealed changes in  percentage of various immune cell types, including CD4+ T cell, CD8+ T cell,  myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell  after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also   altered after anti-PD-L1 therapy. In comparison with baseline, the disease  progressed patients showed sharp increase in tumor marker levels, while those  disease controlled patients were seen with decreased regulatory T cell and  myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell   ratios and plasma tumor marker levels were related with clinical efficacy of  atezolizumab therapy. These factors could be potential predictive marker for  anti-PD-L1 therapy in advanced non-small cell lung cancer.
CANIT0001778	29758930	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	N/A	The circulating immune cell ratios and plasma tumor marker levels could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.	N/A	N/A	N/A	CA125 (Q8WXI7); 	Serum CA125 levels	Gene expression signature in serum	2018	 The potential predictive value of circulating immune cell ratio and tumor marker   in atezolizumab treated advanced non-small cell lung cancer patients.	 Cancer Biomark	 BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in  patients with advanced non-small cell lung cancer. But the predictive marker of  clinical benefit has not been identified. OBJECTIVE: This study aimed to search  for potential predictive factors in circulating blood of patients receiving  atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung  cancer were enrolled in this open-label observing study. Circulating immune cells  and plasma tumor markers were examined in peripheral blood from these patients  before and after atezolizumab treatment respectively. Relation between changes in  circulating factors and anti-tumor efficacy were analyzed. RESULTS: Blood routine  test showed that atezolizumab therapy induced slightly elevation of white blood  cells count generally. The lymphocyte ratio was increased slightly in disease  controlled patients but decreased prominently in disease progressed patients in  response to atezolizumab therapy. Flow cytometric analysis revealed changes in  percentage of various immune cell types, including CD4+ T cell, CD8+ T cell,  myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell  after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also   altered after anti-PD-L1 therapy. In comparison with baseline, the disease  progressed patients showed sharp increase in tumor marker levels, while those  disease controlled patients were seen with decreased regulatory T cell and  myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell   ratios and plasma tumor marker levels were related with clinical efficacy of  atezolizumab therapy. These factors could be potential predictive marker for  anti-PD-L1 therapy in advanced non-small cell lung cancer.
CANIT0001779	29758930	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	N/A	The circulating immune cell ratios and plasma tumor marker levels could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.	N/A	N/A	N/A	CA199 (Q969X2); 	Serum CA199 levels	Gene expression signature in serum	2018	 The potential predictive value of circulating immune cell ratio and tumor marker   in atezolizumab treated advanced non-small cell lung cancer patients.	 Cancer Biomark	 BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in  patients with advanced non-small cell lung cancer. But the predictive marker of  clinical benefit has not been identified. OBJECTIVE: This study aimed to search  for potential predictive factors in circulating blood of patients receiving  atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung  cancer were enrolled in this open-label observing study. Circulating immune cells  and plasma tumor markers were examined in peripheral blood from these patients  before and after atezolizumab treatment respectively. Relation between changes in  circulating factors and anti-tumor efficacy were analyzed. RESULTS: Blood routine  test showed that atezolizumab therapy induced slightly elevation of white blood  cells count generally. The lymphocyte ratio was increased slightly in disease  controlled patients but decreased prominently in disease progressed patients in  response to atezolizumab therapy. Flow cytometric analysis revealed changes in  percentage of various immune cell types, including CD4+ T cell, CD8+ T cell,  myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell  after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also   altered after anti-PD-L1 therapy. In comparison with baseline, the disease  progressed patients showed sharp increase in tumor marker levels, while those  disease controlled patients were seen with decreased regulatory T cell and  myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell   ratios and plasma tumor marker levels were related with clinical efficacy of  atezolizumab therapy. These factors could be potential predictive marker for  anti-PD-L1 therapy in advanced non-small cell lung cancer.
CANIT0001780	29758930	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	N/A	The circulating immune cell ratios and plasma tumor marker levels could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.	N/A	N/A	N/A	Treg cells (CL:0000815); T-Lymphocyte (NCIT:C12476); 	Percentage of regulatory T-cell 	Cell percentage/counts in blood	2018	 The potential predictive value of circulating immune cell ratio and tumor marker   in atezolizumab treated advanced non-small cell lung cancer patients.	 Cancer Biomark	 BACKGROUND: The PD-L1 antibody atezolizumab has shown promising efficacy in  patients with advanced non-small cell lung cancer. But the predictive marker of  clinical benefit has not been identified. OBJECTIVE: This study aimed to search  for potential predictive factors in circulating blood of patients receiving  atezolizumab. METHODS: Ten patients diagnosed with advanced non-small cell lung  cancer were enrolled in this open-label observing study. Circulating immune cells  and plasma tumor markers were examined in peripheral blood from these patients  before and after atezolizumab treatment respectively. Relation between changes in  circulating factors and anti-tumor efficacy were analyzed. RESULTS: Blood routine  test showed that atezolizumab therapy induced slightly elevation of white blood  cells count generally. The lymphocyte ratio was increased slightly in disease  controlled patients but decreased prominently in disease progressed patients in  response to atezolizumab therapy. Flow cytometric analysis revealed changes in  percentage of various immune cell types, including CD4+ T cell, CD8+ T cell,  myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell  after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also   altered after anti-PD-L1 therapy. In comparison with baseline, the disease  progressed patients showed sharp increase in tumor marker levels, while those  disease controlled patients were seen with decreased regulatory T cell and  myeloid-derived suppressor cell ratios. CONCLUSIONS: The circulating immune cell   ratios and plasma tumor marker levels were related with clinical efficacy of  atezolizumab therapy. These factors could be potential predictive marker for  anti-PD-L1 therapy in advanced non-small cell lung cancer.
CANIT0001781	29764245	Clinical research	Relapsed and refractory classical Hodgkin's lymphoma progressing after brentuximab vedotin	Classic hodgkin lymphoma	MONDO:0009348	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Brentuximab vedotin	Immune checkpoint therapy	Pembrolizumab (DB09037); brentuximab vedotin (DB08870); 	175	N/A	A meta-analysis	Pembrolizumab offers a significant improvement in PFS compared to standard of care (SOC) in this population.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Pembrolizumab versus the standard of care for relapsed and refractory classical  Hodgkin's lymphoma progressing after brentuximab vedotin: an indirect treatment  comparison.	 Expert Rev Hematol	 BACKGROUND: There is significant unmet need among patients with relapsed and  refractory classical Hodgkin's lymphoma (RRcHL) who have failed multiple lines of  therapy, including brentuximab vedotin (BV). Pembrolizumab, an immune checkpoint   inhibitor, is one possible treatment solution for this population. RESEARCH  METHODS: The objective of this study was to compare progression-free survival  (PFS) with standard of care (SOC) versus pembrolizumab in previously BV treated  RRcHL patients. A systematic literature review identified one observational study  of SOC that was suitable for comparison with KEYNOTE-087, the principal trial of   pembrolizumab in this population. Both naive and population-adjusted (using  outcomes regression) pairwise indirect comparisons were conducted. The primary  analysis included all patients who had failed BV, with a secondary analysis  conducted including only those known to have failed BV that was part of  definitive treatment. RESULTS: In the primary analysis, SOC was inferior to  pembrolizumab in both the unadjusted comparison (HR 5.00 [95% confidence interval  (CI) 3.56-7.01]) and the adjusted comparison (HR 6.35 [95% CI 4.04-9.98]). These   HRs increased to 5.16 (95% CI 3.61-7.38) and 6.56 (95% CI 4.01-10.72),  respectively, in the secondary analysis. CONCLUSION: Pembrolizumab offers a  significant improvement in PFS compared to SOC in this population.
CANIT0001782	29768369	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Case	Reinvigoration of exhausted T cells by pembrolizumab induced systemic inflammation possibly resulting in development of thrombosis. Although acute thrombosis is a rare irAE, it may lead to cessation of treatment and can be lethal.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 May	 Pembrolizumab-induced acute thrombosis: A case report.	 Medicine (Baltimore)	 RATIONALE: Acute thrombosis has not been reported in the literature so far in  lung cancer patients as an immune-related adverse event (irAE) associated with  PD-1 pathway inhibitors. PATIENTS CONCERNS: Here, we for the first time present  two NSCLC (non-small cell lung cancer) patients suffering from acute thrombosis  as a pembrolizumab-induced irAE. Immediate treatment with continuous heparin  infusion improved their symptoms and enabled them to continue pembrolizumab  administration. METHODS: Ethical approval was given by the ethics committee of  Osaka International Cancer Institute and the informed consents were given by the   patients. DIAGNOSIS: Serum D-dimer level testing, venous ultrasonography,  enhanced computed tomography (CT). INTERVENTIONS: Continuous heparin infusion,  direct oral anticoagulants (DOAC). OUTCOMES: Immediate continuous heparin  infusion improved their symptoms and continuing pembrolizumab with direct oral  anticoagulant successfully induced tumor shrinkage. LESSONS: Reinvigoration of  exhausted T cells by pembrolizumab induced systemic inflammation possibly  resulting in development of thrombosis. Although acute thrombosis is a rare irAE,  it may lead to cessation of treatment and can be lethal.
CANIT0001783	29772919	Case report	Metastatic ocular amelanotic choroid melanoma	Amelanotic melanoma	EFO:1001937	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Sarcoidosis-like syndrome with lymphadenopathy is a rare adverse event that is important to recognize since it can be mistaken for metastatic disease progression. Tissue biopsy of new lesions during immunotherapy is an important step in patient evaluation.	Sarcoidosis-like syndrome with lymphadenopathy	N/A	N/A	N/A	N/A	N/A	 2018 Nov/Dec	 Erythema Nodosum as the Initial Presentation of Nivolumab-Induced  Sarcoidosis-Like Reaction.	 J Cutan Med Surg	 BACKGROUND: We report a case of nivolumab-related sarcoidosis-like syndrome that   initially presented with erythema nodosum. Sarcoidosis development has been  described in single and combination immunotherapy. CASE PRESENTATION: A  68-year-old white woman with metastatic ocular amelanotic choroid melanoma was  treated with nivolumab. The patient developed histologically confirmed erythema  nodosum lesions and pulmonary granuloma sarcoidosis. Nivolumab was discontinued  and the patient started ipilimumab therapy. CONCLUSION: Sarcoidosis-like syndrome  with lymphadenopathy is a rare adverse event that is important to recognize since  it can be mistaken for metastatic disease progression. Tissue biopsy of new  lesions during immunotherapy is an important step in patient evaluation.
CANIT0001784	29773326	Clinical research	Unresectable pleural or peritoneal mesothelioma	Peritoneal mesothelioma	EFO:1000467	Soft tissue	PD-L1 (Q9NZQ7); CTLA-4 (P16410); 	PD-L1; CTLA-4	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); durvalumab (DB11714); 	40	N/A	An open-label, non-randomised, phase II study	The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration. Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival.	30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Jun	 Tremelimumab combined with durvalumab in patients with mesothelioma  (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study.	 Lancet Respir Med	 BACKGROUND: Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed  good activity when used alone in patients with mesothelioma, but did not improve   the overall survival of patients who failed on first-line or second-line  chemotherapy compared with placebo in the DETERMINE study. We aimed to  investigate the efficacy and safety of first-line or second-line tremelimumab  combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with  malignant mesothelioma. METHODS: In this open-label, non-randomised, phase 2  trial, patients with unresectable pleural or peritoneal mesothelioma received  intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg  bodyweight) every 4 weeks for four doses, followed by maintenance intravenous  durvalumab at the same dose and schedule for nine doses. The primary endpoint was  the proportion of patients with an immune-related objective response according to  the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST;  for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal  mesothelioma). The primary analysis was done by intention to treat, whereas the  safety analysis included patients who received at least one dose of study drug.  This trial is registered with the European Clinical Trials Database, number  2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no  longer recruiting patients. FINDINGS: From Oct 30, 2015, to Oct 12, 2016, 40  patients with mesothelioma were enrolled and received at least one dose each of  tremelimumab and durvalumab. Patients were followed-up for a median of 19.2  months (IQR 13.8-20.5). 11 (28%) of 40 patients had an immune-related objective  response (all partial responses; confirmed in ten patients), with a median  response duration of 16.1 months (IQR 11.5-20.5). 26 (65%) patients had  immune-related disease control and 25 (63%) had disease control. Median  immune-related progression-free survival was 8.0 months (95% CI 6.7-9.3), median   progression-free survival was 5.7 months (1.7-9.7), and median overall survival  was 16.6 months (13.1-20.1). Baseline tumour PD-L1 expression did not correlate  with the proportion of patients who had an immune-related objective response or  immune-related disease control, with immune-related progression-free survival, or  with overall survival. 30 (75%) patients experienced treatment-related adverse  events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse   events. Treatment-related toxicity was generally manageable and reversible with  protocol guidelines. INTERPRETATION: The combination of tremelimumab and  durvalumab appeared active, with a good safety profile in patients with  mesothelioma, warranting further exploration. FUNDING: Network Italiano per la  Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul  Cancro, AstraZeneca, and Istituto Toscano Tumori.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001785	29773326	Clinical research	Unresectable pleural or peritoneal mesothelioma	Pleural mesothelioma	EFO:1000485	Soft tissue	PD-L1 (Q9NZQ7); CTLA-4 (P16410); 	PD-L1; CTLA-4	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); durvalumab (DB11714); 	40	N/A	An open-label, non-randomised, phase II study	The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration. Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival.	30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Jun	 Tremelimumab combined with durvalumab in patients with mesothelioma  (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study.	 Lancet Respir Med	 BACKGROUND: Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed  good activity when used alone in patients with mesothelioma, but did not improve   the overall survival of patients who failed on first-line or second-line  chemotherapy compared with placebo in the DETERMINE study. We aimed to  investigate the efficacy and safety of first-line or second-line tremelimumab  combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with  malignant mesothelioma. METHODS: In this open-label, non-randomised, phase 2  trial, patients with unresectable pleural or peritoneal mesothelioma received  intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg  bodyweight) every 4 weeks for four doses, followed by maintenance intravenous  durvalumab at the same dose and schedule for nine doses. The primary endpoint was  the proportion of patients with an immune-related objective response according to  the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST;  for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal  mesothelioma). The primary analysis was done by intention to treat, whereas the  safety analysis included patients who received at least one dose of study drug.  This trial is registered with the European Clinical Trials Database, number  2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no  longer recruiting patients. FINDINGS: From Oct 30, 2015, to Oct 12, 2016, 40  patients with mesothelioma were enrolled and received at least one dose each of  tremelimumab and durvalumab. Patients were followed-up for a median of 19.2  months (IQR 13.8-20.5). 11 (28%) of 40 patients had an immune-related objective  response (all partial responses; confirmed in ten patients), with a median  response duration of 16.1 months (IQR 11.5-20.5). 26 (65%) patients had  immune-related disease control and 25 (63%) had disease control. Median  immune-related progression-free survival was 8.0 months (95% CI 6.7-9.3), median   progression-free survival was 5.7 months (1.7-9.7), and median overall survival  was 16.6 months (13.1-20.1). Baseline tumour PD-L1 expression did not correlate  with the proportion of patients who had an immune-related objective response or  immune-related disease control, with immune-related progression-free survival, or  with overall survival. 30 (75%) patients experienced treatment-related adverse  events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse   events. Treatment-related toxicity was generally manageable and reversible with  protocol guidelines. INTERPRETATION: The combination of tremelimumab and  durvalumab appeared active, with a good safety profile in patients with  mesothelioma, warranting further exploration. FUNDING: Network Italiano per la  Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul  Cancro, AstraZeneca, and Istituto Toscano Tumori.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001786	29774766	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	389	N/A	N/A	Patients with poor prognostic features may derive relevant benefits from nivolumab.	The safety profile of the subgroups was in line with the expanded access program population. No new safety signals were reported.	N/A	N/A	Poor performance (NCIT:C115331); 	Brain metastasis	Disease status	 2018 Jun	 Negative prognostic factors and resulting clinical outcome in patients with  metastatic renal cell carcinoma included in the Italian nivolumab-expanded access  program.	 Future Oncol	 AIM: We report the outcomes observed with nivolumab in metastatic renal cell  carcinoma patients with poor prognostic features enrolled in the Italian expanded  access program. PATIENTS & METHODS: Nivolumab was available for patients who  relapsed after at least one prior systemic treatment in the advanced or  metastatic setting. RESULTS: Of 389 patients, 32 (8%) had brain metastasis, 129  (33%) had liver and 193 (50%) had bone metastasis. These subpopulations achieved   a disease control rate of 53, 45 and 47%, respectively. Fifty-one patients had G4  tumor, and they showed 23% objective response rate. The safety profile of the  subgroups was in line with the expanded access program population. No new safety   signals were reported. CONCLUSION: Patients with poor prognostic features may  derive relevant benefits from nivolumab.
CANIT0001787	29782069	Clinical research	Non-small cell lung cancer with preexisting interstitial lung disease	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	216	N/A	A retrospective cohort study	Relative to the non-ILD  group, nivolumab-related pneumonitis was observed more frequently in the ILD group; however, most cases were manageable.	The incidences of total and severe nivolumab-related pneumonitis were significantly higher in the Interstitial lung disease (ILD) group than in the non-ILD group (31% vs. 12%, P = 0.014 and 19% vs. 5%, P = 0.022, respectively). No death from nivolumab-related pneumonitis occurred. Over 50% of the patients in both groups with nivolumab-related pneumonitis showed improvement over time.	N/A	N/A	Interstitial lung disease (NCIT:C27006); 	Pre-existing interstitial lung disease	Disease status	 2018 Jul	 Efficacy and safety of nivolumab in non-small cell lung cancer with preexisting  interstitial lung disease.	 Thorac Cancer	 BACKGROUND: The risk of developing lung cancer is high in patients with  interstitial lung disease (ILD), as few treatment options are available. Immune  checkpoint inhibitors (ICI) are used for the treatment of non-small cell lung  cancer (NSCLC) in clinical practice; however, in patients with preexisting ILD,  the risk of ICI-related pneumonitis is unknown. We evaluated the efficacy and  lung toxicity of nivolumab in patients with NSCLC and ILD. METHODS: We  retrospectively reviewed the medical records of 216 NSCLC patients who had  received nivolumab therapy. The existence of ILD in these patients was determined  by lung computed tomography findings; 26 patients had ILD. We evaluated the  efficacy of nivolumab by measuring the response rate (RR), progression-free  survival (PFS) duration, and lung toxicity by incidence, severity, and outcome of  nivolumab-related ILD. RESULTS: The RR and median PFS of the ILD and non-ILD  groups were 27% versus 13% (P = 0.078) and 2.7 (95% confidence interval [CI],  1.7-5.3) versus 2.9 months (95% CI 2.1-3.4; P = 0.919), respectively. The  incidences of total and severe nivolumab-related pneumonitis were significantly  higher in the ILD group than in the non-ILD group (31% vs. 12%, P = 0.014 and 19%  vs. 5%, P = 0.022, respectively). No death from nivolumab-related pneumonitis  occurred. Over 50% of the patients in both groups with nivolumab-related  pneumonitis showed improvement over time. CONCLUSION: Relative to the non-ILD  group, nivolumab-related pneumonitis was observed more frequently in the ILD  group; however, most cases were manageable.CI  - (c) 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and   John Wiley & Sons Australia, Ltd.
CANIT0001788	29801705	Case report	Non-Small-cell Lung Cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Nivolumab-induced Enteropathy	Nivolumab-induced Enteropathy	N/A	N/A	N/A	N/A	N/A	 2018 Sep	 Widespread Nivolumab-induced Enteropathy in a Long Responder Non-Small-cell Lung   Cancer Patient.	 Clin Lung Cancer	Unable to provide
CANIT0001789	29801747	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	This case showed that even if at a late phase, long-term use of immune checkpoint inhibitors might to lead immune-related adverse events including myocarditis.	Late-Onset Fulminant Myocarditis	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Late-Onset Fulminant Myocarditis With Immune Checkpoint Inhibitor Nivolumab.	 Can J Cardiol	 A 60-year-old man was diagnosed with melanoma. After receiving 13 infusions of  nivolumab, he had fulminant myocarditis. The myocardial biopsy specimen revealed   extensive lymphocytic infiltration, interstitial edema, and myocardial necrosis,   with predominant CD4+, CD8+, CD20-, and programmed death-1- markers. Programmed  death-1 ligand 1 (PD-L1) was predominantly expressed on the surface of the  damaged myocardium. Although it is reported that myocarditis induced by the human  anti-programmed death-1 inhibitor nivolumab therapy rarely occurred at > 2 months  use in clinical trials, this case showed that even if at a late phase, long-term   use of immune checkpoint inhibitors might to lead immune-related adverse events  including myocarditis.CI  - Copyright (c) 2018 Canadian Cardiovascular Society. Published by Elsevier Inc.  All rights reserved.
CANIT0001790	29843107	Clinical research	NRAS-mutated melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	364	N/A	N/A	Nevertheless, median overall survival of patients with NRAS mutant melanoma (n=128) was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma (n=236)  patients (P = 0.034). 	N/A	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	 2018 Jul	 MEK inhibition may increase survival of NRAS-mutated melanoma patients treated  with checkpoint blockade: Results of a retrospective multicentre analysis of 364   patients.	 Eur J Cancer	 BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and  KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though  BRAF mutations can be effectively targeted with specific inhibitors, this  approach has proven more challenging in cases of NRAS mutations. Previous reports  suggested that immunotherapy might be more successful in NRAS-mutated compared to  BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study,  overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and  anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were  assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients.  Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which   Q61 mutations were predominant (95%). RESULTS: Patients with NRAS mutant melanoma  showed similar response rates to checkpoint inhibitor therapy compared to NRAS  wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13%   for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and  anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median  overall survival of patients with NRAS mutant melanoma was significantly lower  with 21 months compared to 33 months in NRAS wildtype melanoma patients (P =  0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor  therapy showed a trend toward a survival benefit in patients with NRAS mutant  melanoma. CONCLUSIONS: Immune checkpoint inhibition shows comparable response  rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less  favourable in case of NRAS mutation. Additional MEK inhibition might improve  clinical benefit.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001791	29843107	Clinical research	NRAS-mutated melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	364	N/A	N/A	Nevertheless, median overall survival of patients with NRAS mutant melanoma (n=128) was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma (n=236)  patients (P = 0.034). 	N/A	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	 2018 Jul	 MEK inhibition may increase survival of NRAS-mutated melanoma patients treated  with checkpoint blockade: Results of a retrospective multicentre analysis of 364   patients.	 Eur J Cancer	 BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and  KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though  BRAF mutations can be effectively targeted with specific inhibitors, this  approach has proven more challenging in cases of NRAS mutations. Previous reports  suggested that immunotherapy might be more successful in NRAS-mutated compared to  BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study,  overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and  anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were  assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients.  Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which   Q61 mutations were predominant (95%). RESULTS: Patients with NRAS mutant melanoma  showed similar response rates to checkpoint inhibitor therapy compared to NRAS  wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13%   for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and  anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median  overall survival of patients with NRAS mutant melanoma was significantly lower  with 21 months compared to 33 months in NRAS wildtype melanoma patients (P =  0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor  therapy showed a trend toward a survival benefit in patients with NRAS mutant  melanoma. CONCLUSIONS: Immune checkpoint inhibition shows comparable response  rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less  favourable in case of NRAS mutation. Additional MEK inhibition might improve  clinical benefit.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001792	29843107	Clinical research	NRAS-mutated melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	364	N/A	N/A	Nevertheless, median overall survival of patients with NRAS mutant melanoma (n=128) was significantly lower with 21 months compared to 33 months in NRAS wildtype melanoma (n=236)  patients (P = 0.034). 	N/A	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	 2018 Jul	 MEK inhibition may increase survival of NRAS-mutated melanoma patients treated  with checkpoint blockade: Results of a retrospective multicentre analysis of 364   patients.	 Eur J Cancer	 BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and  KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though  BRAF mutations can be effectively targeted with specific inhibitors, this  approach has proven more challenging in cases of NRAS mutations. Previous reports  suggested that immunotherapy might be more successful in NRAS-mutated compared to  BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study,  overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and  anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were  assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients.  Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which   Q61 mutations were predominant (95%). RESULTS: Patients with NRAS mutant melanoma  showed similar response rates to checkpoint inhibitor therapy compared to NRAS  wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13%   for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and  anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median  overall survival of patients with NRAS mutant melanoma was significantly lower  with 21 months compared to 33 months in NRAS wildtype melanoma patients (P =  0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor  therapy showed a trend toward a survival benefit in patients with NRAS mutant  melanoma. CONCLUSIONS: Immune checkpoint inhibition shows comparable response  rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less  favourable in case of NRAS mutation. Additional MEK inhibition might improve  clinical benefit.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001793	29843107	Clinical research	NRAS-mutated melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Immune checkpoint therapy (nivolumab or pembrolizumab or ipilimumab)	Immune checkpoint therapy	Ipilimumab (DB06186); 	58	178	N/A	Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma.	N/A	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	 2018 Jul	 MEK inhibition may increase survival of NRAS-mutated melanoma patients treated  with checkpoint blockade: Results of a retrospective multicentre analysis of 364   patients.	 Eur J Cancer	 BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and  KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though  BRAF mutations can be effectively targeted with specific inhibitors, this  approach has proven more challenging in cases of NRAS mutations. Previous reports  suggested that immunotherapy might be more successful in NRAS-mutated compared to  BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study,  overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and  anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were  assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients.  Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which   Q61 mutations were predominant (95%). RESULTS: Patients with NRAS mutant melanoma  showed similar response rates to checkpoint inhibitor therapy compared to NRAS  wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13%   for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and  anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median  overall survival of patients with NRAS mutant melanoma was significantly lower  with 21 months compared to 33 months in NRAS wildtype melanoma patients (P =  0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor  therapy showed a trend toward a survival benefit in patients with NRAS mutant  melanoma. CONCLUSIONS: Immune checkpoint inhibition shows comparable response  rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less  favourable in case of NRAS mutation. Additional MEK inhibition might improve  clinical benefit.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001794	29843107	Clinical research	NRAS-mutated melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	Immune checkpoint therapy (nivolumab or pembrolizumab or ipilimumab)	Immune checkpoint therapy	Nivolumab (DB09035); 	58	178	N/A	Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma.	N/A	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	 2018 Jul	 MEK inhibition may increase survival of NRAS-mutated melanoma patients treated  with checkpoint blockade: Results of a retrospective multicentre analysis of 364   patients.	 Eur J Cancer	 BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and  KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though  BRAF mutations can be effectively targeted with specific inhibitors, this  approach has proven more challenging in cases of NRAS mutations. Previous reports  suggested that immunotherapy might be more successful in NRAS-mutated compared to  BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study,  overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and  anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were  assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients.  Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which   Q61 mutations were predominant (95%). RESULTS: Patients with NRAS mutant melanoma  showed similar response rates to checkpoint inhibitor therapy compared to NRAS  wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13%   for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and  anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median  overall survival of patients with NRAS mutant melanoma was significantly lower  with 21 months compared to 33 months in NRAS wildtype melanoma patients (P =  0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor  therapy showed a trend toward a survival benefit in patients with NRAS mutant  melanoma. CONCLUSIONS: Immune checkpoint inhibition shows comparable response  rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less  favourable in case of NRAS mutation. Additional MEK inhibition might improve  clinical benefit.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001795	29843107	Clinical research	NRAS-mutated melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Immune checkpoint therapy (nivolumab or pembrolizumab or ipilimumab)	Immune checkpoint therapy	Pembrolizumab (DB09037); 	58	178	N/A	Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma.	N/A	N/A	N/A	NRAS (P01111); 	NRAS mutational status	Mutational status	 2018 Jul	 MEK inhibition may increase survival of NRAS-mutated melanoma patients treated  with checkpoint blockade: Results of a retrospective multicentre analysis of 364   patients.	 Eur J Cancer	 BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and  KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though  BRAF mutations can be effectively targeted with specific inhibitors, this  approach has proven more challenging in cases of NRAS mutations. Previous reports  suggested that immunotherapy might be more successful in NRAS-mutated compared to  BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study,  overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and  anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were  assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients.  Subtyping of NRAS mutation in 211 cases revealed 12 different genotypes of which   Q61 mutations were predominant (95%). RESULTS: Patients with NRAS mutant melanoma  showed similar response rates to checkpoint inhibitor therapy compared to NRAS  wildtype patients with 15% versus 13% for ipilimumab (P = 0.731), 21% versus 13%   for anti-PD-1 monotherapy (P = 0.210) and 40% versus 39% for ipilimumab and  anti-PD-1 therapy in combination or sequence (P = 0.859). Nevertheless, median  overall survival of patients with NRAS mutant melanoma was significantly lower  with 21 months compared to 33 months in NRAS wildtype melanoma patients (P =  0.034). Therapy with oral MEK inhibitors before or after checkpoint inhibitor  therapy showed a trend toward a survival benefit in patients with NRAS mutant  melanoma. CONCLUSIONS: Immune checkpoint inhibition shows comparable response  rates in NRAS-mutated and NRAS wildtype melanoma even though survival is less  favourable in case of NRAS mutation. Additional MEK inhibition might improve  clinical benefit.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001796	29844203	Case report	Advanced mucosal melanoma and concomitant acute myeloid leukemia	Mucosal melanoma	MONDO:0000544	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	SIngle-agent therapy with pembrolizumab might display disease-modifying activity in a subset of AML patients.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jun 12	 Clinical, molecular, and immunological responses to pembrolizumab treatment of  synchronous melanoma and acute myeloid leukemia.	 Blood Adv	Unable to provide
CANIT0001797	29855288	Case report	Pulmonary adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	This was a rare case of hyperprogressive disease with rapid progression of peritoneal dissemination after pembrolizumab treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 May 31	 A case of pulmonary adenocarcinoma showing rapid progression of peritoneal  dissemination after immune checkpoint inhibitor therapy.	 BMC Cancer	 BACKGROUND: Immune checkpoint inhibitors are standard treatments for non-small  cell lung cancer. Unique cases with paradoxical acceleration of the disease after  immunotherapy have been reported. These have been described as cases of  hyperprogressive disease. CASE PRESENTATION: A 76-year-old man was diagnosed with  pulmonary adenocarcinoma with pleural dissemination and liver and adrenal  metastases. Genomic analysis revealed neither EGFR mutations nor ALK  translocations. Immunohistochemical analysis revealed a programmed death-ligand 1  tumor proportion score of 23%. Chemotherapy with carboplatin, paclitaxel, and  bevacizumab resulted in Grade 3 skin eruption and disease progression.  Pembrolizumab was initiated as a second-line treatment. However, peritoneal  dissemination and ascites developed. The patient died 2 weeks later. The autopsy   revealed widespread peritoneal dissemination and an extensive hemorrhagic  infarction. CONCLUSION: This was a rare case of hyperprogressive disease with  rapid progression of peritoneal dissemination after pembrolizumab treatment.
CANIT0001798	29855323	Case report	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Our case reports confirms the existence of abscopal effects in NSCLC and suggests synergism between immune-checkpoint inhibition and local ablative stereotactic body radiotherapy. We suggest that this approach is now further studied in prospective clinical trials on oligo-metastatic or oligo-progressing NSCLC.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 May 31	 Report of an abscopal effect induced by stereotactic body radiotherapy and  nivolumab in a patient with metastatic non-small cell lung cancer.	 Radiat Oncol	 BACKGROUND: The existence of abscopal effects has been suggested already a long  time ago, but only recently with the advent of immune checkpoint inhibition in  clinical oncology and modern imaging techniques has it become possible to  directly observe such effects in patients. They have been well described in  patients with malignant melanoma being treated with immune-checkpoint inhibitors   and stereotactic radiotherapy, but experience in other malignancies is very  limited. CASE PRESENTATION: Here, we describe a case of a patient with metastatic  non-small cell lung cancer, who experienced a complete response secondary to an  abscopal effect on treatment with anti-PD-1 therapy and stereotactic body  radiotherapy to some of the involved sites. CONCLUSIONS: Our case reports  confirms the existence of abscopal effects in NSCLC and suggests synergism  between immune-checkpoint inhibition and local ablative RT. We suggest that this   approach is now further studied in prospective clinical trials on  oligo-metastatic or oligo-progressing NSCLC.
CANIT0001799	29857970	Clinical research	Advanced pleomorphic carcinoma of the lung	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	N/A	In our case, the autopsy findings showed that microglia were abundant, and CD8-positive T cells and macrophages invaded the LE lesions. These findings led us to hypothesize that nivolumab treatment in the presence of anti-Hu antibody caused the onset of LE. A positive anti-Hu antibody titer may be a predictor of nivolumab-induced encephalitis.	Limbic encephalitis with anti-hu antibody	N/A	N/A	N/A	N/A	N/A	 2018 Sep	 Nivolumab-induced Limbic Encephalitis with Anti-Hu Antibody in a Patient With  Advanced Pleomorphic Carcinoma of the Lung.	 Clin Lung Cancer	Unable to provide
CANIT0001800	29859759	Clinical research	Non-Small-cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	39	N/A	N/A	The clinical benefit from nivolumab therapy was significantly associated with the baseline plasma sPD-L1 levels. Plasma sPD-L1 levels might represent a novel biomarker for the prediction of the efficacy of nivolumab therapy against NSCLC.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	Serum PD-L1 expression levels	Gene expression signature in serum	 2018 Sep	 Soluble Programmed Cell Death Ligand 1 as a Novel Biomarker for Nivolumab Therapy  for Non-Small-cell Lung Cancer.	 Clin Lung Cancer	 BACKGROUND: Biomarkers for predicting the effect of anti-programmed cell death 1   (PD-1) monoclonal antibody against non-small-cell lung cancer (NSCLC) are  urgently required. Although it is known that the blood levels of soluble  programmed cell death ligand 1 (sPD-L1) are elevated in various malignancies, the  nature of sPD-L1 has not been thoroughly elucidated. We investigated the  significance of plasma sPD-L1 levels as a biomarker for anti-PD-1 monoclonal  antibody, nivolumab therapy. PATIENTS AND METHODS: The present prospective study   included 39 NSCLC patients. The patients were treated with nivolumab at the dose   of 3 mg/kg every 2 weeks, and the effects of nivolumab on NSCLC were assessed  according to the change in tumor size, time to treatment failure (TTF), and  overall survival (OS). The baseline plasma sPD-L1 concentration was determined  using an enzyme-linked immunosorbent assay. RESULTS: The area under the curve of   the receiver operating characteristic curve was 0.761. The calculated optimal  cutoff point for sPD-L1 in the plasma samples was 3.357 ng/mL. Of the 39  patients, 59% with low plasma sPD-L1 levels achieved a complete response or  partial response and 25% of those with high plasma sPD-L1 levels did so. In  addition, 22% of the patients with low plasma sPD-L1 levels developed progressive  disease compared with 75% of those with high plasma sPD-L1 levels. The TTF and OS  were significantly longer for those patients with low plasma sPD-L1 levels  compared with the TTF and OS for those with high plasma sPD-L1 levels.  CONCLUSION: The clinical benefit from nivolumab therapy was significantly  associated with the baseline plasma sPD-L1 levels. Plasma sPD-L1 levels might  represent a novel biomarker for the prediction of the efficacy of nivolumab  therapy against NSCLC.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001801	29863955	Clinical research	Metastatic Nonsquamous NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab plus carboplatin plus paclitaxel	Bevacizumab plus carboplatin plus paclitaxel	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); paclitaxel (DB01229); carboplatin (DB00958); bevacizumab (DB00112); 	356	336	An open-label, phase III study	The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status.	The safety profile of atezolizumab plus bevacizumab plus carboplatin plus paclitaxel(ABCP) was consistent with previously reported safety risks of the individual medicines.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Jun 14	 Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.	 N Engl J Med	 BACKGROUND: The cancer-cell-killing property of atezolizumab may be enhanced by  the blockade of vascular endothelial growth factor-mediated immunosuppression  with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus  bevacizumab plus chemotherapy in patients with metastatic nonsquamous  non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy.   METHODS: We randomly assigned patients to receive atezolizumab plus carboplatin  plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or  atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by  maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end   points were investigator-assessed progression-free survival both among patients  in the intention-to-treat population who had a wild-type genotype (WT population;  patients with EGFR or ALK genetic alterations were excluded) and among patients  in the WT population who had high expression of an effector T-cell (Teff) gene  signature in the tumor (Teff-high WT population) and overall survival in the WT  population. The ABCP group was compared with the BCP group before the ACP group  was compared with the BCP group. RESULTS: In the WT population, 356 patients were  assigned to the ABCP group, and 336 to the BCP group. The median progression-free  survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8  months; hazard ratio for disease progression or death, 0.62; 95% confidence  interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high   WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38  to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group  than in the BCP group in the entire intention-to-treat population (including  those with EGFR or ALK genetic alterations) and among patients with low or  negative programmed death ligand 1 (PD-L1) expression, those with low Teff  gene-signature expression, and those with liver metastases. Median overall  survival among the patients in the WT population was longer in the ABCP group  than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78;  95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with  previously reported safety risks of the individual medicines. CONCLUSIONS: The  addition of atezolizumab to bevacizumab plus chemotherapy significantly improved   progression-free survival and overall survival among patients with metastatic  nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic  alteration status. (Funded by F. Hoffmann-La Roche/Genentech; IMpower150  ClinicalTrials.gov number, NCT02366143 .).
CANIT0001802	29863955	Clinical research	Metastatic Nonsquamous NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab plus carboplatin plus paclitaxel	Bevacizumab plus carboplatin plus paclitaxel	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); paclitaxel (DB01229); carboplatin (DB00958); bevacizumab (DB00112); atezolizumab (DB11595); 	356	336	An open-label, phase III study	The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status.	The safety profile of atezolizumab plus bevacizumab plus carboplatin plus paclitaxel(ABCP) was consistent with previously reported safety risks of the individual medicines.	N/A	N/A	EGFR/ALK (P00533); 	EGFR/ALK mutational status	Mutational status	 2018 Jun 14	 Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC.	 N Engl J Med	 BACKGROUND: The cancer-cell-killing property of atezolizumab may be enhanced by  the blockade of vascular endothelial growth factor-mediated immunosuppression  with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus  bevacizumab plus chemotherapy in patients with metastatic nonsquamous  non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy.   METHODS: We randomly assigned patients to receive atezolizumab plus carboplatin  plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or  atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by  maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end   points were investigator-assessed progression-free survival both among patients  in the intention-to-treat population who had a wild-type genotype (WT population;  patients with EGFR or ALK genetic alterations were excluded) and among patients  in the WT population who had high expression of an effector T-cell (Teff) gene  signature in the tumor (Teff-high WT population) and overall survival in the WT  population. The ABCP group was compared with the BCP group before the ACP group  was compared with the BCP group. RESULTS: In the WT population, 356 patients were  assigned to the ABCP group, and 336 to the BCP group. The median progression-free  survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8  months; hazard ratio for disease progression or death, 0.62; 95% confidence  interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high   WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38  to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group  than in the BCP group in the entire intention-to-treat population (including  those with EGFR or ALK genetic alterations) and among patients with low or  negative programmed death ligand 1 (PD-L1) expression, those with low Teff  gene-signature expression, and those with liver metastases. Median overall  survival among the patients in the WT population was longer in the ABCP group  than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78;  95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with  previously reported safety risks of the individual medicines. CONCLUSIONS: The  addition of atezolizumab to bevacizumab plus chemotherapy significantly improved   progression-free survival and overall survival among patients with metastatic  nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic  alteration status. (Funded by F. Hoffmann-La Roche/Genentech; IMpower150  ClinicalTrials.gov number, NCT02366143 .).
CANIT0001803	29867230	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab	Sunitinib	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); bevacizumab (DB00112); 	101	101	A randomized phase II study	Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN- response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments.	N/A	N/A	N/A	Angiogenesis (NCIT:C19361); 	Angiogenesis	Disease status	 2018 Jun	 Clinical activity and molecular correlates of response to atezolizumab alone or  in combination with bevacizumab versus sunitinib in renal cell carcinoma.	 Nat Med	 We describe results from IMmotion150, a randomized phase 2 study of atezolizumab   (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in  305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary  endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+  populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or   atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI),  0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios  were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively.  Exploratory biomarker analyses indicated that tumor mutation and neoantigen  burden were not associated with PFS. Angiogenesis, T-effector/IFNG response,  and myeloid inflammatory gene expression signatures were strongly and  differentially associated with PFS within and across the treatments. These  molecular profiles suggest that prediction of outcomes with anti-VEGF and  immunotherapy may be possible and offer mechanistic insights into how blocking  VEGF may overcome resistance to immune checkpoint blockade.
CANIT0001804	29867230	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab	Sunitinib	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); bevacizumab (DB00112); 	101	101	A randomized phase II study	Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN- response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments.	N/A	N/A	N/A	Myeloid inflammatory (NCIT:C20151); 	Myeloid inflammatory gene expression signatures	Gene expression signature on/in immune cell	 2018 Jun	 Clinical activity and molecular correlates of response to atezolizumab alone or  in combination with bevacizumab versus sunitinib in renal cell carcinoma.	 Nat Med	 We describe results from IMmotion150, a randomized phase 2 study of atezolizumab   (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in  305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary  endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+  populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or   atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI),  0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios  were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively.  Exploratory biomarker analyses indicated that tumor mutation and neoantigen  burden were not associated with PFS. Angiogenesis, T-effector/IFNG response,  and myeloid inflammatory gene expression signatures were strongly and  differentially associated with PFS within and across the treatments. These  molecular profiles suggest that prediction of outcomes with anti-VEGF and  immunotherapy may be possible and offer mechanistic insights into how blocking  VEGF may overcome resistance to immune checkpoint blockade.
CANIT0001805	29867230	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab	Sunitinib	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); bevacizumab (DB00112); 	101	101	A randomized phase II study	Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN- response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Jun	 Clinical activity and molecular correlates of response to atezolizumab alone or  in combination with bevacizumab versus sunitinib in renal cell carcinoma.	 Nat Med	 We describe results from IMmotion150, a randomized phase 2 study of atezolizumab   (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in  305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary  endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+  populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or   atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI),  0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios  were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively.  Exploratory biomarker analyses indicated that tumor mutation and neoantigen  burden were not associated with PFS. Angiogenesis, T-effector/IFNG response,  and myeloid inflammatory gene expression signatures were strongly and  differentially associated with PFS within and across the treatments. These  molecular profiles suggest that prediction of outcomes with anti-VEGF and  immunotherapy may be possible and offer mechanistic insights into how blocking  VEGF may overcome resistance to immune checkpoint blockade.
CANIT0001806	29867230	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab	Sunitinib	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); bevacizumab (DB00112); 	101	101	A randomized phase II study	Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN- response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments.	N/A	N/A	N/A	IFNA (P48551); T-Lymphocyte (NCIT:C12476); 	T-effector/IFN- response	Immune response	 2018 Jun	 Clinical activity and molecular correlates of response to atezolizumab alone or  in combination with bevacizumab versus sunitinib in renal cell carcinoma.	 Nat Med	 We describe results from IMmotion150, a randomized phase 2 study of atezolizumab   (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in  305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary  endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+  populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or   atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI),  0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios  were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively.  Exploratory biomarker analyses indicated that tumor mutation and neoantigen  burden were not associated with PFS. Angiogenesis, T-effector/IFNG response,  and myeloid inflammatory gene expression signatures were strongly and  differentially associated with PFS within and across the treatments. These  molecular profiles suggest that prediction of outcomes with anti-VEGF and  immunotherapy may be possible and offer mechanistic insights into how blocking  VEGF may overcome resistance to immune checkpoint blockade.
CANIT0001807	29867230	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Sunitinib	Immune checkpoint therapy	Atezolizumab (DB11595); 	103	101	A randomized phase II study	Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN- response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments.	N/A	N/A	N/A	Angiogenesis (NCIT:C19361); 	Angiogenesis	Disease status	 2018 Jun	 Clinical activity and molecular correlates of response to atezolizumab alone or  in combination with bevacizumab versus sunitinib in renal cell carcinoma.	 Nat Med	 We describe results from IMmotion150, a randomized phase 2 study of atezolizumab   (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in  305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary  endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+  populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or   atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI),  0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios  were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively.  Exploratory biomarker analyses indicated that tumor mutation and neoantigen  burden were not associated with PFS. Angiogenesis, T-effector/IFNG response,  and myeloid inflammatory gene expression signatures were strongly and  differentially associated with PFS within and across the treatments. These  molecular profiles suggest that prediction of outcomes with anti-VEGF and  immunotherapy may be possible and offer mechanistic insights into how blocking  VEGF may overcome resistance to immune checkpoint blockade.
CANIT0001808	29867230	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Sunitinib	Immune checkpoint therapy	Atezolizumab (DB11595); 	103	101	A randomized phase II study	Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN- response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments.	N/A	N/A	N/A	Myeloid inflammatory (NCIT:C20151); 	Myeloid inflammatory gene expression signatures	Gene expression signature on/in immune cell	 2018 Jun	 Clinical activity and molecular correlates of response to atezolizumab alone or  in combination with bevacizumab versus sunitinib in renal cell carcinoma.	 Nat Med	 We describe results from IMmotion150, a randomized phase 2 study of atezolizumab   (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in  305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary  endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+  populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or   atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI),  0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios  were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively.  Exploratory biomarker analyses indicated that tumor mutation and neoantigen  burden were not associated with PFS. Angiogenesis, T-effector/IFNG response,  and myeloid inflammatory gene expression signatures were strongly and  differentially associated with PFS within and across the treatments. These  molecular profiles suggest that prediction of outcomes with anti-VEGF and  immunotherapy may be possible and offer mechanistic insights into how blocking  VEGF may overcome resistance to immune checkpoint blockade.
CANIT0001809	29867230	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Sunitinib	Immune checkpoint therapy	Atezolizumab (DB11595); 	103	101	A randomized phase II study	Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN- response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments.	N/A	N/A	N/A	IFNA (P48551); T-Lymphocyte (NCIT:C12476); 	T-effector/IFN- response	Immune response	 2018 Jun	 Clinical activity and molecular correlates of response to atezolizumab alone or  in combination with bevacizumab versus sunitinib in renal cell carcinoma.	 Nat Med	 We describe results from IMmotion150, a randomized phase 2 study of atezolizumab   (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in  305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary  endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+  populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or   atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI),  0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios  were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively.  Exploratory biomarker analyses indicated that tumor mutation and neoantigen  burden were not associated with PFS. Angiogenesis, T-effector/IFNG response,  and myeloid inflammatory gene expression signatures were strongly and  differentially associated with PFS within and across the treatments. These  molecular profiles suggest that prediction of outcomes with anti-VEGF and  immunotherapy may be possible and offer mechanistic insights into how blocking  VEGF may overcome resistance to immune checkpoint blockade.
CANIT0001810	29875066	Clinical research	Advanced hepatocellular carcinoma previously treated with sorafenib	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	104	N/A	A non-randomised, open-label phase II trial.	Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma.	 Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares.	N/A	N/A	N/A	N/A	N/A	 2018 Jul	 Pembrolizumab in patients with advanced hepatocellular carcinoma previously  treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.	 Lancet Oncol	 BACKGROUND: Immune checkpoint blockade therapy has shown promising results in  patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy   and safety of pembrolizumab in this patient population. METHODS: KEYNOTE-224 is a  non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical   centres and hospitals across ten countries. Eligible patients had pathologically   confirmed hepatocellular carcinoma; had previously been treated with sorafenib  and were either intolerant to this treatment or showed radiographic progression  of their disease after treatment; an Eastern Cooperative Oncology Group  performance status of 0-1; adequate organ function, and were Child-Pugh class A.   Participants received 200 mg pembrolizumab intravenously every 3 weeks for about   2 years or until disease progression, unacceptable toxicity, patient withdrawal,   or investigator decision. The primary endpoint was objective response, defined as  the proportion of patients with complete or partial response in all patients who   received at least one dose of pembrolizumab, which was radiologically confirmed  by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central  review. Safety was also assessed in all treated patients. This trial is ongoing  but closed to enrolment and is registered with ClinicalTrials.gov number  NCT02702414. FINDINGS: Between June 7, 2016, and Feb 9, 2017, we screened 169  patients with advanced hepatocellular carcinoma, of whom 104 eligible patients  were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients  were still receiving pembrolizumab. We recorded an objective response in 18 (17%;  95% CI 11-26) of 104 patients. The best overall responses were one (1%) complete   and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease,   34 (33%) had progressive disease, and six (6%) patients who did not have a  post-baseline assessment on the cutoff date were considered not to be assessable.  Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were  serious in 16 (15%) patients. Grade 3 treatment-related events were reported in  25 (24%) of the 104 patients; the most common were increased aspartate  aminotransferase concentration in seven (7%) patients, increased alanine  aminotransferase concentration in four (4%) patients, and fatigue in four (4%)  patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia  occurred. One death associated with ulcerative oesophagitis was attributed to  treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there  were no reported cases of viral flares. INTERPRETATION: Pembrolizumab was  effective and tolerable in patients with advanced hepatocellular carcinoma who  had previously been treated with sorafenib. These results indicate that  pembrolizumab might be a treatment option for these patients. This drug is  undergoing further assessment in two phase 3, randomised trials as a second-line   treatment in patients with hepatocellular carcinoma. FUNDING: Merck & Co, Inc.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001811	29877257	Case report	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	A case of lung cancer with complete atrioventricular block associated with acute myocarditis, which developed 16 days after the administration of pembrolizumab. The clinical course of this case suggested a strong need for close cardiac monitoring when pembrolizumab is administered on an outpatient basis.	Complete atrioventricular block	N/A	N/A	N/A	N/A	N/A	 2018 Nov 1	 Complete Atrioventricular Block Associated with Pembrolizumab-induced Acute  Myocarditis: The Need for Close Cardiac Monitoring.	 Intern Med	 Pembrolizumab, a humanized monoclonal IgG4 antibody directed against programmed  death-1, is an immune checkpoint inhibitor that has been introduced for the  treatment of non-small-cell lung cancer. However, immune checkpoint inhibitors  may cause severe immune-related adverse events. We herein present a case of lung   cancer with complete atrioventricular block associated with acute myocarditis,  which developed 16 days after the administration of pembrolizumab. The clinical  course of this case suggested a strong need for close cardiac monitoring when  pembrolizumab is administered on an outpatient basis.
CANIT0001812	29877291	Case report	PD-L1-negative stage IV lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Our case indicates that the efficacy of programmed cell death 1 inhibitors is not solely predicted by the PD-L1 status, and that immune checkpoint inhibitors might be effective for the treatment of central nervous system metastasis.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Nov 1	 Intracranial Response to Nivolumab in a Patient with PD-L1-negative Lung  Adenocarcinoma.	 Intern Med	 We herein report the case of a 52-year-old man with stage IV lung adenocarcinoma.  The patient was negative for epidermal growth factor receptor (EGFR) mutations  and echinoderm microtubule-associated protein-like 4 (EML4) /anaplastic lymphoma   kinase (ALK) rearrangement. He was treated with nivolumab as a third-line  chemotherapy. After four cycles of nivolumab treatment, a partial response was  observed in the brain and at the primary tumor site. Nivolumab treatment has been  continued for 11 months without progression. Immunohistochemistry revealed that  the programmed death-ligand 1 (PD-L1) expression was 0% (according to the tumor  proportion score). Our case indicates that the efficacy of programmed cell death   1 inhibitors is not solely predicted by the PD-L1 status, and that immune  checkpoint inhibitors might be effective for the treatment of central nervous  system metastasis.
CANIT0001813	29880231	Clinical research	Advanced gastric or gastro-oesophageal junction cancer	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Paclitaxel	Immune checkpoint therapy	Paclitaxel (DB01229); pembrolizumab (DB09037); 	296	296	A randomised, open-label, controlled, phase 3 trial.	Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel.	These events were of grade 3C5 severity in 42 (14%) of 294 patients in the pembrolizumab group and 96 (35%) of 276 patients in the paclitaxel group and led to discontinuation of study treatment in nine (3%) patients and 15 (5%) patients, respectively. Deaths attributed to study treatment occurred in three (1%) of 294 patients in the pembrolizumab group (colitis, interstitial lung disease, and death in one patient each) and in one (<1%) of 276 patients in the paclitaxel group (pulmonary embolism).	N/A	N/A	N/A	N/A	N/A	 2018 Jul 14	 Pembrolizumab versus paclitaxel for previously treated, advanced gastric or  gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label,  controlled, phase 3 trial.	 Lancet	 BACKGROUND: Patients with advanced gastric or gastro-oesophageal junction cancer   that progresses on chemotherapy have poor outcomes. We compared pembrolizumab  with paclitaxel in patients with advanced gastric or gastro-oesophageal junction   cancer that progressed on first-line chemotherapy with a platinum and  fluoropyrimidine. METHODS: This randomised, open-label, phase 3 study was done at  148 medical centres in 30 countries. Eligible patients were randomised (1:1) in  blocks of four per stratum with an interactive voice-response and integrated  web-response system to receive either pembrolizumab 200 mg every 3 weeks for up  to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival  and progression-free survival in patients with a programmed cell death ligand 1  (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all   patients, irrespective of CPS. The significance threshold for overall survival  was p=0.0135 (one-sided). This trial is registered at ClinicalTrials.gov, number   NCT02370498. FINDINGS: Between June 4, 2015, and July 26, 2016, 592 patients were  enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients  were assigned to receive pembrolizumab and 199 patients were assigned to receive   paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or  higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175  [88%] of 199 patients in the paclitaxel group). Median overall survival was 9.1  months (95% CI 6.2-10.7) with pembrolizumab and 8.3 months (7.6-9.0) with  paclitaxel (hazard ratio [HR] 0.82, 95% CI 0.66-1.03; one-sided p=0.0421). Median  progression-free survival was 1.5 months (95% CI 1.4-2.0) with pembrolizumab and   4.1 months (3.1-4.2) with paclitaxel (HR 1.27, 95% CI 1.03-1.57). In the total  population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of  the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients  treated with paclitaxel. INTERPRETATION: Pembrolizumab did not significantly  improve overall survival compared with paclitaxel as second-line therapy for  advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or  higher. Pembrolizumab had a better safety profile than paclitaxel. Additional  trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing.  FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001814	29884162	Clinical research	Malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A retrospective cohort study	Thyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced thyroid dysfunction. A conventional ATA-independent mechanism might be involved in thyroid immune-related adverse events.	Thyroid irAEs were observed in seven patients (29%). Three patients had hypothyroidism after preceding transient thyrotoxicosis, and the other four patients had hypothyroidism without thyrotoxicosis. Levothyroxine-Na replacement was required in three patients. Antithyroid antibody (ATA) titer was elevated in one of four assessable patients. The average (SD) time to onset of thyroid irAE was 33.6 (21.9) weeks. The administration period of nivolumab was longer in patients with thyroid irAEs than in those without thyroid irAEs (P < 0.01). There were no significant differences between patients with and without thyroid irAEs regarding age, sex, tumor stage, response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab).	N/A	N/A	N/A	N/A	N/A	 2018 Jun 8	 Nivolumab-induced thyroid dysfunction lacking antithyroid antibody is frequently   evoked in Japanese patients with malignant melanoma.	 BMC Endocr Disord	 BACKGROUND: Nivolumab, an anti-programmed cell death-1 monoclonal antibody, has  improved the survival of patients with malignant melanoma. Despite its efficacy,   nivolumab inconsistently induces thyroid dysfunction as an immune-related adverse  event (irAE). This study aimed to evaluate nivolumab-induced thyroid dysfunction   to determine the risks and mechanisms of thyroid irAEs. METHODS: After excluding   10 patients, data of 24 patients with malignant melanoma (aged 17-85 years; 54%  female) were retrospectively analyzed. RESULTS: Thyroid irAEs were observed in  seven patients (29%). Three patients had hypothyroidism after preceding transient  thyrotoxicosis, and the other four patients had hypothyroidism without  thyrotoxicosis. Levothyroxine-Na replacement was required in three patients.  Antithyroid antibody (ATA) titer was elevated in one of four assessable patients.  The average (+/-SD) time to onset of thyroid irAE was 33.6 (+/-21.9) weeks. The  administration period of nivolumab was longer in patients with thyroid irAEs than  in those without thyroid irAEs (P < 0.01). There were no significant differences   between patients with and without thyroid irAEs regarding age, sex, tumor stage,   response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase   antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab). CONCLUSIONS:   Thyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither  anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced  thyroid dysfunction. A conventional ATA-independent mechanism might be involved  in thyroid irAEs. Further studies are required to clarify the mechanism and  identify the predictive factors of thyroid irAEs.
CANIT0001815	29906735	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	385	N/A	A retrospective cohort study	In our study, extracranial (ec) disease control was the dominant predictive factor for OS in both patients with or without melanoma brain metastases. These data indicate that clinical trials in melanoma patients with brain metastases should address end-points such as symptom control, quality of life or OS in addition to ic response rates.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Patterns of disease control and survival in patients with melanoma brain  metastases undergoing immune-checkpoint blockade.	 Eur J Cancer	 OBJECTIVES: Immune-checkpoint blockers (ICBs) significantly prolong overall  survival (OS) in patients with advanced melanoma. Limited data are available on  the efficacy and clinical benefit in patients with melanoma brain metastases  (MBMs). The aim of this study was to determine whether ICB is active in an  unselected cohort treated of patients with known brain metastases and if disease   control correlates with the survival. METHODS: A total of 385 patients with  metastatic malignant melanoma treated with ICB as monotherapy between 2005 and  2017 in two tertiary referral centres were included. Patient records were  searched for the development of brain metastases. Demographic and clinical data  of all patients were collected retrospectively. RESULTS: We identified 177  patients with MBM who received ICBs (ipilimumab, nivolumab, pembrolizumab).  Patients with and without brain metastases received similar ICB regimens.  Prognosis was inferior in patients with brain metastases; patients with >1 brain   metastasis showed even poorer survival. For extracranial (ec) metastases, disease  control was associated with improved survival. However, when comparing patients  with intracranial (ic) disease control during immunotherapy to patients with ic  disease progression, no difference in OS could be observed. CONCLUSIONS: In our  study, ec disease control was the dominant predictive factor for OS in both  patients with or without melanoma brain metastases. These data indicate that  clinical trials in melanoma patients with brain metastases should address  end-points such as symptom control, quality of life or OS in addition to ic  response rates.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001816	29906735	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	385	N/A	A retrospective cohort study	In our study, extracranial (ec) disease control was the dominant predictive factor for OS in both patients with or without melanoma brain metastases. These data indicate that clinical trials in melanoma patients with brain metastases should address end-points such as symptom control, quality of life or OS in addition to ic response rates.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Patterns of disease control and survival in patients with melanoma brain  metastases undergoing immune-checkpoint blockade.	 Eur J Cancer	 OBJECTIVES: Immune-checkpoint blockers (ICBs) significantly prolong overall  survival (OS) in patients with advanced melanoma. Limited data are available on  the efficacy and clinical benefit in patients with melanoma brain metastases  (MBMs). The aim of this study was to determine whether ICB is active in an  unselected cohort treated of patients with known brain metastases and if disease   control correlates with the survival. METHODS: A total of 385 patients with  metastatic malignant melanoma treated with ICB as monotherapy between 2005 and  2017 in two tertiary referral centres were included. Patient records were  searched for the development of brain metastases. Demographic and clinical data  of all patients were collected retrospectively. RESULTS: We identified 177  patients with MBM who received ICBs (ipilimumab, nivolumab, pembrolizumab).  Patients with and without brain metastases received similar ICB regimens.  Prognosis was inferior in patients with brain metastases; patients with >1 brain   metastasis showed even poorer survival. For extracranial (ec) metastases, disease  control was associated with improved survival. However, when comparing patients  with intracranial (ic) disease control during immunotherapy to patients with ic  disease progression, no difference in OS could be observed. CONCLUSIONS: In our  study, ec disease control was the dominant predictive factor for OS in both  patients with or without melanoma brain metastases. These data indicate that  clinical trials in melanoma patients with brain metastases should address  end-points such as symptom control, quality of life or OS in addition to ic  response rates.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001817	29906735	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	385	N/A	A retrospective cohort study	In our study, extracranial (ec) disease control was the dominant predictive factor for OS in both patients with or without melanoma brain metastases. These data indicate that clinical trials in melanoma patients with brain metastases should address end-points such as symptom control, quality of life or OS in addition to ic response rates.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Patterns of disease control and survival in patients with melanoma brain  metastases undergoing immune-checkpoint blockade.	 Eur J Cancer	 OBJECTIVES: Immune-checkpoint blockers (ICBs) significantly prolong overall  survival (OS) in patients with advanced melanoma. Limited data are available on  the efficacy and clinical benefit in patients with melanoma brain metastases  (MBMs). The aim of this study was to determine whether ICB is active in an  unselected cohort treated of patients with known brain metastases and if disease   control correlates with the survival. METHODS: A total of 385 patients with  metastatic malignant melanoma treated with ICB as monotherapy between 2005 and  2017 in two tertiary referral centres were included. Patient records were  searched for the development of brain metastases. Demographic and clinical data  of all patients were collected retrospectively. RESULTS: We identified 177  patients with MBM who received ICBs (ipilimumab, nivolumab, pembrolizumab).  Patients with and without brain metastases received similar ICB regimens.  Prognosis was inferior in patients with brain metastases; patients with >1 brain   metastasis showed even poorer survival. For extracranial (ec) metastases, disease  control was associated with improved survival. However, when comparing patients  with intracranial (ic) disease control during immunotherapy to patients with ic  disease progression, no difference in OS could be observed. CONCLUSIONS: In our  study, ec disease control was the dominant predictive factor for OS in both  patients with or without melanoma brain metastases. These data indicate that  clinical trials in melanoma patients with brain metastases should address  end-points such as symptom control, quality of life or OS in addition to ic  response rates.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001818	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001819	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001820	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001821	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001822	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001823	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001824	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001825	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Prostate cancer	MONDO:0008315	Prostate	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001826	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001827	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001828	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001829	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001830	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001831	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001832	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001833	29909921	Case report	Melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	6	N/A	Case	Myositis can occur early after onset of ICI therapy with serious adverse outcomes.	Myositis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	 Myositis as an adverse event of immune checkpoint blockade for cancer therapy.	 Semin Arthritis Rheum	 OBJECTIVES: Immune checkpoint inhibitors (ICIs) can successfully treat cancer,  but their use can be hindered by serious immune-related adverse events. We report  six patients receiving ICIs who presented with de novo myositis. METHODS: We  identified patients with myositis who were receiving ICIs between January 2004  and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS:  Six patients developed de novo myositis. The mean age was 64.3 years and five  patients were male. Cancer types included melanoma, urothelial carcinoma, renal  cell carcinoma, and prostate cancer. ICI regimens included single-agent  ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and  ipilimumab (n = 3). The median time to development of de novo myositis from first  infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had  elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them   developed rhabdomyolysis, one with concurrent myocarditis. Five patients were  treated with 1-2mg/kg corticosteroids, with variable response rates; one patient   received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as  a result of cancer progression. CONCLUSION: We found several occurrences of de  novo myositis following ICI therapy. These preliminary data suggest that myositis  can occur early after onset of ICI therapy with serious adverse outcomes.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001834	29914537	Case report	Malignant melanoma with Hashimoto's disease and diabetes mellitus	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	It might be important to be aware of the possibility of thyroid storm induced by immune checkpoint inhibitors.	Thyroid storm	N/A	N/A	N/A	N/A	N/A	 2018 Jun 19	 Combination therapy of ipilimumab and nivolumab induced thyroid storm in a  patient with Hashimoto's disease and diabetes mellitus: a case report.	 J Med Case Rep	 BACKGROUND: Recently, immune checkpoint inhibitors have widely been used for the   management of advanced melanoma. However, high-grade immune-related adverse  events can occur, particularly with combination immunotherapy. We report a case  of a patient with melanoma who developed thyroid storm following treatment with  ipilimumab and nivolumab. CASE PRESENTATION: An 85-year-old Japanese man with a  history of malignant melanoma presented to our department with severe  thyrotoxicosis and poor blood glucose control. He was already being treated for  Hashimoto's disease and type 2 diabetes mellitus before the treatment for the  melanoma. During admission, laboratory investigations revealed the following  thyroid functions: thyroid-stimulating hormone below sensitivity, free  triiodothyronine 31.7 pg/ml, and thyroglobulin 48,000 IU/ml. Thyroid-stimulating   hormone receptor antibody was negative, and a (99m)Tc-labeled thyroid scan  revealed a markedly decreased uptake. He was treated with beta-blocker, orally  administered potassium iodine, a relatively low dose of prednisolone, and insulin  injection therapy to control his blood glucose, resulting in an improvement in  thyroid function and his symptoms. CONCLUSION: It might be important to be aware   of the possibility of thyroid storm induced by immune checkpoint inhibitors.
CANIT0001835	29915891	Clinical research	Advanced or metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	A retrospective cohort study	African Americans patients with advanced or metastatic NSCLC on Nivolumab had increased  overall survival and progression-free survival with similar grade 3 or 4 treatment-related adverse events. Providing adequate access to immunotherapy is indispensable to maximize survival benefit for AA patients.	Treatment-related adverse events of grade 3 or 4 were reported in 8 and 10% in all patients and African Americans (AA), respectively, similar to the rates previously shown. AA patients with advanced or metastatic NSCLC on Nivolumab had increased overall survival and progression-free survival with similar grade 3 or 4 treatment-related adverse events.	N/A	N/A	N/A	N/A	N/A	 2018 Jun 18	 Clinical outcomes of African American patients with advanced or metastatic  non-small cell lung cancer on Nivolumab in a single community-based cancer  center.	 Med Oncol	 African Americans (AA) have the highest incidence and mortality rates with lung  cancer. They are diagnosed at an earlier age with more advanced disease.  Programmed cell death protein-1 inhibitor, Nivolumab, was approved as a  second-line agent after failure of platinum-based therapy for advanced or  metastatic non-small cell lung cancer (NSCLC). The original studies leading to  the approval of Nivolumab had insufficient AA patients, thus there is still  inadequate knowledge on treatment outcomes among AA patients. Our primary study  endpoints were to determine the median overall survival, 1-year overall survival   rate, median progression-free survival, and 1-year progression-free survival rate  of patients with advanced or metastatic non-small cell lung cancer on Nivolumab.   Our secondary study endpoints were to determine the overall tumor response rate,   median time to response, median duration of response, and incidence of  treatment-related adverse events of grade 3 or 4. In this retrospective study, we  reviewed the charts of 38 patients, 29 of which were AA, with advanced or  metastatic NSCLC who received Nivolumab from March 1, 2015 until November 30,  2017 from a single community-based cancer center and compared our results with  historical data. Adenocarcinoma was the most common histology (71%) among all  patients. Seven (18%) continued to use Nivolumab while 21 (55%) discontinued the   treatment mainly due to progression of the disease. The median overall survival  was 21.4 months (95% CI 13.5-27.4) and 17.6 months (95% CI 11.5-27.6) for all the  patients and AA, respectively. Both have statistically significant difference (P   < 0.001) compared to the historical studies of Borghaei et al. and Brahmer et al.  At 1 year, the overall survival rate was 73% (95% CI 50-86) and 66% (95% CI  40-82) for all patients and AA, respectively. The median progression-free  survival was also statistically significant (P < 0.001) between all the patients   6.3 months (95% CI 2.8-8), AA 6.0 months (95% CI 2.3-8.0), and the said  historical studies. The 1-year progression-free survival rate was 23% (95% CI  10-39) and 28% (95% CI 12-47) for all patients and AA, respectively. Overall  tumor response rate which includes complete and partial responses was 21% (95% CI  10-37) and 24% (95% CI 10-43) for all patients and AA, respectively. The median  time to response was 3 and 2.8 months for all patients and AA, respectively. The   median duration of response was 3.8 and 4.0 months for all patients and AA,  respectively. Treatment-related adverse events of grade 3 or 4 were reported in 8  and 10% in all patients and AA, respectively, similar to the rates previously  shown. AA patients with advanced or metastatic NSCLC on Nivolumab had increased  overall survival and progression-free survival with similar grade 3 or 4  treatment-related adverse events. Providing adequate access to immunotherapy is  indispensable to maximize survival benefit for AA patients.
CANIT0001836	29916989	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	N/A	Painful acute thyroiditis	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Painful acute thyroiditis following a first cure of Ipilimumab plus Nivolumab for  metastatic melanoma.	 Melanoma Res	Unable to provide
CANIT0001837	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001838	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001839	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001840	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001841	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001842	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001843	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001844	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001845	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001846	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001847	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001848	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001849	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Triple-negative breast cancer	EFO:0005537	Breast	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001850	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Triple-negative breast cancer	EFO:0005537	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001851	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001852	29922039	Clinical research	Melanoma, Urothelial carcinoma, renal cell carcinoma, Hepatocellular carcinoma, Triple-negative breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, small cell lung carcinoma etc.	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5088	N/A	A meta-analysis	The risks of PD-1 inhibitor-related hematologic toxicities were higher in renal cell carcinoma (RCC)  than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.	Hematologic toxicities	N/A	N/A	N/A	N/A	N/A	2018	 Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer   patients: a meta-analysis of current studies.	 Drug Des Devel Ther	 Background: Programmed cell death-1 (PD-1) inhibitor-related hematologic  toxicities are a category of rare but clinically serious and potentially  life-threatening adverse events; however, little is known about their risks  across different treatment regimens and tumor types. The objective of this study   was to compare the incidences of PD-1 inhibitor-related hematologic toxicities  among different therapeutic regimens and tumor types. Methods: Twenty-six  original articles on PD-1 inhibitor trials were identified based on a PubMed  search completed on September 26, 2017. The incidences of hematologic toxicities   were collected. Results: A total of 26 studies containing 5,088 patients were  included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an   increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%),  particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%),  compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95%   CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of  high-grade hematologic toxicities were observed in cancer patients treated with  PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with  ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than  PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%),  thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia  (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In  addition, all-grade and high-grade hematologic toxicities in chemotherapy and  everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy  arms. Conclusion: The risks of PD-1 inhibitor-related hematologic toxicities were  higher in RCC than in other cancers, and during combination therapy. These  results may contribute toward enhancing awareness among clinicians about frequent  clinical monitoring when managing PD-1 inhibitors.
CANIT0001853	29923635	Case report	Dabrafenib and trametinib therapy-failed advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	Two cases of dabrafenib and trametinib therapy-failed advanced melanoma successfully controlled by nivolumab monotherapy. 	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Sep	 Two cases of dabrafenib and trametinib therapy-failed advanced melanoma  successfully controlled by nivolumab monotherapy.	 J Dermatol	 Although therapies for advanced melanoma have been greatly improved by the  development of immune checkpoint inhibitors and BRAF/mitogen-activated protein  kinase kinase inhibitors, there are still many concerns about the administration   of these novel drugs. Therefore, to combine these therapies sequentially at  appropriate time points of the disease is important. In this report, we report  two cases in which dabrafenib and trametinib therapy for advanced melanoma failed  but were successfully controlled by nivolumab monotherapy, and investigated the  sera sCD163, CCL22 and CXCL10 as biomarkers for tumor progression. Interestingly,  the sera levels of sCD163, CXCL10 and CCL22, both of which are produced by  activated tumor-associated macrophages, were increased in parallel with the tumor  progression in each case. Because this report presents only two cases, further  data will need to be accumulated to provide more fundamental insights into the  usefulness of these biomarkers for predicting disease progression in melanoma.CI  - (c) 2018 Japanese Dermatological Association.
CANIT0001854	29936475	Clinical research	Lung tumors	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A multicentre, retrospective cohort study	IAOT was strongly associated with the occurrence of ILD after therapy with nivolumab.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jul-Aug	 Association Between Imaging Findings of Airway Obstruction Adjacent to Lung  Tumors and the Onset of Interstitial Lung Disease After Nivolumab.	 In Vivo	 BACKGROUND: Compared to conventional cytotoxic chemotherapy, immune checkpoint  inhibitors have shown a significant efficacy in the treatment of lung cancer.  Although interstitial lung disease (ILD) is an important adverse event in  immunotherapy, risk factors for ILD remain unclear. PATIENTS AND METHODS: In this  multicenter cohort study (UMIN000025908), 201 patients who were treated with  nivolumab were retrospectively reviewed. Associations between the incidence of  ILD and patient characteristics were evaluated. ILD grade and progression-free  survival were analyzed according to the presence or absence of imaging findings  of airway obstruction adjacent to lung tumors (IAOT). RESULTS: In the  multivariate analysis, the odds ratio (OR) of ILD for patients with a history of   radiation pneumonitis or IAOT was 3.96 (p=0.012) and 6.59 (p=0.004),  respectively. ILD occurred in six (37.5%) out of 16 patients with IAOT and 19  (10.3%) out of 185 patients without IAOT. Three out of the six patients with ILD   and IAOT had ILD of grade 4 or more. The median progression-free survival of  patients with and without IAOT was 0.9 and 3.2 months, respectively (p<0.001).  CONCLUSION: IAOT was strongly associated with the occurrence of ILD after therapy  with nivolumab.CI  - Copyright(c) 2018, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001855	29946908	Case report	Classical Hodgkin lymphoma (HL), mixed cellularity type	Classic hodgkin lymphoma	MONDO:0009348	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	In our case, blockade of PD-1 may have accelerated   T cell clonal proliferation occurring during prolonged HL-associated inflammation.We assumed that overactivated T cell-mediated immune responses triggered by PD-1 inhibitor led to the patients severe inflammatory condition and aggressive clinical course. PD-1 blockade is a promising therapeutic approach for refractory malignancies, but attention should be paid to secondary T cell lymphoma as well as autoimmune-related events.	Autoimmune-related events	N/A	N/A	N/A	N/A	N/A	 2019 Jan	 gammadelta T cell clonal proliferation early after PD-1 blockade.	 Ann Hematol	Unable to provide
CANIT0001856	29948463	Case report	Small cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	Acute cerebellitis after administration of nivolumab and ipilimumab	A 57-year-old man with SCLC who previously received four cycles of cisplatin and irinotecan was treated with nivolumab and ipilimumab in a clinical trial. The day after the fifth cycle (56 days after the first administration of ICIs), the patient developed staggering, diplopia, and dysarthria. The scheduled sixth administration was canceled, and the patient was referred to our hospital 10 days after the onset. Neurological examination revealed ocular dysmetria, gaze-evoked nystagmus, scanning speech, and limb and truncal ataxia.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	 Acute cerebellitis after administration of nivolumab and ipilimumab for small  cell lung cancer.	 Neurol Sci	Unable to provide
CANIT0001857	29948466	Case report	Metastatic malign melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Our patient had unfavorable disease course after treatment but more data are needed to determine the risks of ipilimumab on long-term prognosis of known myasthenia gravis.	Myasthenic crises 	N/A	N/A	N/A	N/A	N/A	 2018 Oct	 Ipilimumab treatment associated with myasthenic crises and unfavorable disease  course.	 Neurol Sci	 Ipilimumab, a monoclonal antibody targeting the cytotoxic T lymphocyte antigen-4   is a treatment option for metastatic melanoma. This receptor serves as an  inhibitor receptor on T lymphocytes and blockage of these results predisposition   to autoimmune diseases. The patients with autoimmune disorders were excluded in  clinical trials and there is no sufficient data of the treatment on these  patients who already have an autoimmune disorder. Here, we report a case of  myasthenia gravis who was treated with ipilimumab and we presented the long-term   prognosis of the patient after treatment.
CANIT0001858	29948974	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	22	N/A	Retrospective analysis	The finding that absolute lymphocyte counts (ALC) at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. The result that the previous radiation is associated with lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2019 Feb	 The absolute lymphocyte count can predict the overall survival of patients with  non-small cell lung cancer on nivolumab: a clinical study.	 Clin Transl Oncol	 INTRODUCTION: The neutrophil-to-lymphocyte (ANC/ALC) ratio is associated with  worse prognosis in patients with NSCLC on immunotherapies, but the role of ALC  remains unclear. The previous radiation therapy causes lymphopenia, and given  approaches of combining radiation with immunotherapies, it is critical to better   understand the impact of peripheral lymphocytes. PATIENTS AND METHODS: We  evaluated retrospectively 22 patients with advanced NSCLC treated with nivolumab   at Boston Medical Center from January 2014 to September 2016 and correlated the  peripheral blood counts with the overall survival (OS) and overall time on  treatment. We assessed the effect of the previous radiation on peripheral blood  counts and clinical outcomes. RESULTS: Baseline ALC and ANC/ALC ratios are  positively and negatively correlated, respectively, with the OS on nivolumab. The  ALC and ALC/WBC ratios at 6 weeks on treatment are positively associated with the  OS. Kaplan-Meier analysis at baseline and at 6 weeks showed significantly  increased OS in the group of patients with the highest ALC. The previous  radiation therapy was positively correlated with the ANC and negatively  correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab.  CONCLUSION: Our finding that ALC at baseline and at 6 weeks on treatment is  positively correlated with the OS provides an easily obtained predictive marker.   Our result that the previous radiation is associated with higher ANC and lower  ALC during treatment supports that the combination of radiation therapy with  immunotherapy should be carefully applied and potentially peripheral blood counts  can be utilized to stratify patients for this approach.
CANIT0001859	29959458	Basic research	Advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy	Hepatocellular carcinoma	EFO:0000182	Liver	CTLA-4 (P16410); 	CTLA-4; 	Anti-CTLA-4 9H10	N/A	Immune checkpoint therapy	Anti-CTLA-4 9H10 (NCIT:C128036); 	Cell lines/ animal models	N/A	Basic research	Inhibiting IDO in combination with immune checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO and should be considered for clinical evaluation in HCC.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	IDO1 (P14902); 	IDO1 expression levels in tumor cells	Gene expression signature on/in tumor cell	 2018 Aug	 Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint  inhibitors in hepatocellular carcinoma.	 Cancer Immunol Immunother	 Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related  death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1  antibodies has shown promising results in the treatment of patients with advanced  HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had  progressive disease on the current standard of care. However, a subset of  patients with advanced HCC treated with immune checkpoint inhibitors failed to  respond to therapy. Here, we provide evidence of adaptive resistance to immune  checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO)  in HCC. Anti-CTLA-4 treatment promoted an induction of IDO1 in resistant HCC  tumors but not in tumors sensitive to immune checkpoint blockade. Using both  subcutaneous and hepatic orthotopic models, we found that the addition of an IDO   inhibitor increases the efficacy of treatment in HCC resistant tumors with high  IDO induction. Furthermore, in vivo neutralizing studies demonstrated that the  IDO induction by immune checkpoint blockade was dependent on IFN-gamma. Similar  findings were observed with anti-PD-1 therapy. These results provide evidence  that IDO may play a role in adaptive resistance to immune checkpoint inhibitors  in patients with HCC. Therefore, inhibiting IDO in combination with immune  checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO  and should be considered for clinical evaluation in HCC.
CANIT0001860	29959458	Basic research	Advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	RMP1-14	N/A	Immune checkpoint therapy	RMP1-14 (NCIT:C128037); 	Cell lines/ animal models	N/A	Basic research	Inhibiting IDO in combination with immune checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO and should be considered for clinical evaluation in HCC.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	IDO1 (P14902); 	IDO1 expression levels in tumor cells	Gene expression signature on/in tumor cell	 2018 Aug	 Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint  inhibitors in hepatocellular carcinoma.	 Cancer Immunol Immunother	 Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related  death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1  antibodies has shown promising results in the treatment of patients with advanced  HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had  progressive disease on the current standard of care. However, a subset of  patients with advanced HCC treated with immune checkpoint inhibitors failed to  respond to therapy. Here, we provide evidence of adaptive resistance to immune  checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO)  in HCC. Anti-CTLA-4 treatment promoted an induction of IDO1 in resistant HCC  tumors but not in tumors sensitive to immune checkpoint blockade. Using both  subcutaneous and hepatic orthotopic models, we found that the addition of an IDO   inhibitor increases the efficacy of treatment in HCC resistant tumors with high  IDO induction. Furthermore, in vivo neutralizing studies demonstrated that the  IDO induction by immune checkpoint blockade was dependent on IFN-gamma. Similar  findings were observed with anti-PD-1 therapy. These results provide evidence  that IDO may play a role in adaptive resistance to immune checkpoint inhibitors  in patients with HCC. Therefore, inhibiting IDO in combination with immune  checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO  and should be considered for clinical evaluation in HCC.
CANIT0001861	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	32	N/A	A retrospective cohort study	Although baseline absolute neutrophil counts (ANCs) did not have any prognostic value, ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  4200/mm3 after first dose were more likely to respond than those with ANCs > 4200/mm3 (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of ANC before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001862	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab followed by nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	32	N/A	A retrospective cohort study	Although baseline absolute neutrophil counts (ANCs) did not have any prognostic value, ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  4200/mm3 after first dose were more likely to respond than those with ANCs > 4200/mm3 (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of ANC before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001863	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	32	N/A	A retrospective cohort study	Although baseline absolute neutrophil counts (ANCs) did not have any prognostic value, ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  4200/mm3 after first dose were more likely to respond than those with ANCs > 4200/mm3 (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of ANC before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001864	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	32	N/A	A retrospective cohort study	Higher pre-therapy absolute monocyte counts (AMCs) correlated to shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of responders, those with AMCs > 700/mm3 had a significantly shorter median TTR than those with AMCs  700/mm3 (8 weeks vs 12 weeks; p = 0.048). Analysis of AMC  before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy.	N/A	N/A	N/A	Monocyte counts (NCIT:C12547); 	Absolute monocyte counts	Cell percentage/counts in blood	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001865	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	32	N/A	A retrospective cohort study	There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001866	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	32	N/A	A retrospective cohort study	There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001867	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	32	N/A	A retrospective cohort study	There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders.	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001868	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab followed by nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	32	N/A	A retrospective cohort study	Higher pre-therapy absolute monocyte counts (AMCs) correlated to shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of responders, those with AMCs > 700/mm3 had a significantly shorter median TTR than those with AMCs  700/mm3 (8 weeks vs 12 weeks; p = 0.048). Analysis of AMC  before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy.	N/A	N/A	N/A	Monocyte counts (NCIT:C12547); 	Absolute monocyte counts	Cell percentage/counts in blood	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001869	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab followed by nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	32	N/A	A retrospective cohort study	There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001870	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab followed by nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	32	N/A	A retrospective cohort study	There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001871	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab followed by nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	32	N/A	A retrospective cohort study	There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders.	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001872	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	32	N/A	A retrospective cohort study	Higher pre-therapy absolute monocyte counts (AMCs) correlated to shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of responders, those with AMCs > 700/mm3 had a significantly shorter median TTR than those with AMCs  700/mm3 (8 weeks vs 12 weeks; p = 0.048). Analysis of AMC  before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy.	N/A	N/A	N/A	Monocyte counts (NCIT:C12547); 	Absolute monocyte counts	Cell percentage/counts in blood	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001873	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	32	N/A	A retrospective cohort study	There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001874	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	32	N/A	A retrospective cohort study	There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001875	29968154	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	32	N/A	A retrospective cohort study	There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders.	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2018 Sep	 Peripheral monocytes and neutrophils predict response to immune checkpoint  inhibitors in patients with metastatic non-small cell lung cancer.	 Cancer Immunol Immunother	 We carried out a retrospective cohort study on patients with metastatic non-small  cell lung cancer (mNSCLC) to identify the peripheral blood count parameters  associated with response to immune checkpoint inhibitors (ICIs). There were 17  males and 15 females. Their median age was 64.5 years (range 20-84). History of  smoking was present in 25/32 (78%) patients. Twelve patients received  pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by  pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial  responses. There was no difference in the distribution of sex, age, and smoking  status between responders and non-responders. The median time to response (TTR)  was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks   (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to  shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of  responders, those with AMCs > 700/mm(3) had a significantly shorter median TTR  than those with AMCs </= 700/mm(3) (8 weeks vs 12 weeks; p = 0.048). Although  baseline absolute neutrophil counts (ANCs) did not have any prognostic value,  ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs  </= 4200/mm(3) after first dose were more likely to respond than those with ANCs   > 4200/mm(3) (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC  before and during therapy may, therefore, provide an easy method to identify  those mNSCLC patients most likely to benefit from ICI therapy.
CANIT0001876	29970025	Clinical research	Advanced melanoma after BRAF inhibitor failure	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	74	N/A	N/A	Anti-PD-1 was less effective in BRAF-mutated cases (n=41) as a majority of patients presented aggressive tumor evolution after BRAFi discontinuation. These data are consistent with previous studies suggesting a negative impact of BRAFi prior to immunotherapy.	N/A	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2018 Jul 3	 Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma.	 BMC Cancer	 BACKGROUND: Anti-PD-1 and BRAF-inhibitors (BRAFi) have been approved as  first-line treatments in advanced melanoma. To date, no prospective data are  available to give the best sequence of treatment. The objective of this study was  to evaluate in real-life the efficacy of anti-PD-1 after BRAFi, ipilimumab, or  chemotherapy failure. METHODS: This was a single institution cohort analysis in  patients treated with anti-PD-1 right after BRAFi, ipilimumab, or chemotherapy  failure. Melanoma evolution after anti-PD-1 initiation was analyzed in  BRAF-mutated and BRAF wild-type patients. The efficacy of treatment was evaluated  by Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free  Survival (PFS), and Overall Survival (OS). RESULTS: Seventy-four patients were  included: 33 wild-type and 41 BRAF-mutated melanoma. ORR to anti-PD-1 was  significantly lower in BRAF-mutated patients (12.2% vs. 45.5%, p = 0.002). After   anti-PD-1 initiation, the median PFS and OS was significantly shorter in the BRAF  mutated group (2 vs. 5 months and 7 vs. 20 months, p = 0.001). The hazard ratio  for disease progression was of 2.3 (95%CI:1.3-3.9; p = 0.003) and 2.5  (95%CI:1.3-4.5; p = 0.005) for death. Thirty-nine percent of  BRAF-mutated-patients died within 3 months after anti-PD-1 initiation. Rapid  death (</=3 months) was significantly higher in BRAF-mutated patients (55.2% vs.   20.0%, p = 0.014). DISCUSSION: This is the largest series of unselected patients   treated in real-life with anti-PD-1 as second-or-higher line of treatment.  Anti-PD-1 was less effective in BRAF-mutated cases as a majority of patients  presented aggressive tumor evolution after BRAFi discontinuation. These data are   consistent with previous studies suggesting a negative impact of BRAFi prior to  immunotherapy.
CANIT0001877	29970876	Case report	Malignant pleural mesothelioma	Pleural mesothelioma	EFO:1000485	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Good outcome	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jul 4	 Nivolumab Immunotherapy in Malignant Mesothelioma: A Case Report Highlighting a  New Opportunity for Exceptional Outcomes.	 Am J Case Rep	 BACKGROUND Malignant pleural mesothelioma (MPM) is a highly lethal cancer with a   median survival of ~12 months even with aggressive intervention. Frontline  therapy relies on systemic cisplatin and pemetrexed chemotherapy and has a  response rate of ~35-41%; currently, there are no US Food and Drug Administration  approved second-line therapies for MPM. Herein, we present a patient with MPM who  experienced rapid disease progression after standard therapy but who had an  exceptional and sustained response to immune checkpoint inhibition with single  agent nivolumab. CASE REPORT A 68-year-old male with a history of work-related  asbestos exposure was diagnosed with MPM. He was treated with primary resection  followed by systemic chemotherapy with cisplatin and pemetrexed. When  chemotherapy failed, he was switched to immunotherapy with nivolumab and achieved  an exceptional response. CONCLUSIONS We report the first case of a patient with  MPM who experienced rapid disease progression after standard therapy but had an  exceptional and sustained response to immune checkpoint inhibition with single  agent nivolumab. As outcomes with traditional chemotherapy regimens remain  disappointing, there is a substantial need for new approaches to MPM; our case  highlights a new therapeutic opportunity even in the face of aggressive disease.   Indeed, a new era of investigation utilizing immunotherapy for mesothelioma is  beginning, with much anticipation.
CANIT0001878	29978949	Case report	Squamous cancer (SqCC) of the lung 	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus nab-paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); nab-paclitaxel (DB01229); 	1	N/A	Case	During treatment of this case, we advocated the early control of pleural effusion as an indicator for pseudoprogression. Our experience might be helpful to identify pseudoprogression for the clinical management of immunotherapy.	N/A	N/A	N/A	Pleural effusion (NCIT:C3331); 	Pleural effusion	Disease status	 2018 Sep	 Well-controlled pleural effusion indicated pseudoprogression after immunotherapy   in lung cancer: A case report.	 Thorac Cancer	 Squamous cancer (SqCC) of the lung has a poor prognosis. With the advent of  immunotherapy, prognosis has tended to improve; however, pseudoprogression poses   a challenge to the management of immunotherapy. Herein, we discuss the case of a   47-year-old heavy smoker with advanced SqCC. The patient had recurrent disease  after initial successful control of the tumor by concurrent radiochemotherapy,  together with ample pleural effusion. Pleural effusion was well controlled with  systematic nivolumab and intra-thoracic recombinant endostatin; however with  simultaneous deterioration of performance and tumor progression. Nivolumab was  maintained with the addition of nab-paclitaxel. The combination soon led to a  partial response and rapid improvement of the patient's performance. During  treatment of this case, we advocated the early control of pleural effusion as an   indicator for pseudoprogression. Our experience might be helpful to identify  pseudoprogression for the clinical management of immunotherapy.CI  - (c) 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and   John Wiley & Sons Australia, Ltd.
CANIT0001879	29979712	Clinical research	Elderly patients with metastatic renal cell carcinoma 	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	389	N/A	A phase III clinical trial	The final results suggest that elderly patients with pretreated metastatic RCC may benefit from therapy with nivolumab.	N/A	N/A	N/A	N/A	N/A	N/A	2018	 Efficacy and safety data in elderly patients with metastatic renal cell carcinoma  included in the nivolumab Expanded Access Program (EAP) in Italy.	 PLoS One	 BACKGROUND: Results from phase III clinical trial CheckMate 025 have established   nivolumab as the standard of care for treatment of metastatic renal-cell  carcinoma (mRCC) after VEGF inhibitor failure; however, elderly patients are  under-represented in the registration trial and little is known about the  activity of nivolumab in this subgroup. The purpose of the Expanded Access  Program was to provide nivolumab to patients with mRCC who had progressed despite  treatment with other agents that were considered standard of care. METHODS:  Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24  months or until progression or unacceptable toxicity. The current analysis  included all patients from the EAP Italian cohort who had received >/=1 dose of  nivolumab. Adverse events (AEs) were monitored using Common Terminology Criteria   for Adverse Events v4.0. RESULTS: A total of 389 patients with advanced RCC were   enrolled in the Italian cohort of the EAP and treated with nivolumab. Of these  patients, 125 (32%) were at least 70 years of age and 70 (18%) were at least 75  years of age. Efficacy with nivolumab in the elderly patients was similar to that  observed in the overall EAP population and in the CheckMate 025 trial. Safety was  comparable between the elderly patients and the overall EAP population, and was  consistent with what previously reported. CONCLUSION: The final results suggest  that elderly patients with pretreated metastatic RCC may benefit from therapy  with nivolumab.
CANIT0001880	29995236	Case report	NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Our case study indicates that fulminant hyperglycemia can occur extremely rapidly. The blood glucose of patients receiving PD-1 antibody therapy should be closely monitored.	Fulminant type 1 diabetes	N/A	N/A	N/A	N/A	N/A	 2018 Sep	 Fulminant onset of insulin-dependent diabetes with positive anti-GAD antibody  titers during treatment with nivolumab in a patient with NSCLC.	 Cancer Immunol Immunother	 Programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1)  inhibitors have been highlighted in the field of cancer treatment. The  interaction between PD-1 and PD-L1 is thought to play an important role in the  regulation of the self-immune tolerance mechanism, so blocking these molecules  may cause serious immune-related adverse events (IrAE), including fulminant  insulin-dependent (type 1) diabetes. Here, we describe a patient with fulminant  type 1 diabetes induced by nivolumab, an anti-PD-1 antibody. The patient, a  78-year-old man, was being treated with nivolumab as a third-line treatment for  squamous cell carcinoma of the lung. After three cycles, he experienced an abrupt  flare-up of the blood glucose within half a day. His blood glucose further  increased without clinical symptoms until his hospital visit. Laboratory data  showed the complete exhaustion of intrinsic insulin and the elevation of serum  antibody titer to glutamic acid decarboxylase (GAD). Although the patient was  previously diagnosed with non-insulin-dependent (type 2) diabetes, his disease  activity had been well controlled with oral medication and low-dose insulin  therapy until just before the flare-up. Because of the laboratory findings and  the extremely rapid onset of hyperglycemia, a diagnosis of fulminant, rather than  the rapid onset, type 1 diabetes related to nivolumab therapy was strongly  suspected. Our case study indicates that fulminant hyperglycemia can occur  extremely rapidly. The blood glucose of patients receiving PD-1 antibody therapy   should be closely monitored.
CANIT0001881	29996818	Case report	Advanced squamous cell carcinoma of the cervix	Cervical squamous cell carcinoma	EFO:1000172	Cervix	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Durvalumab plus cediranib	N/A	Immune checkpoint therapy plus Target therapy	Cediranib (DB04849); durvalumab (DB11714); 	1	N/A	Case	A 45-year-old woman with advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and evidence of right heart failure during a phase I clinical trial with cediranib and durvalumab. After an extensive evaluation, pre-capillary pulmonary hypertension was confirmed by right heart catheterization. Vasodilator therapy was initiated but resulted in the development of symptomatic hypoxemia and was discontinued. Despite continued supportive care, she continued to decline and was transitioned to hospice care. At autopsy, the cause of her right heart failure was found to be due to PTTM with features of pulmonary veno-occlusive disease (PVOD).	PTTM and PVOD are important diagnoses to consider in patients with a malignancy and the development of right heart failure and may be manifestations of a spectrum of similar disease processes.	N/A	N/A	N/A	N/A	N/A	 2018 Jul 11	 Pulmonary tumor thrombotic microangiopathy and pulmonary veno-occlusive disease  in a woman with cervical cancer treated with cediranib and durvalumab.	 BMC Pulm Med	 BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of   pulmonary hypertension that is associated with malignancies and is marked by the   presence of non-occlusive tumor emboli and fibrocellular intimal proliferation of  small pulmonary arteries leading to increased pulmonary vascular resistance and  right heart failure. The diagnosis of PTTM is challenging to make pre-mortem and   guidelines on treatment are lacking. CASE PRESENTATION: A 45-year-old woman with   advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and   evidence of right heart failure during a phase I clinical trial with cediranib  and durvalumab. After an extensive evaluation, pre-capillary pulmonary  hypertension was confirmed by right heart catheterization. Vasodilator therapy  was initiated but resulted in the development of symptomatic hypoxemia and was  discontinued. Despite continued supportive care, she continued to decline and was  transitioned to hospice care. At autopsy, the cause of her right heart failure  was found to be due to PTTM with features of pulmonary veno-occlusive disease  (PVOD). CONCLUSION: PTTM and PVOD are important diagnoses to consider in patients  with a malignancy and the development of right heart failure and may be  manifestations of a spectrum of similar disease processes.
CANIT0001882	30002209	Case report	Metastatic Merkel-cell carcinoma	Merkel cell skin cancer	EFO:1001471	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Complete response maintained for at least 19 months, no clinical or radiological evidence of recurrence and treatment is ongoing	Quality of life was unaffected, and toxicity from immunotherapy was minimal.	N/A	N/A	N/A	N/A	N/A	 2018 Jul 11	 Metastatic Merkel-cell carcinoma: the dawn of a new era.	 BMJ Case Rep	 Merkel-cell carcinoma (MCC) is a rare but aggressive cutaneous malignancy arising  most often in sun-exposed Caucasians who are immunosuppressed or the elderly.  Patients with metastatic disease treated with chemotherapy have a median  progression-free survival of just 3 months. This report describes a 58-year-old  man with a background history of psoriasis treated with immunosuppressive therapy  and subsequently diagnosed with metastatic MCC. Chemotherapy produced a partial  response. Then, a novel immunotherapy agent, pembrolizumab, induced a complete  response maintained for at least 19 months. Quality of life was unaffected, and  toxicity from immunotherapy was minimal. At the time of writing, there was no  clinical or radiological evidence of recurrence and treatment is ongoing.CI  - (c) BMJ Publishing Group Limited 2018. No commercial re-use. See rights and  permissions. Published by BMJ.
CANIT0001883	30005106	Case report	Lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Physicians should be aware of the possibility of severe mucositis in the setting of PD-1 inhibitors, as well as the management.	Severe oral mucositis	N/A	N/A	N/A	N/A	N/A	 2018 Jul 1	 Severe Oral Mucositis: A Rare Adverse Event of Pembrolizumab.	 J Drugs Dermatol	 Treatment of malignancy with anti-programmed cell death 1 (PD-1) immune  checkpoint inhibitors can cause mucocutaneous side effects resulting from T cell   activation. Due to their recent development, the full side effect profile remains  to be fully elucidated, however dermatologic adverse events are most common. The   main oral toxicities of these immune checkpoint inhibitors include: xerostomia,  dysgeusia, and lichenoid reactions. Oral mucositis occurs more rarely in the  setting of PD-1 inhibition, and few other reports of a Grade 3 or higher, severe,  stomatitis have been reported in the literature. We present a case of a  78-year-old woman with Grade 3 ulcerative oral mucositis that occurred 13 months   after initiation of PD-1 inhibitor, pembrolizumab, for the treatment for lung  adenocarcinoma. She was successfully treated with prednisone, and pembrolizumab  was temporarily held by her oncologist. Physicians should be aware of the  possibility of severe mucositis in the setting of PD-1 inhibitors, as well as the  management. J Drugs Dermatol. 2018;17(7):807-809.
CANIT0001884	30005183	Clinical research	Melanoma and chronic lymphocytic leukemia	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus dacarbazine	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); dacarbazine (DB00851); 	4	N/A	N/A	In patients with metastatic melanoma, combined treatment with targeted kinase inhibitors and ICIs can be successful and tolerable.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Management of melanoma in patients with chronic lymphocytic leukemia.	 Leuk Res	 Melanoma is significantly more common and is associated with a poorer prognosis  in patients with an underlying B-cell malignancy. This study reports on the  management of patients with chronic lymphocytic leukemia/small lymphocytic  lymphoma (CLL) and a subsequent diagnosis of melanoma. In the Wilmot Cancer  Institute CLL cohort, which includes 470 patients followed for 2849 person-years,  18 patients (3.8%) developed 22 melanomas. Fourteen melanomas were invasive, a  significantly higher rate as compared with the age and sex matched general  population (standardized incidence ratio [SIR] 6.32 (95% CI 3.45; 10.60).  Melanomas were most often detected (n=15; 68.2%) through active surveillance in a  dermatology clinic. Most melanomas (n=17; 77.3%) were detected at a non-advanced   stage (pathological stage grouping<III). The most common management was wide  local excision without sentinel lymph node biopsy (n=13, 59.1%). Management for  the 4 (18.2%) patients with metastatic disease included the immune checkpoint  inhibitor (ICI) pembrolizumab (n=1), systemic chemotherapy with dacarbazine  (n=1), and palliative care (n=2). The patient treated with ICI is in sustained  remission of her melanoma after 23 cycles of therapy while her TP53 disrupted CLL  continues to respond to ibrutinib therapy. We conclude that patients with CLL may  benefit from active surveillance for melanoma leading to early excision of  locally-manageable disease. In patients with metastatic melanoma, combined  treatment with targeted kinase inhibitors and ICIs can be successful and  tolerable. Larger prospective studies should be considered to further evaluate  these approaches.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001885	30008296	Case report	Lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	While alectinib might induce resistance to ALK-TKI, it could increase PD-L1 positive cells to become sensitive to PD-1/PD-L1 inhibitors.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jul	 A successful pembrolizumab treatment case of lung adenocarcinoma after becoming  resistant to ALK-TKI treatment due to G1202R mutation.	 Respir Investig	 BACKGROUND: In current guidelines, the role of immune checkpoint inhibitors is  not yet determined in the treatment strategy for NSCLC harboring ALK  translocations. CASE: A 51-year-old woman with lung adenocarcinoma harboring ALK   translocation was treated with alectinib until PD. After the second (CDDP/PEM)  and third (crizotinib) line treatment, a second biopsy was performed, revealing  PD-L1 tumor proportion score of 70-80% and G1202R mutation of ALK. Pembrolizumab   was selected for the fourth line, leading to PR for more than 6 months.  CONCLUSIONS: While alectinib might induce resistance to ALK-TKI, it could  increase PD-L1 positive cells to become sensitive to PD-1/PD-L1 inhibitors.CI  - Copyright (c) 2018 The Japanese Respiratory Society. Published by Elsevier B.V.  All rights reserved.
CANIT0001886	30012528	Clinical research	Muscle-invasive/Metastatic Bladder cancer	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus weekly hypofractionated radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Radiotherapy (NCIT:C15313); pembrolizumab (DB09037); 	5	N/A	A phase I clinical trial	Dose-limiting urinary toxicity with pembrolizumab plus weekly hypofractionated radiation rherapy in bladder cancer. This advise caution to those combining radiation therapy and immune checkpoint blockade (ICB), particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMB trial met the protocol-defined definition of dose-limiting toxicity and will be amended to reduce radiation therapy dose.	The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction.	N/A	N/A	N/A	N/A	N/A	 2018 Aug 1	 Dose-limiting Urinary Toxicity With Pembrolizumab Combined With Weekly  Hypofractionated Radiation Therapy in Bladder Cancer.	 Int J Radiat Oncol Biol Phys	 There is currently significant interest in the potential benefits of combining  radiation and immune checkpoint blockade (ICB) to stimulate both regional and  distant abscopal immune responses. In melanoma and lung cancer, patients who have  received radiation therapy during ICB appear to have prolonged survival. The  PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer)  (NCT02560636) is a phase I study to test the tolerability of a combination of  weekly radiation therapy with pembrolizumab in patients with metastatic or  locally advanced urothelial cancer of the bladder. In the first dose-cohort,  patients received pembrolizumab 100 mg 3-weekly, starting 2 weeks before  commencing weekly adaptive bladder radiation therapy to a dose of 36 Gy in 6  fractions. The first dose-cohort was stopped after 5 patients, having met the  predefined definition of dose-limiting toxicity. Three patients experienced grade  3 urinary toxicities, 2 of which were attributable to therapy. One patient  experienced a grade 4 rectal perforation. In view of these findings, the trial  has been paused and the protocol will be amended to reduce radiation therapy dose  per fraction. The authors advise caution to those combining radiation therapy and  ICB, particularly when radiation therapy is given at high dose per fraction for  pelvic tumours. The PLUMMB trial met the protocol-defined definition of  dose-limiting toxicity and will be amended to reduce radiation therapy dose.CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001887	30013322	Clinical research	Melanoma, pancreatic cancer, prostate cancer, spongioblastoma, non-small-cell carcinoma, and so on	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); GM-CSF (P04141); T/B-LYMPHOCYTE (N/A); 	CTLA-4 ;  GM-CSF ;  T/B-LYMPHOCYTE 	Ipilimumab plus GM-CSF	Ipilimumab	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386)	221	224	A meta-analysis	The combination of ipilimumab and GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate and progression-free survival among the cancer patients. Therefore, large-scale and well-designed studies are needed to summarize and analyze the data to draw a more convincing conclusion.	N/A	N/A	N/A	N/A	N/A	N/A	2018	 Comparisons of therapeutic efficacy and safety of ipilimumab plus GM-CSF versus  ipilimumab alone in patients with cancer: a meta-analysis of outcomes.	 Drug Des Devel Ther	 Background: Recent clinical studies have shown that initial therapy with combined  cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade and  granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapies  can enhance the antitumor efficacy of this approach. A key unanswered question is  whether systemic GM-CSF enhances CTLA-4 blockade. Thus, the objective of this  study was taking a meta-analysis of randomized controlled trials to compare the  effect of ipilimumab plus GM-CSF versus ipilimumab alone on overall response,  overall survival, and progression-free survival, as well as the risk of adverse  events (AEs) in patients with cancer. Materials and methods: Searches were made  in electronic databases PubMed and Embase, and conference abstracts published by   the American Society of Clinical Oncology from 2000 to 2017. Statistical analyses  were carried out using either random-effects or fixed-effects models according to  the heterogeneity of eligible studies. Results: Six trials comprising of 445  patients were included in the meta-analysis. Combination group was superior to  the ipilimumab alone in overall response rate, progression-free survival, and  overall survival rate (combined relative risk [RR]=1.34, 95% CI: 1.24-1.45,  P=0.09; combined hazard ratio [HR]=0.57, 95% CI: 0.32-1.02, P=0.06; combined  HR=0.70, 95% CI: 0.60-0.82, P<0.001). Patients with combination therapies had a  lower incidence of AEs including high-grade diarrhea (combined RR=0.27, 95% CI:  0.11-0.70, P=0.007), nausea (combined RR=0.25, 95% CI: 0.07-0.89, P=0.03),  colitis (combined RR=0.34, 95% CI: 0.13-0.86, P=0.02), and fatigue (combined  RR=0.91, 95% CI: 0.37-2.2.3, P=0.84) compared to the group having ipilimumab  alone. Conclusion: These data suggested that the combination of ipilimumab and  GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate   and progression-free survival among the cancer patients. Therefore, large-scale  and well-designed studies are needed to summarize and analyze the data to draw a   more convincing conclusion.
CANIT0001888	30013322	Clinical research	Melanoma, pancreatic cancer, prostate cancer, spongioblastoma, non-small-cell carcinoma, and so on	Non-small cell carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); GM-CSF (P04141); T/B-LYMPHOCYTE (N/A); 	CTLA-4 ;  GM-CSF ;  T/B-LYMPHOCYTE 	Ipilimumab plus GM-CSF	Ipilimumab	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386)	221	224	A meta-analysis	The combination of ipilimumab and GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate and progression-free survival among the cancer patients. Therefore, large-scale and well-designed studies are needed to summarize and analyze the data to draw a more convincing conclusion.	N/A	N/A	N/A	N/A	N/A	N/A	2018	 Comparisons of therapeutic efficacy and safety of ipilimumab plus GM-CSF versus  ipilimumab alone in patients with cancer: a meta-analysis of outcomes.	 Drug Des Devel Ther	 Background: Recent clinical studies have shown that initial therapy with combined  cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade and  granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapies  can enhance the antitumor efficacy of this approach. A key unanswered question is  whether systemic GM-CSF enhances CTLA-4 blockade. Thus, the objective of this  study was taking a meta-analysis of randomized controlled trials to compare the  effect of ipilimumab plus GM-CSF versus ipilimumab alone on overall response,  overall survival, and progression-free survival, as well as the risk of adverse  events (AEs) in patients with cancer. Materials and methods: Searches were made  in electronic databases PubMed and Embase, and conference abstracts published by   the American Society of Clinical Oncology from 2000 to 2017. Statistical analyses  were carried out using either random-effects or fixed-effects models according to  the heterogeneity of eligible studies. Results: Six trials comprising of 445  patients were included in the meta-analysis. Combination group was superior to  the ipilimumab alone in overall response rate, progression-free survival, and  overall survival rate (combined relative risk [RR]=1.34, 95% CI: 1.24-1.45,  P=0.09; combined hazard ratio [HR]=0.57, 95% CI: 0.32-1.02, P=0.06; combined  HR=0.70, 95% CI: 0.60-0.82, P<0.001). Patients with combination therapies had a  lower incidence of AEs including high-grade diarrhea (combined RR=0.27, 95% CI:  0.11-0.70, P=0.007), nausea (combined RR=0.25, 95% CI: 0.07-0.89, P=0.03),  colitis (combined RR=0.34, 95% CI: 0.13-0.86, P=0.02), and fatigue (combined  RR=0.91, 95% CI: 0.37-2.2.3, P=0.84) compared to the group having ipilimumab  alone. Conclusion: These data suggested that the combination of ipilimumab and  GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate   and progression-free survival among the cancer patients. Therefore, large-scale  and well-designed studies are needed to summarize and analyze the data to draw a   more convincing conclusion.
CANIT0001889	30013322	Clinical research	Melanoma, pancreatic cancer, prostate cancer, spongioblastoma, non-small-cell carcinoma, and so on	Pancreatic carcinoma	EFO:0002618	Pancreas	CTLA-4 (P16410); GM-CSF (P04141); T/B-LYMPHOCYTE (N/A); 	CTLA-4 ;  GM-CSF ;  T/B-LYMPHOCYTE 	Ipilimumab plus GM-CSF	Ipilimumab	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386)	221	224	A meta-analysis	The combination of ipilimumab and GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate and progression-free survival among the cancer patients. Therefore, large-scale and well-designed studies are needed to summarize and analyze the data to draw a more convincing conclusion.	N/A	N/A	N/A	N/A	N/A	N/A	2018	 Comparisons of therapeutic efficacy and safety of ipilimumab plus GM-CSF versus  ipilimumab alone in patients with cancer: a meta-analysis of outcomes.	 Drug Des Devel Ther	 Background: Recent clinical studies have shown that initial therapy with combined  cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade and  granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapies  can enhance the antitumor efficacy of this approach. A key unanswered question is  whether systemic GM-CSF enhances CTLA-4 blockade. Thus, the objective of this  study was taking a meta-analysis of randomized controlled trials to compare the  effect of ipilimumab plus GM-CSF versus ipilimumab alone on overall response,  overall survival, and progression-free survival, as well as the risk of adverse  events (AEs) in patients with cancer. Materials and methods: Searches were made  in electronic databases PubMed and Embase, and conference abstracts published by   the American Society of Clinical Oncology from 2000 to 2017. Statistical analyses  were carried out using either random-effects or fixed-effects models according to  the heterogeneity of eligible studies. Results: Six trials comprising of 445  patients were included in the meta-analysis. Combination group was superior to  the ipilimumab alone in overall response rate, progression-free survival, and  overall survival rate (combined relative risk [RR]=1.34, 95% CI: 1.24-1.45,  P=0.09; combined hazard ratio [HR]=0.57, 95% CI: 0.32-1.02, P=0.06; combined  HR=0.70, 95% CI: 0.60-0.82, P<0.001). Patients with combination therapies had a  lower incidence of AEs including high-grade diarrhea (combined RR=0.27, 95% CI:  0.11-0.70, P=0.007), nausea (combined RR=0.25, 95% CI: 0.07-0.89, P=0.03),  colitis (combined RR=0.34, 95% CI: 0.13-0.86, P=0.02), and fatigue (combined  RR=0.91, 95% CI: 0.37-2.2.3, P=0.84) compared to the group having ipilimumab  alone. Conclusion: These data suggested that the combination of ipilimumab and  GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate   and progression-free survival among the cancer patients. Therefore, large-scale  and well-designed studies are needed to summarize and analyze the data to draw a   more convincing conclusion.
CANIT0001890	30013322	Clinical research	Melanoma, pancreatic cancer, prostate cancer, spongioblastoma, non-small-cell carcinoma, and so on	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); GM-CSF (P04141); T/B-LYMPHOCYTE (N/A); 	CTLA-4 ;  GM-CSF ;  T/B-LYMPHOCYTE 	Ipilimumab plus GM-CSF	Ipilimumab	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386)	221	224	A meta-analysis	The combination of ipilimumab and GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate and progression-free survival among the cancer patients. Therefore, large-scale and well-designed studies are needed to summarize and analyze the data to draw a more convincing conclusion.	N/A	N/A	N/A	N/A	N/A	N/A	2018	 Comparisons of therapeutic efficacy and safety of ipilimumab plus GM-CSF versus  ipilimumab alone in patients with cancer: a meta-analysis of outcomes.	 Drug Des Devel Ther	 Background: Recent clinical studies have shown that initial therapy with combined  cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade and  granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapies  can enhance the antitumor efficacy of this approach. A key unanswered question is  whether systemic GM-CSF enhances CTLA-4 blockade. Thus, the objective of this  study was taking a meta-analysis of randomized controlled trials to compare the  effect of ipilimumab plus GM-CSF versus ipilimumab alone on overall response,  overall survival, and progression-free survival, as well as the risk of adverse  events (AEs) in patients with cancer. Materials and methods: Searches were made  in electronic databases PubMed and Embase, and conference abstracts published by   the American Society of Clinical Oncology from 2000 to 2017. Statistical analyses  were carried out using either random-effects or fixed-effects models according to  the heterogeneity of eligible studies. Results: Six trials comprising of 445  patients were included in the meta-analysis. Combination group was superior to  the ipilimumab alone in overall response rate, progression-free survival, and  overall survival rate (combined relative risk [RR]=1.34, 95% CI: 1.24-1.45,  P=0.09; combined hazard ratio [HR]=0.57, 95% CI: 0.32-1.02, P=0.06; combined  HR=0.70, 95% CI: 0.60-0.82, P<0.001). Patients with combination therapies had a  lower incidence of AEs including high-grade diarrhea (combined RR=0.27, 95% CI:  0.11-0.70, P=0.007), nausea (combined RR=0.25, 95% CI: 0.07-0.89, P=0.03),  colitis (combined RR=0.34, 95% CI: 0.13-0.86, P=0.02), and fatigue (combined  RR=0.91, 95% CI: 0.37-2.2.3, P=0.84) compared to the group having ipilimumab  alone. Conclusion: These data suggested that the combination of ipilimumab and  GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate   and progression-free survival among the cancer patients. Therefore, large-scale  and well-designed studies are needed to summarize and analyze the data to draw a   more convincing conclusion.
CANIT0001891	30013322	Clinical research	Melanoma, pancreatic cancer, prostate cancer, spongioblastoma, non-small-cell carcinoma, and so on	Spongioblastoma	EFO:1000488	Brain	CTLA-4 (P16410); GM-CSF (P04141); T/B-LYMPHOCYTE (N/A); 	CTLA-4 ;  GM-CSF ;  T/B-LYMPHOCYTE 	Ipilimumab plus GM-CSF	Ipilimumab	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); GM-CSF (DB05386)	221	224	A meta-analysis	The combination of ipilimumab and GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate and progression-free survival among the cancer patients. Therefore, large-scale and well-designed studies are needed to summarize and analyze the data to draw a more convincing conclusion.	N/A	N/A	N/A	N/A	N/A	N/A	2018	 Comparisons of therapeutic efficacy and safety of ipilimumab plus GM-CSF versus  ipilimumab alone in patients with cancer: a meta-analysis of outcomes.	 Drug Des Devel Ther	 Background: Recent clinical studies have shown that initial therapy with combined  cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade and  granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapies  can enhance the antitumor efficacy of this approach. A key unanswered question is  whether systemic GM-CSF enhances CTLA-4 blockade. Thus, the objective of this  study was taking a meta-analysis of randomized controlled trials to compare the  effect of ipilimumab plus GM-CSF versus ipilimumab alone on overall response,  overall survival, and progression-free survival, as well as the risk of adverse  events (AEs) in patients with cancer. Materials and methods: Searches were made  in electronic databases PubMed and Embase, and conference abstracts published by   the American Society of Clinical Oncology from 2000 to 2017. Statistical analyses  were carried out using either random-effects or fixed-effects models according to  the heterogeneity of eligible studies. Results: Six trials comprising of 445  patients were included in the meta-analysis. Combination group was superior to  the ipilimumab alone in overall response rate, progression-free survival, and  overall survival rate (combined relative risk [RR]=1.34, 95% CI: 1.24-1.45,  P=0.09; combined hazard ratio [HR]=0.57, 95% CI: 0.32-1.02, P=0.06; combined  HR=0.70, 95% CI: 0.60-0.82, P<0.001). Patients with combination therapies had a  lower incidence of AEs including high-grade diarrhea (combined RR=0.27, 95% CI:  0.11-0.70, P=0.007), nausea (combined RR=0.25, 95% CI: 0.07-0.89, P=0.03),  colitis (combined RR=0.34, 95% CI: 0.13-0.86, P=0.02), and fatigue (combined  RR=0.91, 95% CI: 0.37-2.2.3, P=0.84) compared to the group having ipilimumab  alone. Conclusion: These data suggested that the combination of ipilimumab and  GM-CSF was associated with a significant improvement in overall survival and  lower high-grade toxicities, but there is no difference in overall response rate   and progression-free survival among the cancer patients. Therefore, large-scale  and well-designed studies are needed to summarize and analyze the data to draw a   more convincing conclusion.
CANIT0001892	30013326	Clinical research	Solid tumors	Colorectal cancer	EFO:0005842	Intestines	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1529	N/A	A meta-analysis	Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. Higher PD-L1 expression was associated with a superior objective response rate.	The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.	 Drug Des Devel Ther	 Introduction: The prominent immune checkpoint molecule, programmed cell death  ligand-1 (PD-L1), is the object of increasing attention. Here, we report a  meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an   inhibitor of PD-L1, in various solid tumors. Methods: A systematic search of  PubMed, Embase, and related articles was performed. Safety data were analyzed  using Comprehensive Meta-Analysis software program version 2. Ultimately, 17  studies with 1,529 patients were included in our analysis. Results: The major  adverse events associated with durvalumab were pruritus and fatigue, while  pruritus, increased alanine transaminase, and increased aspartate  aminotransferase were common among patients treated with a combination of  durvalumab and tremelimumab. Higher PD-L1 expression was associated with a  superior objective response rate. Conclusion: Durvalumab is safe in patients with  many solid cancers and, in combination with tremelimumab, it has a tolerable  safety profile and is associated with improved prognosis. PD-L1 expression is a  biomarker of the efficacy of durvalumab.
CANIT0001893	30013326	Clinical research	Solid tumors	Gastrointestinal cancer	EFO:0008346	Stomach	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1529	N/A	A meta-analysis	Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. Higher PD-L1 expression was associated with a superior objective response rate.	The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.	 Drug Des Devel Ther	 Introduction: The prominent immune checkpoint molecule, programmed cell death  ligand-1 (PD-L1), is the object of increasing attention. Here, we report a  meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an   inhibitor of PD-L1, in various solid tumors. Methods: A systematic search of  PubMed, Embase, and related articles was performed. Safety data were analyzed  using Comprehensive Meta-Analysis software program version 2. Ultimately, 17  studies with 1,529 patients were included in our analysis. Results: The major  adverse events associated with durvalumab were pruritus and fatigue, while  pruritus, increased alanine transaminase, and increased aspartate  aminotransferase were common among patients treated with a combination of  durvalumab and tremelimumab. Higher PD-L1 expression was associated with a  superior objective response rate. Conclusion: Durvalumab is safe in patients with  many solid cancers and, in combination with tremelimumab, it has a tolerable  safety profile and is associated with improved prognosis. PD-L1 expression is a  biomarker of the efficacy of durvalumab.
CANIT0001894	30013326	Clinical research	Solid tumors	Lung carcinoma	EFO:0001071	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1529	N/A	A meta-analysis	Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. Higher PD-L1 expression was associated with a superior objective response rate.	The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.	 Drug Des Devel Ther	 Introduction: The prominent immune checkpoint molecule, programmed cell death  ligand-1 (PD-L1), is the object of increasing attention. Here, we report a  meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an   inhibitor of PD-L1, in various solid tumors. Methods: A systematic search of  PubMed, Embase, and related articles was performed. Safety data were analyzed  using Comprehensive Meta-Analysis software program version 2. Ultimately, 17  studies with 1,529 patients were included in our analysis. Results: The major  adverse events associated with durvalumab were pruritus and fatigue, while  pruritus, increased alanine transaminase, and increased aspartate  aminotransferase were common among patients treated with a combination of  durvalumab and tremelimumab. Higher PD-L1 expression was associated with a  superior objective response rate. Conclusion: Durvalumab is safe in patients with  many solid cancers and, in combination with tremelimumab, it has a tolerable  safety profile and is associated with improved prognosis. PD-L1 expression is a  biomarker of the efficacy of durvalumab.
CANIT0001895	30013326	Clinical research	Solid tumors	Ovarian carcinoma	EFO:0001075	Ovary	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1529	N/A	A meta-analysis	Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. Higher PD-L1 expression was associated with a superior objective response rate.	The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.	 Drug Des Devel Ther	 Introduction: The prominent immune checkpoint molecule, programmed cell death  ligand-1 (PD-L1), is the object of increasing attention. Here, we report a  meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an   inhibitor of PD-L1, in various solid tumors. Methods: A systematic search of  PubMed, Embase, and related articles was performed. Safety data were analyzed  using Comprehensive Meta-Analysis software program version 2. Ultimately, 17  studies with 1,529 patients were included in our analysis. Results: The major  adverse events associated with durvalumab were pruritus and fatigue, while  pruritus, increased alanine transaminase, and increased aspartate  aminotransferase were common among patients treated with a combination of  durvalumab and tremelimumab. Higher PD-L1 expression was associated with a  superior objective response rate. Conclusion: Durvalumab is safe in patients with  many solid cancers and, in combination with tremelimumab, it has a tolerable  safety profile and is associated with improved prognosis. PD-L1 expression is a  biomarker of the efficacy of durvalumab.
CANIT0001896	30013326	Clinical research	Solid tumors	Prostate cancer	MONDO:0008315	Prostate	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1529	N/A	A meta-analysis	Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. Higher PD-L1 expression was associated with a superior objective response rate.	The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.	 Drug Des Devel Ther	 Introduction: The prominent immune checkpoint molecule, programmed cell death  ligand-1 (PD-L1), is the object of increasing attention. Here, we report a  meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an   inhibitor of PD-L1, in various solid tumors. Methods: A systematic search of  PubMed, Embase, and related articles was performed. Safety data were analyzed  using Comprehensive Meta-Analysis software program version 2. Ultimately, 17  studies with 1,529 patients were included in our analysis. Results: The major  adverse events associated with durvalumab were pruritus and fatigue, while  pruritus, increased alanine transaminase, and increased aspartate  aminotransferase were common among patients treated with a combination of  durvalumab and tremelimumab. Higher PD-L1 expression was associated with a  superior objective response rate. Conclusion: Durvalumab is safe in patients with  many solid cancers and, in combination with tremelimumab, it has a tolerable  safety profile and is associated with improved prognosis. PD-L1 expression is a  biomarker of the efficacy of durvalumab.
CANIT0001897	30013326	Clinical research	Solid tumors	Thoracic cancer	MONDO:0003274	Other	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1529	N/A	A meta-analysis	Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. Higher PD-L1 expression was associated with a superior objective response rate.	The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.	 Drug Des Devel Ther	 Introduction: The prominent immune checkpoint molecule, programmed cell death  ligand-1 (PD-L1), is the object of increasing attention. Here, we report a  meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an   inhibitor of PD-L1, in various solid tumors. Methods: A systematic search of  PubMed, Embase, and related articles was performed. Safety data were analyzed  using Comprehensive Meta-Analysis software program version 2. Ultimately, 17  studies with 1,529 patients were included in our analysis. Results: The major  adverse events associated with durvalumab were pruritus and fatigue, while  pruritus, increased alanine transaminase, and increased aspartate  aminotransferase were common among patients treated with a combination of  durvalumab and tremelimumab. Higher PD-L1 expression was associated with a  superior objective response rate. Conclusion: Durvalumab is safe in patients with  many solid cancers and, in combination with tremelimumab, it has a tolerable  safety profile and is associated with improved prognosis. PD-L1 expression is a  biomarker of the efficacy of durvalumab.
CANIT0001898	30013326	Clinical research	Solid tumors	Triple-negative breast cancer	EFO:0005537	Breast	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1529	N/A	A meta-analysis	Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. Higher PD-L1 expression was associated with a superior objective response rate.	The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Safety and efficacy of durvalumab (MEDI4736) in various solid tumors.	 Drug Des Devel Ther	 Introduction: The prominent immune checkpoint molecule, programmed cell death  ligand-1 (PD-L1), is the object of increasing attention. Here, we report a  meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an   inhibitor of PD-L1, in various solid tumors. Methods: A systematic search of  PubMed, Embase, and related articles was performed. Safety data were analyzed  using Comprehensive Meta-Analysis software program version 2. Ultimately, 17  studies with 1,529 patients were included in our analysis. Results: The major  adverse events associated with durvalumab were pruritus and fatigue, while  pruritus, increased alanine transaminase, and increased aspartate  aminotransferase were common among patients treated with a combination of  durvalumab and tremelimumab. Higher PD-L1 expression was associated with a  superior objective response rate. Conclusion: Durvalumab is safe in patients with  many solid cancers and, in combination with tremelimumab, it has a tolerable  safety profile and is associated with improved prognosis. PD-L1 expression is a  biomarker of the efficacy of durvalumab.
CANIT0001899	30014881	Clinical research	Elderly patients with advanced squamous non-small-cell lung cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	371	N/A	The Italian cohort of an expanded access programme	Elderly patients with advanced squamous NSCLC benefit from nivolumab, with tolerability similar to that in the overall population.	The incidence of grade 3-4 treatment-related AEs was low in patients aged 65, 65-<75 and 75 years and the overall population (3%, 9%, 3%, 6%, respectively). Discontinuation rates due to treatment-related AEs were low irrespective of age (4-5%).	N/A	N/A	N/A	N/A	N/A	 2018 Sep	 Use of nivolumab in elderly patients with advanced squamous non-small-cell lung  cancer: results from the Italian cohort of an expanded access programme.	 Eur J Cancer	 AIM: This analysis evaluated the efficacy and safety of nivolumab, an immune  checkpoint inhibitor, in elderly patients with stage IIIB or IV squamous  non-small-cell lung cancer (NSCLC) enrolled in the expanded access programme  (EAP) in Italy. METHODS: Nivolumab was available on physician request. Safety  data included adverse events (AEs). Efficacy data included investigator-assessed   tumour response, progression date and survival information. Results were analysed  for patients aged <65, 65-<75 and >/=75 years and for the overall population.  RESULTS: A total of 371 patients with squamous NSCLC were enrolled at 96 centres   between April 2015 and September 2015; 34% (n = 126), 47% (n = 175) and 19% (n =   70) were aged <65, 65-<75 and >/=75 years, respectively. Efficacy was similar  among patients aged <65, 65-<75 and >/=75 years and the overall population  (objective response rates: 18%, 18%, 19% and 18%, respectively; disease control  rates: 49%, 47%, 43% and 47%, respectively). Median overall survival was reduced   in patients aged >/=75 years (5.8 months) versus patients aged <65; years (8.6  months), patients aged 65-<75 years (8.0 months) and the overall population (7.9   months). The incidence of grade 3-4 treatment-related AEs was low in patients  aged 65, 65-<75 and >/=75 years and the overall population (3%, 9%, 3%, 6%,  respectively). Discontinuation rates due to treatment-related AEs were low  irrespective of age (4-5%). CONCLUSIONS: These EAP results suggest that elderly  patients with advanced squamous NSCLC benefit from nivolumab, with tolerability  similar to that in the overall population.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001900	30016251	Case report	Stage IV Hodgkin lymphoma underwent several chemotherapy sessions	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	N/A	Progressive multifocal leukoencephalopathy after treatment with nivolumab	N/A	N/A	N/A	N/A	N/A	 2018 Aug	 Progressive Multifocal Leukoencephalopathy after Treatment with Nivolumab.	 Emerg Infect Dis	 Progressive multifocal leukoencephalopathy (PML) is increasingly being reported  in patients undergoing immunotherapy. We report a case of progressive multifocal   leukoencephalopathy after treatment with nivolumab, a PD-1 blocker that is used  to restore impaired T-cell responses in patients with cancer and infections. Data  for 4 other cases were obtained from pharmacovigilance databases.
CANIT0001901	30017645	Clinical research	Advanced Non-Small-cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	425	425	A phase III clinical trial	These Patient-reported outcomes (PROs) data support the clinical benefit of atezolizumab in patients with previously treated advanced or metastatic NSCLC. Atezolizumab prolonged the TTD of patients' limitations in role and physical functions compared with docetaxel.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Sep	 Patient-Reported Outcomes in OAK: A Phase III Study of Atezolizumab Versus  Docetaxel in Advanced Non-Small-cell Lung Cancer.	 Clin Lung Cancer	 BACKGROUND: The randomized phase III OAK (a study of atezolizumab compared with  docetaxel in participants with locally advanced or metastatic non-small-cell lung  cancer [NSCLC] who have failed platinum-containing therapy) trial investigated  the anti-programmed cell death ligand 1 (PD-L1) antibody atezolizumab for  advanced or metastatic, previously treated, NSCLC. Atezolizumab significantly  improved overall survival (OS) compared with docetaxel (hazard ratio [HR], 0.73;   95% confidence interval [CI], 0.62-0.87; P = .0003; median OS, 13.8 vs. 9.6  months, respectively). Patient-reported outcomes (PROs) were collected to  evaluate disease-related symptoms and health-related quality of life (HRQoL) to  support the finding of a survival benefit. PATIENTS AND METHODS: The first 850  patients were randomized to receive atezolizumab (1200 mg every 3 weeks) or  docetaxel (75 mg/m(2) every 3 weeks). PROs were collected on day 1 of cycle 1,  day 1 of every subsequent cycle, and at the end-of-treatment visit for patients  who completed >/= 1 baseline and 1 postbaseline PRO assessment. The European  Organisation for the Research and Treatment of Cancer QoL questionnaire and lung   cancer module were used to assess PROs. RESULTS: Atezolizumab delayed the time to  deterioration (TTD) in physical function (HR, 0.75; 95% CI, 0.58-0.98) and role  function (HR, 0.79; 95% CI, 0.62-1.00) and numerically improved patients' HRQoL  from baseline compared with docetaxel. Atezolizumab also prolonged the TTD in  chest pain (HR, 0.71; 95% CI, 0.49-1.05; P = .0823), although both arms showed an  objective reduction relative to baseline. Overall, the patients had no clinically  significant worsening in treatment-related symptoms, although the scores favored   atezolizumab. CONCLUSION: These PRO data support the clinical benefit of  atezolizumab in patients with previously treated advanced or metastatic NSCLC.  Atezolizumab prolonged the TTD of patients' limitations in role and physical  functions compared with docetaxel.CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001902	30053670	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab plus platinum-based doublet chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Atezolizumab (DB11595); platinum-based doublet chemotherapy (DB12257); 	76	N/A	N/A	Atezolizumab with chemotherapy was well tolerated with encouraging efficacy, though the analysis was limited by small numbers. NSCLC chemotherapy combination studies are ongoing. 	 Common treatment-related grade III/IV adverse events were neutropenia (36% atezo/cb/pac, 36% atezo/cb/pem, 42% atezo/cb/nab-pac) and anaemia (16% atezo/cb/pac, 16% atezo/cb/pem, 31% atezo/cb/nab-pac). 	N/A	N/A	N/A	N/A	N/A	 2018 Sep	 Long-term survival follow-up of atezolizumab in combination with platinum-based  doublet chemotherapy in patients with advanced non-small-cell lung cancer.	 Eur J Cancer	 BACKGROUND: Before the availability of immunotherapy, chemotherapy was standard  first-line therapy for non-small-cell lung cancer (NSCLC) lacking actionable gene  alterations. Preclinical evidence suggests chemotherapy is immunomodulatory,  supporting chemotherapy/immunotherapy combinations. Atezolizumab, anti-programmed  death ligand-1 (PD-L1) antibody, blocks programmed cell death protein-1 and B7.1   interaction with PD-L1. GP28328 (NCT01633970) assessed atezolizumab with  chemotherapy in multiple tumours; we report results for advanced, treatment-naive  NSCLC. METHODS: Patients received atezolizumab plus carboplatin with paclitaxel  (Arm C: atezo/cb/pac), pemetrexed (Arm D: atezo/cb/pem, maintenance pemetrexed  permitted), or nab-paclitaxel (Arm E: atezo/cb/nab-pac), four-six cycles, then  atezolizumab maintenance. Primary end-point was safety; secondary end-points were  objective response rate (ORR), progression-free survival (PFS) and overall  survival (OS). RESULTS: Seventy-six NSCLC patients were enrolled (n = 25, 25 and   26 for Arms C, D and E, respectively). Common treatment-related grade III/IV  adverse events were neutropenia (36% atezo/cb/pac, 36% atezo/cb/pem, 42%  atezo/cb/nab-pac) and anaemia (16% atezo/cb/pac, 16% atezo/cb/pem, 31%  atezo/cb/nab-pac). Confirmed ORRs were 36% atezo/cb/pac, 68% atezo/cb/pem (one  complete response [CR]) and 46% atezo/cb/nab-pac (four CRs). Median PFS was 7.1  months, (95% confidence interval [CI]: 4.2-8.3), 8.4 months (95% CI: 4.7-11) and   5.7 months (95% CI: 4.4-14.8), respectively. Median OS was 12.9 months (95% CI:  8.8-21.3), 18.9 months (95% CI: 9.9-27.4) and 17.0 months (95% CI: 12.7-not  evaluable), respectively. CONCLUSION: Atezolizumab with chemotherapy was well  tolerated with encouraging efficacy, though the analysis was limited by small  numbers. NSCLC chemotherapy combination studies are ongoing. CLINICALTRIALS. GOV   IDENTIFIER: NCT01633970.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001903	30055859	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Case	The schema of development of paradoxical response closely resembles that of pseudoprogression in non-small cell lung cancer patients after anti-PD-1 treatment.	Pulmonary tuberculosis	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jan	 Paradoxical response in a patient with non-small cell lung cancer who received  nivolumab followed by anti-Mycobacterium tuberculosis agents.	 J Infect Chemother	 Anti-programmed cell death-1 (PD-1) agents enhance the antitumor immunoresponse.   A number of reports have indicated that patients with malignancies who receive  anti-PD-1 agents are at risk for tuberculosis (TB) infection. In this report, we   present a patient with non-small cell lung cancer who developed pulmonary  tuberculosis while receiving the anti-PD-1 agent nivolumab, and who subsequently   demonstrated a paradoxical response (PR) 10 days after initiation of anti-MTB  treatment. We suggest that anti-PD-1 agents not only induce the development of  pulmonary TB, but also development of PR after anti-MTB treatment, through  upregulation of the immune response. Furthermore, based on their radiological and  immunological similarity, we speculate that the schema of development of PR  closely resembles that of pseudoprogression in non-small cell lung cancer  patients after anti-PD-1 treatment.CI  - Copyright (c) 2018 Japanese Society of Chemotherapy and The Japanese Association   for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
CANIT0001904	30056599	Clinical research	Older melanoma patients aged 75 and above	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Pembrolizumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); 	44	32	A retrospective cohort study	Our study suggests that immunotherapy is effective and well tolerated in the elderly. The PFS on pembrolizumab was greater than expected, a finding that needs to be investigated further.	Pembrolizumab and ipilimumab grade 3-4 DRT rates were equal to 24.2 and 32.7% respectively, while discontinuation rates were equal to 43.5and 28.8%, respectively.	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2018 Oct	 Older melanoma patients aged 75 and above retain responsiveness to anti-PD1  therapy: results of a retrospective single-institution cohort study.	 Cancer Immunol Immunother	 INTRODUCTION: The utility of immunotherapy in elderly melanoma patients is  debated. We aimed in this study to evaluate the efficacy and tolerability of  immunotherapy among elderly patients. METHOD: This is a retrospective  single-institution cohort study. Patients aged 75 years and above who had been  treated with nivolumab, pembrolizumab or ipilimumab for advanced or metastatic  melanoma, were included. Patients and disease characteristics were collected  using electronic medical records. Objective response was determined according to   the immune-related response criteria. Drug-related toxicities (DRT) were graded  according to the CTCAE v4.03. RESULTS: 99 patients were included with a mean age   of 80 years (SD = 4). One patient received nivolumab and ipilimumab combination,   but died because of drug-related diverticulitis. Median PFS on pembrolizumab,  nivolumab or ipilimumab were equal to 11.9 (95% CI 5.4-18.4), 1.4 (95% CI  0.01-2.8), and 2.8 months (95% CI 2.6-3), respectively, while objective response   rates were equal to 51.6, 12.5, and 17.3%, respectively. Median OS was not  reached in patients who received only pembrolizumab, 8.7 months in the ipilimumab  only group, and 23 months in patients receiving several immune therapies  sequentially. Pembrolizumab, nivolumab, and ipilimumab grade 3-4 DRT rates were  equal to 24.2, 62.5, and 32.7% respectively, while discontinuation rates were  equal to 43.5, 62.5, and 28.8%, respectively. CONCLUSIONS: Our study suggests  that immunotherapy is effective and well tolerated in the elderly. The PFS on  pembrolizumab was greater than expected, a finding that needs to be investigated   further.
CANIT0001905	30061241	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	Baseline clinical characteristics were a strong predictor of outcome in nivolumab-treated patients with liver metastasis.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2018 Aug	 Clinical Characteristics of Liver Metastasis in Nivolumab-treated Patients with  Non-small Cell Lung Cancer.	 Anticancer Res	 BACKGROUND: Recent studies have revealed that liver metastasis is associated with  poor outcomes after treatment using immune checkpoint inhibitors, although the  cause remains unclear. PATIENTS AND METHODS: We retrospectively identified 201  patients at three Japanese Centers who received nivolumab for advanced non-small   cell lung cancer between December 2015 and July 2016. The patients' baseline  clinical characteristics and subsequent outcomes were compared according to liver  metastasis status. RESULTS: Liver metastasis was associated with inferior  progression-free survival (PFS) and a lower response rate. Additionally, liver  metastasis was significantly associated with younger age, poorer Eastern  Cooperative Oncology Group performance status (ECOG PS), and more metastatic  sites. Multivariate analyses revealed that poor PFS was independently associated   with poor baseline ECOG PS (p=0.039) and high number of metastatic sites  (p=0.007), although liver metastasis (p=0.2) was not. CONCLUSION: Baseline  clinical characteristics were a strong predictor of outcome in nivolumab-treated   patients with liver metastasis.CI  - Copyright(c) 2018, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001906	30061241	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	201	N/A	A retrospective cohort study	Baseline clinical characteristics were a strong predictor of outcome in nivolumab-treated patients with liver metastasis.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Number of metastatic sites	Disease status	 2018 Aug	 Clinical Characteristics of Liver Metastasis in Nivolumab-treated Patients with  Non-small Cell Lung Cancer.	 Anticancer Res	 BACKGROUND: Recent studies have revealed that liver metastasis is associated with  poor outcomes after treatment using immune checkpoint inhibitors, although the  cause remains unclear. PATIENTS AND METHODS: We retrospectively identified 201  patients at three Japanese Centers who received nivolumab for advanced non-small   cell lung cancer between December 2015 and July 2016. The patients' baseline  clinical characteristics and subsequent outcomes were compared according to liver  metastasis status. RESULTS: Liver metastasis was associated with inferior  progression-free survival (PFS) and a lower response rate. Additionally, liver  metastasis was significantly associated with younger age, poorer Eastern  Cooperative Oncology Group performance status (ECOG PS), and more metastatic  sites. Multivariate analyses revealed that poor PFS was independently associated   with poor baseline ECOG PS (p=0.039) and high number of metastatic sites  (p=0.007), although liver metastasis (p=0.2) was not. CONCLUSION: Baseline  clinical characteristics were a strong predictor of outcome in nivolumab-treated   patients with liver metastasis.CI  - Copyright(c) 2018, International Institute of Anticancer Research (Dr. George J.   Delinasios), All rights reserved.
CANIT0001907	30063847	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); LYMPHOCYTE (N/A); 	CTLA-4 ;  PD-1 ;  LYMPHOCYTE 	Ipilimumab plus thymosin alpha-1	Thymosin alpha-1	Immune checkpoint therapy plus Tumor vaccine 	Ipilimumab (DB06186); thymosin alpha-1 (NCIT:C1253); 	21	40	A phase II trial	This is the first report on long-term follow-up of T1-treated patients. Moreover, an advantage in OS in patients sequentially treated with T1 and IPI was seen that suggests a synergistic effect.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jul	 Long-term follow up of metastatic melanoma patients treated with Thymosin  alpha-1: investigating immune checkpoints synergy.	 Expert Opin Biol Ther	 BACKGROUND: Immune checkpoint blockade antibodies (imAbs), such as the anti  Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) ipilimumab (IPI) raised overall  survival (OS) in metastatic melanoma (MM). Further, long-term OS is a crucial  endpoint in MM. Thymosin alpha-1 (Talpha1) with dacarbazine (DTIC) showed  activity in a phase II trial and a compassionate use program (EAP). We report on   long-term follow-up of patients treated with Talpha1 to investigate the  preconditioning role of Talpha1 in imAbs-treated patients. METHODS: Records of  patients with melanoma treated with Talpha1 within a phase II trial and EAP  program were reviewed comparing median OS among patients that sequentially  received anti-CTLA-4 imAb and Talpha1. Further, the effect of Talpha1 on IPI  long-term survivor patients was investigated. RESULTS: Among patients treated  with Talpha1, 21/61 patients received sequentially even anti CTLA-4 imAbs. Median  OS at the data cut-off was 57.8 and 7.4 months in patients treated sequentially  with anti-CTLA-4 imAbs or not, respectively. Moreover, pretreatment with Talpha1   in all (95) IPI-evaluable patients confirmed a significant increase in long-term   OS. CONCLUSION: This is the first report on long-term follow-up of  Talpha1-treated patients. Moreover, an advantage in OS in patients sequentially  treated with Talpha1 and IPI was seen that suggests a synergistic effect.
CANIT0001908	30063847	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); LYMPHOCYTE (N/A); 	CTLA-4 ;  PD-1 ;  LYMPHOCYTE 	Ipilimumab	Thymosin alpha-1	Immune checkpoint therapy	Ipilimumab (DB06186); thymosin alpha-1 (NCIT:C1253); 	95	40	A phase II trial	Median  OS at the data cut-off was 57.8 and 7.4 months in patients treated sequentially  with anti-CTLA-4 imAbs or not, respectively. Moreover, pretreatment with TA1   in all (95) IPI-evaluable patients confirmed a significant increase in long-term   OS. 	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jul	 Long-term follow up of metastatic melanoma patients treated with Thymosin  alpha-1: investigating immune checkpoints synergy.	 Expert Opin Biol Ther	 BACKGROUND: Immune checkpoint blockade antibodies (imAbs), such as the anti  Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) ipilimumab (IPI) raised overall  survival (OS) in metastatic melanoma (MM). Further, long-term OS is a crucial  endpoint in MM. Thymosin alpha-1 (Talpha1) with dacarbazine (DTIC) showed  activity in a phase II trial and a compassionate use program (EAP). We report on   long-term follow-up of patients treated with Talpha1 to investigate the  preconditioning role of Talpha1 in imAbs-treated patients. METHODS: Records of  patients with melanoma treated with Talpha1 within a phase II trial and EAP  program were reviewed comparing median OS among patients that sequentially  received anti-CTLA-4 imAb and Talpha1. Further, the effect of Talpha1 on IPI  long-term survivor patients was investigated. RESULTS: Among patients treated  with Talpha1, 21/61 patients received sequentially even anti CTLA-4 imAbs. Median  OS at the data cut-off was 57.8 and 7.4 months in patients treated sequentially  with anti-CTLA-4 imAbs or not, respectively. Moreover, pretreatment with Talpha1   in all (95) IPI-evaluable patients confirmed a significant increase in long-term   OS. CONCLUSION: This is the first report on long-term follow-up of  Talpha1-treated patients. Moreover, an advantage in OS in patients sequentially  treated with Talpha1 and IPI was seen that suggests a synergistic effect.
CANIT0001909	30077125	Clinical research	Metastatic non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	89	N/A	A phase I clinical trial	Single-agent atezolizumab was well tolerated with long-term clinical benefits, including durable responses and survival, in pretreated NSCLC. Improved responses and survival rates were seen with increasing baseline PD-L1 expression.	Atezolizumab was well tolerated, with grade III/IV treatment-related adverse events (TRAEs) observed in 10 patients (11%). All-grade TRAEs occurring in >10% of patients were fatigue, nausea and decreased appetite; grade III/IV TRAEs occurring in >2% of patients were fatigue, dyspnoea, hyponatremia and hypoxia. One patient died from treatment-unrelated pneumonia. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Sep	 Safety and clinical activity of atezolizumab monotherapy in metastatic  non-small-cell lung cancer: final results from a phase I study.	 Eur J Cancer	 INTRODUCTION: Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody,  inhibits PD-L1:PD-1 and PD-L1:B7.1 interactions, restoring anticancer immunity.  Here, we report final analyses from the non-small-cell lung cancer (NSCLC) cohort  of the first atezolizumab phase I study. METHODS: Patients with NSCLC received  atezolizumab 1-20 mg/kg or 1200 mg intravenously every 3 weeks. Baseline PD-L1  expression on tumour cells (TCs) and tumour-infiltrating immune cells (ICs) was  assessed (VENTANA SP142 immunohistochemistry assay). Exploratory subgroup  analyses investigated responses by baseline PD-L1 expression and oncogenic  mutational status. RESULTS: Eighty-nine patients, 98% of whom had received  previous systemic therapy, were evaluable for safety and antitumour activity.  Atezolizumab was well tolerated, with grade III/IV treatment-related adverse  events (TRAEs) observed in 10 patients (11%). All-grade TRAEs occurring in >10%  of patients were fatigue, nausea and decreased appetite; grade III/IV TRAEs  occurring in >2% of patients were fatigue, dyspnoea, hyponatremia and hypoxia.  One patient died from treatment-unrelated pneumonia. Objective response rate  (ORR) was 50% (95% confidence interval [CI], 28%-72%), 33% (20%-48%), 29%  (18%-41%) and 11% (1%-35%) for the TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3  and TC0 and IC0 subgroups, respectively. All-patient ORR was 23% (95% CI,  14%-33%). Median duration of response was 16.4 months (range, 7.2-53.4+). One-,  2-, and 3-year survival rates were 63% (95% CI, 53%-73%), 37% (26%-47%) and 28%  (18%-38%), respectively. CONCLUSIONS: Single-agent atezolizumab was well  tolerated with long-term clinical benefits, including durable responses and  survival, in pretreated NSCLC. Improved responses and survival rates were seen  with increasing baseline PD-L1 expression. CLINICALTRIALS. GOV IDENTIFIER:  NCT01375842.CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
CANIT0001910	30122019	Clinical research	Malignant Lymphoma patients with high PD-1	Lymphoma	EFO:0000574	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	Same treatment in  healthy volunteers	Immune checkpoint therapy	Nivolumab (DB09035); 	5	5	N/A	Combination of 36 g/ml PD-1 inhibitor and CD19-CAR-T cells could reduce the drug toxicity and enhance the cytotoxicity.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jul 14	 [Effect of PD-1 inhibitor Nivolumab on the proliferation and cytotoxicity of  anti-CD19 chimeric antigen receptor T cells].	 Zhonghua Xue Ye Xue Za Zhi	 Objective: To Evaluation the effect of PD-1 inhibitor Nivolumab on the  proliferation and cytotoxicity of anti-CD19 chimeric antigen receptor T cells  (CD19-CAR-T) in vitro. Methods: Five patients with high PD-1 expression in  peripheral blood and five healthy volunteers were selected. These peripheral  blood mononuclear cells were used as the source of T cells to prepare CD19-CAR-T   cells. Different doses (72, 36, 18 mug/ml) of Nivolumab was added on day 8 to the  culture medium. Patient T cells incubated with 72 mug/ml Nivolumab and CD19-CAR-T  cells of healthy volunteers were used as controls. CCK-8, lactate dehydrogenase  (LDH) cytotoxicity assay and ELASA were used to detect the proliferation  capacity, the specific cytotoxicity and the inflammatory factor secretion.  Results: 1 in circleT cells from patients with high expression of PD-1 as the  source of CD19-CAR-T cells did not affect transfection rate compared with that of  healthy volunteers [(32.80+/-7.22)% vs (35.10+/-5.84)%, t=-0.554, P=0.593]. 2 in   circleIncubation of CD19-CAR-T cells with 72 mug/ml Nivolumab did not affect  CD19-CAR-T cell proliferation, but its cytotoxicity was significantly higher than  that of CD19-CAR-T cells alone or patients' T cells +72 mug/ml Nivolumab (all  P<0.001), there was no significant difference in the killing activity between the  72 mug/ml and 36 mug/ml Nivolumab treated CD19-CAR-T cells on Pfeiffer cells  (P=0.281, 0.267, respectively), and they were all higher than those of 18 mug/ml   Nivolumab treated CD19-CAR-T cells (all P<0.001). 3 in circleDifferent doses of  PD-1 inhibitor Nivolumab combined with CD19-CAR-T cells does not affect the  secretion of IFNG and IFN-alpha (all P>0.05). Conclusion: Combination of 36   mug/ml PD-1 inhibitor and CD19-CAR-T cells could reduce the drug toxicity and  enhance the cytotoxicity.
CANIT0001911	30122486	Clinical research	Melanoma, Hematologic tumors, Solid tumors	Hematopoietic and lymphoid cell neoplasm	MONDO:0044881	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab or cytokines	Chemotherapy or targeted therapy	Immune checkpoint therapy	Ipilimumab (DB06186); non-immunologic agents (N/A); cytokines (NCIT:C1283); 	134	3287	A retrospective cohort study	Overall, 71 (2%) patients suffered iodinated contrast media (ICM)-related acute adverse reactions (ARs). The incidence of ICM-related ARs was higher in Ipi- and cytokines (Cys)-treated patients than in those who received chemotherapy/targeted therapy (CHT) (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly ipilimumab (Ipi), considerably increase the proportion of patients suffering contrast-enhanced computed tomography (CECT)-related immediate ARs with respect to non-immunologic agents.	Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in ipilimumab(Ipi) and cytokines (Cys)-treated patients than in those who received non-immunologic agents (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering Contrast-enhanced computed tomography related immediate adverse reactions with respect to non-immunologic agents. 	N/A	N/A	N/A	N/A	N/A	 2018 Oct	 Increased frequency of acute reactions to iodinated contrast media in cancer  patients treated with anti-CTLA-4 immunomodulatory antibodies.	 Med Hypotheses	Contrast-enhanced computed tomography (CECT) is an indispensable tool in the management of cancer patients. However, this procedure can be complicated by the development of acute adverse reactions (ARs) to iodinated contrast media (ICM). On the basis of the hypothesis that cancer immunotherapy, in particular with immune checkpoint inhibitors, increases the incidence of allergic-like immediate ARs to ICM with respect to standard cancer chemotherapy/targeted therapy (CHT) we retrospectively evaluated the incidence of CECT-related immediate ARs in cancer patients undergoing cancer treatments. All patients who underwent at least one CECT scan after starting any cancer treatment between 2006 and 2014 were included in a mono-institutional radiological database. The staff of the Radiology Unit recorded any ARs that occurred within 30 min of the ICM injection and classified them as allergic-like or physiologic and graded as mild, moderate, or severe according to the American College of Radiology (ACR) Manual on Contrast Media, version 10.1. Fifty-nine of the 3,521 patients included in the database received ipilimumab (Ipi), 75 received cytokines (Cys), and the remaining 3,387 received non-immunologic agents (CHT). Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in Ipi- and Cy-treated patients than in those who received CHT (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering CECT-related immediate ARs with respect to non-immunologic agents. Although these findings need to be validated in larger prospective studies, they serve as a wake-up call for radiologists to closely monitor patients who have previously received cancer immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies when using ICM in order to reduce the risk of potentially severe immediate ARs.
CANIT0001912	30122486	Clinical research	Melanoma, Hematologic tumors, Solid tumors	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab or cytokines	Chemotherapy or targeted therapy	Immune checkpoint therapy	Ipilimumab (DB06186); non-immunologic agents (N/A); cytokines (NCIT:C1283); 	134	3287	A retrospective cohort study	Overall, 71 (2%) patients suffered iodinated contrast media (ICM)-related acute adverse reactions (ARs). The incidence of ICM-related ARs was higher in Ipi- and cytokines (Cys)-treated patients than in those who received chemotherapy/targeted therapy (CHT) (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly ipilimumab (Ipi), considerably increase the proportion of patients suffering contrast-enhanced computed tomography (CECT)-related immediate ARs with respect to non-immunologic agents.	Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in ipilimumab(Ipi) and cytokines (Cys)-treated patients than in those who received non-immunologic agents (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering Contrast-enhanced computed tomography related immediate adverse reactions with respect to non-immunologic agents. 	N/A	N/A	N/A	N/A	N/A	 2018 Oct	 Increased frequency of acute reactions to iodinated contrast media in cancer  patients treated with anti-CTLA-4 immunomodulatory antibodies.	 Med Hypotheses	Contrast-enhanced computed tomography (CECT) is an indispensable tool in the management of cancer patients. However, this procedure can be complicated by the development of acute adverse reactions (ARs) to iodinated contrast media (ICM). On the basis of the hypothesis that cancer immunotherapy, in particular with immune checkpoint inhibitors, increases the incidence of allergic-like immediate ARs to ICM with respect to standard cancer chemotherapy/targeted therapy (CHT) we retrospectively evaluated the incidence of CECT-related immediate ARs in cancer patients undergoing cancer treatments. All patients who underwent at least one CECT scan after starting any cancer treatment between 2006 and 2014 were included in a mono-institutional radiological database. The staff of the Radiology Unit recorded any ARs that occurred within 30 min of the ICM injection and classified them as allergic-like or physiologic and graded as mild, moderate, or severe according to the American College of Radiology (ACR) Manual on Contrast Media, version 10.1. Fifty-nine of the 3,521 patients included in the database received ipilimumab (Ipi), 75 received cytokines (Cys), and the remaining 3,387 received non-immunologic agents (CHT). Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in Ipi- and Cy-treated patients than in those who received CHT (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering CECT-related immediate ARs with respect to non-immunologic agents. Although these findings need to be validated in larger prospective studies, they serve as a wake-up call for radiologists to closely monitor patients who have previously received cancer immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies when using ICM in order to reduce the risk of potentially severe immediate ARs.
CANIT0001913	30122486	Clinical research	Melanoma, Hematologic tumors, Solid tumors	Cancer	EFO:0000311	Other	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab or cytokines	Chemotherapy or targeted therapy	Immune checkpoint therapy	Ipilimumab (DB06186); non-immunologic agents (N/A); cytokines (NCIT:C1283); 	134	3287	A retrospective cohort study	Overall, 71 (2%) patients suffered iodinated contrast media (ICM)-related acute adverse reactions (ARs). The incidence of ICM-related ARs was higher in Ipi- and cytokines (Cys)-treated patients than in those who received chemotherapy/targeted therapy (CHT) (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly ipilimumab (Ipi), considerably increase the proportion of patients suffering contrast-enhanced computed tomography (CECT)-related immediate ARs with respect to non-immunologic agents.	Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in ipilimumab(Ipi) and cytokines (Cys)-treated patients than in those who received non-immunologic agents (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering Contrast-enhanced computed tomography related immediate adverse reactions with respect to non-immunologic agents. 	N/A	N/A	N/A	N/A	N/A	 2018 Oct	 Increased frequency of acute reactions to iodinated contrast media in cancer  patients treated with anti-CTLA-4 immunomodulatory antibodies.	 Med Hypotheses	Contrast-enhanced computed tomography (CECT) is an indispensable tool in the management of cancer patients. However, this procedure can be complicated by the development of acute adverse reactions (ARs) to iodinated contrast media (ICM). On the basis of the hypothesis that cancer immunotherapy, in particular with immune checkpoint inhibitors, increases the incidence of allergic-like immediate ARs to ICM with respect to standard cancer chemotherapy/targeted therapy (CHT) we retrospectively evaluated the incidence of CECT-related immediate ARs in cancer patients undergoing cancer treatments. All patients who underwent at least one CECT scan after starting any cancer treatment between 2006 and 2014 were included in a mono-institutional radiological database. The staff of the Radiology Unit recorded any ARs that occurred within 30 min of the ICM injection and classified them as allergic-like or physiologic and graded as mild, moderate, or severe according to the American College of Radiology (ACR) Manual on Contrast Media, version 10.1. Fifty-nine of the 3,521 patients included in the database received ipilimumab (Ipi), 75 received cytokines (Cys), and the remaining 3,387 received non-immunologic agents (CHT). Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in Ipi- and Cy-treated patients than in those who received CHT (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering CECT-related immediate ARs with respect to non-immunologic agents. Although these findings need to be validated in larger prospective studies, they serve as a wake-up call for radiologists to closely monitor patients who have previously received cancer immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies when using ICM in order to reduce the risk of potentially severe immediate ARs.
CANIT0001914	30123214	Clinical research	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	22	N/A	A retrospective cohort study	These findings show that by providing a window into the state of the immune system, peripheral T cell subpopulations inform about the state of the anti-tumor immune response and identify potential blood biomarkers of clinical response to checkpoint inhibitors in melanoma and NSCLC.	N/A	N/A	N/A	Effector T-cells (NCIT:C104083); Central memory T-cells (NCIT:C126420); CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD4(+) central memory T-cell  to effector T-cell ratios	Gene expression signature on/in immune cell	2018	 Circulating T Cell Subpopulations Correlate With Immune Responses at the Tumor  Site and Clinical Response to PD1 Inhibition in Non-Small Cell Lung Cancer.	 Front Immunol	 Agents targeting the PD1-PDL1 axis have transformed cancer therapy. Factors that   influence clinical response to PD1-PDL1 inhibitors include tumor mutational  burden, immune infiltration of the tumor, and local PDL1 expression. To identify   peripheral correlates of the anti-tumor immune response in the absence of  checkpoint blockade, we performed a retrospective study of circulating T cell  subpopulations and matched tumor gene expression in melanoma and non-small cell  lung cancer (NSCLC) patients. Notably, both melanoma and NSCLC patients whose  tumors exhibited increased inflammatory gene transcripts presented high CD4(+)  and CD8(+) central memory T cell (CM) to effector T cell (Eff) ratios in blood.  Consequently, we evaluated CM/Eff T cell ratios in a second cohort of NSCLC. The   data showed that high CM/Eff T cell ratios correlated with increased tumor PDL1  expression. Furthermore, of the 22 patients within this NSCLC cohort who received  nivolumab, those with high CM/Eff T cell ratios, had longer progression-free  survival (PFS) (median survival: 91 vs. 215 days). These findings show that by  providing a window into the state of the immune system, peripheral T cell  subpopulations inform about the state of the anti-tumor immune response and  identify potential blood biomarkers of clinical response to checkpoint inhibitors  in melanoma and NSCLC.
CANIT0001915	30123214	Clinical research	Non-Small Cell Lung Cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	22	N/A	A retrospective cohort study	These findings show that by providing a window into the state of the immune system, peripheral T cell subpopulations inform about the state of the anti-tumor immune response and identify potential blood biomarkers of clinical response to checkpoint inhibitors in melanoma and NSCLC.	N/A	N/A	N/A	Effector T-cells (NCIT:C104083); Central memory T-cells (NCIT:C126420); CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD8(+) central memory T-cell  to effector T-cell ratios	Gene expression signature on/in immune cell	2018	 Circulating T Cell Subpopulations Correlate With Immune Responses at the Tumor  Site and Clinical Response to PD1 Inhibition in Non-Small Cell Lung Cancer.	 Front Immunol	 Agents targeting the PD1-PDL1 axis have transformed cancer therapy. Factors that   influence clinical response to PD1-PDL1 inhibitors include tumor mutational  burden, immune infiltration of the tumor, and local PDL1 expression. To identify   peripheral correlates of the anti-tumor immune response in the absence of  checkpoint blockade, we performed a retrospective study of circulating T cell  subpopulations and matched tumor gene expression in melanoma and non-small cell  lung cancer (NSCLC) patients. Notably, both melanoma and NSCLC patients whose  tumors exhibited increased inflammatory gene transcripts presented high CD4(+)  and CD8(+) central memory T cell (CM) to effector T cell (Eff) ratios in blood.  Consequently, we evaluated CM/Eff T cell ratios in a second cohort of NSCLC. The   data showed that high CM/Eff T cell ratios correlated with increased tumor PDL1  expression. Furthermore, of the 22 patients within this NSCLC cohort who received  nivolumab, those with high CM/Eff T cell ratios, had longer progression-free  survival (PFS) (median survival: 91 vs. 215 days). These findings show that by  providing a window into the state of the immune system, peripheral T cell  subpopulations inform about the state of the anti-tumor immune response and  identify potential blood biomarkers of clinical response to checkpoint inhibitors  in melanoma and NSCLC.
CANIT0001916	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Hepatocellular carcinoma	EFO:0000182	Liver	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001917	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001918	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001919	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Hepatocellular carcinoma	EFO:0000182	Liver	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001920	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001921	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001922	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001923	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001924	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001925	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001926	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001927	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001928	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001929	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001930	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001931	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001932	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001933	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001934	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001935	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001936	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For NSCLC patients, the OS and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001937	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001938	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001939	30142174	Clinical research	Non-small cell lung carcinoma, hepatocellular carcinoma, Melanoma, Renal cell carcinoma etc.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	A retrospective cohort study	The median OS period and PFS for non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively, which were similar to those in many clinical trials. For  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months, respectively.	The most common adverse events in this study included fatigue (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed severe deep venous thrombosis and tissue inflammation, which was not confirmed in previous clinical trials.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Effectiveness and safety of immune checkpoint inhibitors: A retrospective study  in Taiwan.	 PLoS One	 BACKGROUND: Since 2012, several immune checkpoint inhibitors have been approved  by the Taiwan FDA for various types of cancer treatment. However, none of them  are covered by Taiwan National Health Insurance due to the fact that they are  expensive, and there is a lack of clinical evidence as to their effectiveness.  OBJECTIVES: This study was aimed toward an exploration of clinical experiences  with use of immune checkpoint inhibitors, including indications, prescription  types, drug effectiveness, adverse drug event types, and incidence, all of which   shall serve as references for future clinical drug use. METHODS: This is a  retrospective study focusing on three immune checkpoint inhibitors (ipilimumab,  nivolumab, and pembrolizumab), which are available for cancer treatment in  Taiwan. We collected data from medical records for the period from January 1st,  2015 to January 12th, 2017 at National Cheng Kung University Hospital (NCKUH), a   medical center in southern Taiwan, and recorded these cases until May 31st, 2017.  Overall survival (OS) and progression-free survival (PFS) were estimated using  the Kaplan-Meier method, and adverse drug reaction odds ratios were analyzed  using a chi-square analysis. RESULTS: The 50 patients under consideration in this  study had used any one of the immune checkpoint inhibitors in NCKUH. Non-small  cell lung cancer (n = 24, 48%) accounted for the highest percentage, followed by   hepatocellular carcinoma (n = 4, 8%). The median OS was not reached, and the PFS   for all immunotherapies was 4.9 months. The median OS period and PFS for  non-small cell lung cancer (NSCLC) patients were 13 and 4.9 months, respectively,  which were similar to those in many clinical trials. For NSCLC patients, the OS  and PFS were only 0.63 and 1.37 months for squamous cell type NSCLC, and for  patients who were PD-L1 negative, the OS and PFS were only 11.53 and 2.6 months,   respectively. The most common adverse events in this study included fatigue  (42%), rashes (22%), nausea (20%), and fever (20%), while one patient developed  severe deep venous thrombosis and tissue inflammation, which was not confirmed in  previous clinical trials. CONCLUSIONS: The histological subtype, the intensity of  the PD-L1 expression, and the timing of treatment affected the NSCLC therapeutic   results. It is recommended that clinical tests be conducted in order to enhance  therapeutic effectiveness. It is expected that more testing, observation-based  studies, and research results will validate their efficacy and the tolerance  levels of patients.
CANIT0001940	30142712	Case report	Metastatic squamous cell carcinoma of the oropharynx	Oropharynx squamous cell carcinoma	MONDO:0044704	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	This reaction may give insight to the underlying pathophysiology of Stevens-Johnson syndrome, suggesting that immune checkpoint inhibitors can activate T-cells to target keratinocytes and that external factors may be involved in creating distinct epitopes for T-cell recognition.	Stevens-Johnson syndrome	N/A	N/A	N/A	N/A	N/A	 2018 Jun 15	 Striking enhancement at the site of radiation for nivolumab-induced  Stevens-Johnson syndrome.	 Dermatol Online J	 Stevens-Johnson syndrome is a rare adverse cutaneous drug reaction characterized   by epidermal detachment of &lt;10% body surface area with an average mortality  rate of 1-5%. The mechanism of SJS is not fully understood. Nivolumab is a  monoclonal antibody directed against programmed cell death-1 protein (PD-1), a  receptor with immune checkpoint inhibitory and antineoplastic activities. We  present a case of SJS in a patient being treated with anti-PD-1 therapy nivolumab  for metastatic squamous cell carcinoma of the oropharynx. This case is unusual  because of the severe accentuation with striking enhancement at his prior  radiation site and in the cutaneous region with heavier tumor burden from his  metastatic disease. This reaction may give insight to the underlying  pathophysiology of SJS, suggesting that immune checkpoint inhibitors can activate  T-cells to target keratinocytes and that external factors may be involved in  creating distinct epitopes for T-cell recognition. We hope this case adds to the   body of knowledge in the pathogenesis of Stevens-Johnson syndrome and cutaneous  adverse events seen with checkpoint inhibitors.
CANIT0001941	30213236	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus stereotactic radiosurgery	Stereotactic radiosurgery	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); stereotactic ablative radiotherapy (NCIT:C157991); stereotactic ablative radiotherapy (NCIT:C157991); 	128	283	A meta-analysis	Stereotactic radiosurgery with ipilimumab is safe and effective treatment option and can be recommended for the treatment of brain metastases in patients with melanoma.	No difference in the adverse events (intracranial hemorrhage, radionecrosis) was observed in the treatment groups. The odds ratio was 0.57 (95% CI: 0.28-1.17, P = .12) for overall toxicity	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2018 Jan 1	 SRS in Combination With Ipilimumab: A Promising New Dimension for Treating  Melanoma Brain Metastases.	 Technol Cancer Res Treat	 Stereotactic radiosurgery provides effective local control, but high recurrence  rate are observed while ipilimumab have shown promising improvements in survival   in the treatment of melanoma brain metastases. This meta-analysis was done to  review the clinical evidence regarding the combination of stereotactic  radiosurgery and ipilimumab in the treatment of brain metastases from melanoma.  Comprehensive research of the electronic databases (PubMed and Cochrane Library)   was carried out in April 2017. Different combination of MESH headings and words  were used. Review Manager was used to analyze the outcome data of interest.  According to heterogeneity, fixed effects model or random effects model was  adapted. Six retrospective studies comparing stereotactic radiosurgery plus  ipilimumab with stereotactic radiosurgery alone were found. Total of 411  participants were included in this meta-analysis. Of that, 128 patients had  received stereotactic radiosurgery + ipilimumab, while 283 patients had received   stereotactic radiosurgery only. Stereotactic radiosurgery plus ipilimumab  significantly improved survival when compared to stereotactic radiosurgery alone   (hazard ratio: 0.74 [95% confidence interval: 0.56-0.99, P = .04]), with no  significant increase in the incidence of adverse events (odds ratio 0.57 [95%  confidence interval: 0.28-1.17, P = .12]). Stereotactic radiosurgery with  ipilimumab is safe and effective treatment option and can be recommended for the   treatment of brain metastases in patients with melanoma.
CANIT0001942	30261564	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	Ipilimumab may be associated with halo lichenoid reactions surrounding benign nevi and this adverse effect should be added to the various dermatologic reactions that patients can develop while being treated with this agent.	Halo-like inflammatory reactions around nevi	N/A	N/A	N/A	N/A	N/A	 2018 Jul 15	 Ipilimumab-associated halo-like inflammatory reactions around nevi during therapy  for metastatic melanoma.	 Dermatol Online J	 Ipilimumab is an immune-modulating drug that is being used today for various  cancers including metastatic malignant melanoma. Owing to its mechanism of  action, several adverse events have been reported, including some affecting skin.  In this work, we report a novel display of multiple ipilimumab-associated halo  lichenoid reactions surrounding benign nevi during treatment of metastatic  melanoma. A patient underwent treatment with ipilimumab for treatment of stage  IIIC melanoma at our center and was monitored for progress and adverse events  throughout treatment. During treatment with ipilimumab, the patient clinically  developed multiple halo lichenoid reactions surrounding previously present nevi,   which histopathologically showed a lichenoid interface dermatitis associated with  the mildly atypical nevi and ill-formed granulomata within the infiltrate.  Therefore, ipilimumab may be associated with halo lichenoid reactions surrounding  benign nevi and this adverse effect should be added to the various dermatologic  reactions that patients can develop while being treated with this agent.
CANIT0001943	30262398	Case report	Mismatch repair-deficient and cortisol secreting adrenocortical carcinoma	Adrenocortical carcinoma	MONDO:0008734	Adrenal gland	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.	A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure.	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Rapid disease progression in a patient with mismatch repair-deficient and  cortisol secreting adrenocortical carcinoma treated with pembrolizumab.	 Semin Oncol	 CONTEXT: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy  with a poor prognosis and limited therapeutic options. A subset of ACC is due to   Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in   mismatch repair (MMR) genes. It has been demonstrated that several cancers  characterized by MMR deficiency are sensitive to immune checkpoint inhibitors  that target PD-1. Here, we provide the first report of PD-1 blockade with  pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting  metastatic ACC. CASE REPORT: A 58-year-old female with known Lynch syndrome  presented with severe Cushing's syndrome and was diagnosed with a  cortisol-secreting ACC. Three months following surgical resection and adjuvant  mitotane therapy the patient developed metastatic disease and persistent  hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed   due to a transient transaminitis. Computed tomography performed after 12 weeks  and 2 cycles of pembrolizumab administration revealed significant disease  progression and treatment was discontinued. After 7 weeks, the patient became  jaundiced and soon died due to fulminant liver failure. CONCLUSION: Treatment of   MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to  supraphysiological levels of circulating corticosteroids, which may in turn mask   severe drug-induced organ damage.CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
CANIT0001944	30262399	Clinical research	Nonsmall-cell lung cancers	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Pembrolizumab plus chemotherapy	Immune checkpoint therapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	658	594	A meta-analysis	In absence of planned prospective noninferiority trials addressing this issue, addition of chemotherapy to pembrolizumab appears to decrease tumor size and delay disease progression significantly more than pembrolizumab alone, but has no impact on OS. We conclude that the data support deciding between both treatment options on an individual basis by considering a patients' clinical status and disease characteristics.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Jun	 Avoiding chemotherapy for advanced nononcogene addicted NSCLC overexpressing  PD-L1: Rule or option 	 Semin Oncol	 Patients with nonsmall-cell lung cancers expressing high levels of PD-L1 present   a therapeutic dilemma for clinicians who have to choose between pembrolizumab as   a single agent or in combination with chemotherapy. In order to help them as they  ponder over this decision we performed a meta-analysis using the data available  from randomized clinical trials that enrolled patients with untreated advanced  nonsmall-cell lung cancers with PD-L1 expression level >/=50%. We evaluated  interactions according to type of treatment-add-on strategy: pembrolizumab plus  chemotherapy versus chemotherapy or head-to-head strategy: pembrolizumab alone  versus chemotherapy. Hazard and Odds Ratios (HR/OR) for primary (overall  survival, OS) and secondary endpoints (progression-free survival, PFS and  objective response rate, ORR) were extracted and cumulated by adopting a  random-effect model with 95% confidence interval. Four clinical trials that  enrolled 2,754 patients including 1,252 with PD-L1 expression in >/=50% of cells   were examined. We did not find a significant interaction (P = 0.16) between an  add-on strategy and head-to-head comparisons with pembrolizumab for OS (HRs in  favor of immunotherapy of 0.50 and 0.67, respectively). A significant  quantitative interaction favoring the add-on strategy was found for PFS and ORR  (P < 0.001), with a HR for PFS of 0.36 with the add-on strategy and 0.65 in  head-to head comparisons, and an OR for ORR of 5.35 and 1.58, respectively. In  absence of planned prospective noninferiority trials addressing this issue,  addition of chemotherapy to pembrolizumab appears to decrease tumor size and  delay disease progression significantly more than pembrolizumab alone, but has no  impact on OS. We conclude that the data support deciding between both treatment  options on an individual basis by considering a patients' clinical status and  disease characteristics.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001945	30262400	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); ipilimumab (DB06186); 	1	N/A	Case	Viable Pregnancy	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Jun	 Viable Pregnancy in a patient with metastatic melanoma treated with double  checkpoint immunotherapy.	 Semin Oncol	 Metastatic cancers during pregnancy have historically been associated with dismal  outcomes, with greater rates of tumor progression in part because of diminished  treatment alternatives. Immunotherapy with T-cell checkpoint inhibitors has  significantly impacted the survival of several metastatic tumors. However, given   their mechanism of action, immune-related adverse events can occur, especially  with combined immunotherapy treatments. During pregnancy, checkpoint pathways  have a major role, providing immune tolerance to the fetal allograft.  Furthermore, evidence suggests that inhibition of this pathway may be associated   with an increased risk of miscarriage. We describe, to our knowledge, the first  case reported in the literature of a patient 7 weeks pregnant, diagnosed with  metastatic melanoma and treated with nivolumab plus ipilimumab. We also present  the associated immune-related side effects and their treatment, as well as the  oncologic results that lead to favorable pregnancy outcome.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0001946	30282874	Case report	Solitary paraaortic lymph node recurrence of lung squamous cell carcinoma	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	The genetic status of the lymph node recurrence revealed a lack of EGFR mutations, ALK translocations, and ROS1 mutations, while the tumor proportion score (TPS) of PD-L1 was 55%, and we therefore administered pembrolizumab, an immune checkpoint inhibitor. Biopsies are very important for achieving precise diagnoses and determining the genetic statuses of tumors, since molecular-targeting drugs and immune checkpoint inhibitors are available. 	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	2018	 A case of solitary paraaortic lymph node recurrence of lung squamous cell  carcinoma after resection.	 J Med Invest	 Solitary abdominal paraaortic lymph node recurrence after radical lung cancer  surgery is very rare. Here, we report a case of a solitary abdominal paraaortic  lymph node recurrence of lung squamous cell carcinoma (SCC). A 63-year-old man  was diagnosed with lung SCC (cT1cN0M0 stage IA3), underwent a video-assisted  right lower lobectomy (ND2a-1), and the pathological findings showed SCC  (pT1cN0M0 stage IA3). The EGFR mutation and ALK translocation statuses of SCC  were negative, and adjuvant therapy was not performed. Follow-up positron  emission tomography - computed tomography (PET/CT) showed a solitary  fluorodeoxyglucose (FDG)-concentrated region in the swollen paraaortic lymph  node. A paraaortic lymph node biopsy was performed by open laparotomy, to  determine the precise diagnosis and identify the genetic status. Pathological  findings revealed that the paraaortic lymph node contained poorly differentiated   SCC, which was thought to metastasize from the lung cancer. The genetic status of  the lymph node recurrence revealed a lack of EGFR mutations, ALK translocations,   and ROS1 mutations, while the tumor proportion score (TPS) of PD-L1 was 55%, and   we therefore administered pembrolizumab, an immune checkpoint inhibitor. Biopsies  are very important for achieving precise diagnoses and determining the genetic  statuses of tumors, since molecular-targeting drugs and immune checkpoint  inhibitors are available. J. Med. Invest. 65:283-285, August, 2018.
CANIT0001947	30345301	Clinical research	Pretreated Advanced or Metastatic Nonsmall Cell Lung Carcinomas	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Docetaxel	Immune checkpoint therapy	Nivolumab (DB09035); docetaxel (DB01248); 	427	1681	A meta-analysis	OS, PFS, and ORR were significantly more improved for patients treated with anti-PD-1/PD-L1 antibodies than for those treated with docetaxel. Anti-PD-1/PD-L1 therapy resulted in longer OS than docetaxel, regardless of PD-L1 expression; however, higher PD-L1 levels were likely to correlate with better outcome.  Anti-PD-1/PD-L1 antibodies also had a better safety profile than docetaxel.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Anti-PD-1/PD-L1 Antibody Therapy for Pretreated Advanced or Metastatic Nonsmall  Cell Lung Carcinomas and the Correlation between PD-L1 Expression and Treatment  Effectiveness: An Update Meta-Analysis of Randomized Clinical Trials.	 Biomed Res Int	 Purpose: This meta-analysis systematically evaluated the efficacy and safety of  anti-PD-1/PD-L1 antibodies for pretreated advanced or metastatic nonsmall cell  lung cancer (NSCLC) and investigated the correlation between PD-L1 expression  levels and effectiveness of anti-PD-1/PD-L1 antibody. Methods: The methodology  was based on the Preferred Reporting Items for Systematic Reviews and Meta  Analyses (PRISMA) and the Cochrane Collaboration guidelines. Results: Our  research included five randomized-controlled trials involving 3,025 patients. We   compared anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, and atezolizumab)   with docetaxel in pretreated patients with advanced or metastatic NSCLC. The  pooled hazard ratio (HR) for overall survival (OS) and progression-free survival   (PFS) was 0.69 (95%CI: 0.63-0.75, P<0.0001, and Ph=0.67) and 0.87 (95%CI:  0.81-0.94, P=0.0004, and Ph=0.11), respectively. Meanwhile, the pooled risk ratio  (RR) for objective response rate (ORR) was 1.53 (95% CI: 1.16-2.01, P=0.003, and   Ph=0.03) in all patients. Subgroup analyses showed that anti-PD-1/PD-L1 treatment  significantly improved OS in patients with PD-L1 expression at any level, even in  patients with PD-L1<1%. The RR for occurrence of grades 3 to 5 treatment-related   adverse effects was 0.23 (95% CI: 0.15-0.36, and P<0.001). Conclusion: OS, PFS,  and ORR were significantly more improved for patients treated with  anti-PD-1/PD-L1 antibodies than for those treated with docetaxel. Anti-PD-1/PD-L1  therapy resulted in longer OS than docetaxel, regardless of PD-L1 expression;  however, higher PD-L1 levels were likely to correlate with better outcome.  Anti-PD-1/PD-L1 antibodies also had a better safety profile than docetaxel.
CANIT0001948	30345301	Clinical research	Pretreated Advanced or Metastatic Nonsmall Cell Lung Carcinomas	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Docetaxel	Immune checkpoint therapy	Pembrolizumab (DB09037); docetaxel (DB01248); 	569	1681	A meta-analysis	OS, PFS, and ORR were significantly more improved for patients treated with anti-PD-1/PD-L1 antibodies than for those treated with docetaxel. Anti-PD-1/PD-L1 therapy resulted in longer OS than docetaxel, regardless of PD-L1 expression; however, higher PD-L1 levels were likely to correlate with better outcome.  Anti-PD-1/PD-L1 antibodies also had a better safety profile than docetaxel.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Anti-PD-1/PD-L1 Antibody Therapy for Pretreated Advanced or Metastatic Nonsmall  Cell Lung Carcinomas and the Correlation between PD-L1 Expression and Treatment  Effectiveness: An Update Meta-Analysis of Randomized Clinical Trials.	 Biomed Res Int	 Purpose: This meta-analysis systematically evaluated the efficacy and safety of  anti-PD-1/PD-L1 antibodies for pretreated advanced or metastatic nonsmall cell  lung cancer (NSCLC) and investigated the correlation between PD-L1 expression  levels and effectiveness of anti-PD-1/PD-L1 antibody. Methods: The methodology  was based on the Preferred Reporting Items for Systematic Reviews and Meta  Analyses (PRISMA) and the Cochrane Collaboration guidelines. Results: Our  research included five randomized-controlled trials involving 3,025 patients. We   compared anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, and atezolizumab)   with docetaxel in pretreated patients with advanced or metastatic NSCLC. The  pooled hazard ratio (HR) for overall survival (OS) and progression-free survival   (PFS) was 0.69 (95%CI: 0.63-0.75, P<0.0001, and Ph=0.67) and 0.87 (95%CI:  0.81-0.94, P=0.0004, and Ph=0.11), respectively. Meanwhile, the pooled risk ratio  (RR) for objective response rate (ORR) was 1.53 (95% CI: 1.16-2.01, P=0.003, and   Ph=0.03) in all patients. Subgroup analyses showed that anti-PD-1/PD-L1 treatment  significantly improved OS in patients with PD-L1 expression at any level, even in  patients with PD-L1<1%. The RR for occurrence of grades 3 to 5 treatment-related   adverse effects was 0.23 (95% CI: 0.15-0.36, and P<0.001). Conclusion: OS, PFS,  and ORR were significantly more improved for patients treated with  anti-PD-1/PD-L1 antibodies than for those treated with docetaxel. Anti-PD-1/PD-L1  therapy resulted in longer OS than docetaxel, regardless of PD-L1 expression;  however, higher PD-L1 levels were likely to correlate with better outcome.  Anti-PD-1/PD-L1 antibodies also had a better safety profile than docetaxel.
CANIT0001949	30345301	Clinical research	Pretreated Advanced or Metastatic Nonsmall Cell Lung Carcinomas	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Docetaxel	Immune checkpoint therapy	Atezolizumab (DB11595); docetaxel (DB01248); 	690	1681	A meta-analysis	OS, PFS, and ORR were significantly more improved for patients treated with anti-PD-1/PD-L1 antibodies than for those treated with docetaxel. Anti-PD-1/PD-L1 therapy resulted in longer OS than docetaxel, regardless of PD-L1 expression; however, higher PD-L1 levels were likely to correlate with better outcome.  Anti-PD-1/PD-L1 antibodies also had a better safety profile than docetaxel.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	2018	 Anti-PD-1/PD-L1 Antibody Therapy for Pretreated Advanced or Metastatic Nonsmall  Cell Lung Carcinomas and the Correlation between PD-L1 Expression and Treatment  Effectiveness: An Update Meta-Analysis of Randomized Clinical Trials.	 Biomed Res Int	 Purpose: This meta-analysis systematically evaluated the efficacy and safety of  anti-PD-1/PD-L1 antibodies for pretreated advanced or metastatic nonsmall cell  lung cancer (NSCLC) and investigated the correlation between PD-L1 expression  levels and effectiveness of anti-PD-1/PD-L1 antibody. Methods: The methodology  was based on the Preferred Reporting Items for Systematic Reviews and Meta  Analyses (PRISMA) and the Cochrane Collaboration guidelines. Results: Our  research included five randomized-controlled trials involving 3,025 patients. We   compared anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, and atezolizumab)   with docetaxel in pretreated patients with advanced or metastatic NSCLC. The  pooled hazard ratio (HR) for overall survival (OS) and progression-free survival   (PFS) was 0.69 (95%CI: 0.63-0.75, P<0.0001, and Ph=0.67) and 0.87 (95%CI:  0.81-0.94, P=0.0004, and Ph=0.11), respectively. Meanwhile, the pooled risk ratio  (RR) for objective response rate (ORR) was 1.53 (95% CI: 1.16-2.01, P=0.003, and   Ph=0.03) in all patients. Subgroup analyses showed that anti-PD-1/PD-L1 treatment  significantly improved OS in patients with PD-L1 expression at any level, even in  patients with PD-L1<1%. The RR for occurrence of grades 3 to 5 treatment-related   adverse effects was 0.23 (95% CI: 0.15-0.36, and P<0.001). Conclusion: OS, PFS,  and ORR were significantly more improved for patients treated with  anti-PD-1/PD-L1 antibodies than for those treated with docetaxel. Anti-PD-1/PD-L1  therapy resulted in longer OS than docetaxel, regardless of PD-L1 expression;  however, higher PD-L1 levels were likely to correlate with better outcome.  Anti-PD-1/PD-L1 antibodies also had a better safety profile than docetaxel.
CANIT0001950	30359383	Clinical research	Non -small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	109	N/A	N/A	Our study shows that an elevated NLR after two cycles of nivolumab was significantly associated with worse OS in patients with advanced NSCLC. An increase in NLR after two cycles was seen in patients who had disease progression. 	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	2018	 Post-treatment changes in hematological parameters predict response to nivolumab   monotherapy in non-small cell lung cancer patients.	 PLoS One	 BACKGROUND: The absolute neutrophil count (ANC), absolute lymphocyte count (ALC),  absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known   markers of inflammation. We evaluated whether ANC, ALC, AMC and NLR, both before   and after treatment with nivolumab, are indicative markers of overall survival  (OS) and evaluated change in NLR as a predictive marker of response in non -small  cell lung cancer (NSCLC) patients treated with nivolumab. METHODS: A total of 109  patients with advanced NSCLC treated with nivolumab were included. ANC, ALC, AMC   and NLR were examined at initiation of nivolumab therapy and after two cycles.  The prognostic role of ANC, ALC, AMC and NLR with OS and changes in NLR ratio  were examined with Kaplan-Meier curves and proportional hazard model. RESULT:  Post-treatment NLR >/=5 after two cycles of nivolumab was associated with poor OS  (median OS in NLR = <5 vs NLR = >/=5 was 29.1 (16.2-40.9) vs 24.2(16.1-36.2)  months respectively, p<0.001). In addition NLR increased in non-responders after   two cycles of nivolumab by 6.6+/-21.8 as compared to responders (p = 0.027).  CONCLUSIONS: Post-treatment ANC, ALC and NLR are independent prognostic factors  in NSCLC patients treated with nivolumab. Changes in NLR can be an early  biomarker for response in NSCLC patients treated with nivolumab.
CANIT0001951	30359383	Clinical research	Non -small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	109	N/A	N/A	Our study shows that high ALC post-treatment was associated with superior outcomes in NSCLC. 	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	2018	 Post-treatment changes in hematological parameters predict response to nivolumab   monotherapy in non-small cell lung cancer patients.	 PLoS One	 BACKGROUND: The absolute neutrophil count (ANC), absolute lymphocyte count (ALC),  absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known   markers of inflammation. We evaluated whether ANC, ALC, AMC and NLR, both before   and after treatment with nivolumab, are indicative markers of overall survival  (OS) and evaluated change in NLR as a predictive marker of response in non -small  cell lung cancer (NSCLC) patients treated with nivolumab. METHODS: A total of 109  patients with advanced NSCLC treated with nivolumab were included. ANC, ALC, AMC   and NLR were examined at initiation of nivolumab therapy and after two cycles.  The prognostic role of ANC, ALC, AMC and NLR with OS and changes in NLR ratio  were examined with Kaplan-Meier curves and proportional hazard model. RESULT:  Post-treatment NLR >/=5 after two cycles of nivolumab was associated with poor OS  (median OS in NLR = <5 vs NLR = >/=5 was 29.1 (16.2-40.9) vs 24.2(16.1-36.2)  months respectively, p<0.001). In addition NLR increased in non-responders after   two cycles of nivolumab by 6.6+/-21.8 as compared to responders (p = 0.027).  CONCLUSIONS: Post-treatment ANC, ALC and NLR are independent prognostic factors  in NSCLC patients treated with nivolumab. Changes in NLR can be an early  biomarker for response in NSCLC patients treated with nivolumab.
CANIT0001952	30359383	Clinical research	Non -small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	109	N/A	N/A	Our study shows that high ANC after treatment was significantly associated with worse OS in patients with advanced NSCLC.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	2018	 Post-treatment changes in hematological parameters predict response to nivolumab   monotherapy in non-small cell lung cancer patients.	 PLoS One	 BACKGROUND: The absolute neutrophil count (ANC), absolute lymphocyte count (ALC),  absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known   markers of inflammation. We evaluated whether ANC, ALC, AMC and NLR, both before   and after treatment with nivolumab, are indicative markers of overall survival  (OS) and evaluated change in NLR as a predictive marker of response in non -small  cell lung cancer (NSCLC) patients treated with nivolumab. METHODS: A total of 109  patients with advanced NSCLC treated with nivolumab were included. ANC, ALC, AMC   and NLR were examined at initiation of nivolumab therapy and after two cycles.  The prognostic role of ANC, ALC, AMC and NLR with OS and changes in NLR ratio  were examined with Kaplan-Meier curves and proportional hazard model. RESULT:  Post-treatment NLR >/=5 after two cycles of nivolumab was associated with poor OS  (median OS in NLR = <5 vs NLR = >/=5 was 29.1 (16.2-40.9) vs 24.2(16.1-36.2)  months respectively, p<0.001). In addition NLR increased in non-responders after   two cycles of nivolumab by 6.6+/-21.8 as compared to responders (p = 0.027).  CONCLUSIONS: Post-treatment ANC, ALC and NLR are independent prognostic factors  in NSCLC patients treated with nivolumab. Changes in NLR can be an early  biomarker for response in NSCLC patients treated with nivolumab.
CANIT0001953	30427914	Basic research	BRAF mutant colorectal carcinomas	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Basic research	The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	2018	 The role of autophagy in the treatment of BRAF mutant colorectal carcinomas  differs based on microsatellite instability status.	 PLoS One	 Autophagy has been identified as a catabolic mechanism in cells but its' role in   cancer remains controversial. Autophagy has been characterized either as tumor  suppressor or inducer mechanism in many tumor types. Monoclonal antibodies  against EGFR (cetuximab and panitumumab) represent a major step in the treatment   of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy  which reveals a potential resistance mechanism to these agents. The last years  immunotherapy appears to be a novel promising strategy for the treatment of  patients with solid tumors, including colorectal cancer. Checkpoint inhibitors,  such as anti-PD1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab)  antibodies have already been developed and applied in mCRC patients with MSI-H  phenotype. The association between mtBRAF and autophagy or MSI status has already  been characterized. In our study, we identify the autophagy initiation through  anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma  cell lines according to microsatellite status. The combination of autophagy  inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy  targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors  appears to be the best treatment approach for microsatellite instability high and  stable colorectal cancer cell lines, respectively. Both combinatorial approaches   reduce cell viability through the induction of apoptotic cell death. The findings  of this study point out the importance of different approach for the treatment of  BRAF mutant metastatic colorectal cancers based on their microsatelite  instability phenotype.
CANIT0001954	30427914	Basic research	BRAF mutant colorectal carcinomas	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Basic research	The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	Microsatellite instability	Mutational status	2018	 The role of autophagy in the treatment of BRAF mutant colorectal carcinomas  differs based on microsatellite instability status.	 PLoS One	 Autophagy has been identified as a catabolic mechanism in cells but its' role in   cancer remains controversial. Autophagy has been characterized either as tumor  suppressor or inducer mechanism in many tumor types. Monoclonal antibodies  against EGFR (cetuximab and panitumumab) represent a major step in the treatment   of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy  which reveals a potential resistance mechanism to these agents. The last years  immunotherapy appears to be a novel promising strategy for the treatment of  patients with solid tumors, including colorectal cancer. Checkpoint inhibitors,  such as anti-PD1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab)  antibodies have already been developed and applied in mCRC patients with MSI-H  phenotype. The association between mtBRAF and autophagy or MSI status has already  been characterized. In our study, we identify the autophagy initiation through  anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma  cell lines according to microsatellite status. The combination of autophagy  inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy  targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors  appears to be the best treatment approach for microsatellite instability high and  stable colorectal cancer cell lines, respectively. Both combinatorial approaches   reduce cell viability through the induction of apoptotic cell death. The findings  of this study point out the importance of different approach for the treatment of  BRAF mutant metastatic colorectal cancers based on their microsatelite  instability phenotype.
CANIT0001955	30427914	Basic research	BRAF mutant colorectal carcinomas	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	2018	 The role of autophagy in the treatment of BRAF mutant colorectal carcinomas  differs based on microsatellite instability status.	 PLoS One	 Autophagy has been identified as a catabolic mechanism in cells but its' role in   cancer remains controversial. Autophagy has been characterized either as tumor  suppressor or inducer mechanism in many tumor types. Monoclonal antibodies  against EGFR (cetuximab and panitumumab) represent a major step in the treatment   of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy  which reveals a potential resistance mechanism to these agents. The last years  immunotherapy appears to be a novel promising strategy for the treatment of  patients with solid tumors, including colorectal cancer. Checkpoint inhibitors,  such as anti-PD1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab)  antibodies have already been developed and applied in mCRC patients with MSI-H  phenotype. The association between mtBRAF and autophagy or MSI status has already  been characterized. In our study, we identify the autophagy initiation through  anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma  cell lines according to microsatellite status. The combination of autophagy  inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy  targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors  appears to be the best treatment approach for microsatellite instability high and  stable colorectal cancer cell lines, respectively. Both combinatorial approaches   reduce cell viability through the induction of apoptotic cell death. The findings  of this study point out the importance of different approach for the treatment of  BRAF mutant metastatic colorectal cancers based on their microsatelite  instability phenotype.
CANIT0001956	30427914	Basic research	BRAF mutant colorectal carcinomas	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	Microsatellite instability	Mutational status	2018	 The role of autophagy in the treatment of BRAF mutant colorectal carcinomas  differs based on microsatellite instability status.	 PLoS One	 Autophagy has been identified as a catabolic mechanism in cells but its' role in   cancer remains controversial. Autophagy has been characterized either as tumor  suppressor or inducer mechanism in many tumor types. Monoclonal antibodies  against EGFR (cetuximab and panitumumab) represent a major step in the treatment   of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy  which reveals a potential resistance mechanism to these agents. The last years  immunotherapy appears to be a novel promising strategy for the treatment of  patients with solid tumors, including colorectal cancer. Checkpoint inhibitors,  such as anti-PD1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab)  antibodies have already been developed and applied in mCRC patients with MSI-H  phenotype. The association between mtBRAF and autophagy or MSI status has already  been characterized. In our study, we identify the autophagy initiation through  anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma  cell lines according to microsatellite status. The combination of autophagy  inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy  targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors  appears to be the best treatment approach for microsatellite instability high and  stable colorectal cancer cell lines, respectively. Both combinatorial approaches   reduce cell viability through the induction of apoptotic cell death. The findings  of this study point out the importance of different approach for the treatment of  BRAF mutant metastatic colorectal cancers based on their microsatelite  instability phenotype.
CANIT0001957	30427914	Basic research	BRAF mutant colorectal carcinomas	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	Cell lines	N/A	Basic research	The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	2018	 The role of autophagy in the treatment of BRAF mutant colorectal carcinomas  differs based on microsatellite instability status.	 PLoS One	 Autophagy has been identified as a catabolic mechanism in cells but its' role in   cancer remains controversial. Autophagy has been characterized either as tumor  suppressor or inducer mechanism in many tumor types. Monoclonal antibodies  against EGFR (cetuximab and panitumumab) represent a major step in the treatment   of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy  which reveals a potential resistance mechanism to these agents. The last years  immunotherapy appears to be a novel promising strategy for the treatment of  patients with solid tumors, including colorectal cancer. Checkpoint inhibitors,  such as anti-PD1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab)  antibodies have already been developed and applied in mCRC patients with MSI-H  phenotype. The association between mtBRAF and autophagy or MSI status has already  been characterized. In our study, we identify the autophagy initiation through  anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma  cell lines according to microsatellite status. The combination of autophagy  inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy  targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors  appears to be the best treatment approach for microsatellite instability high and  stable colorectal cancer cell lines, respectively. Both combinatorial approaches   reduce cell viability through the induction of apoptotic cell death. The findings  of this study point out the importance of different approach for the treatment of  BRAF mutant metastatic colorectal cancers based on their microsatelite  instability phenotype.
CANIT0001958	30427914	Basic research	BRAF mutant colorectal carcinomas	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	Cell lines	N/A	Basic research	The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	Microsatellite instability	Mutational status	2018	 The role of autophagy in the treatment of BRAF mutant colorectal carcinomas  differs based on microsatellite instability status.	 PLoS One	 Autophagy has been identified as a catabolic mechanism in cells but its' role in   cancer remains controversial. Autophagy has been characterized either as tumor  suppressor or inducer mechanism in many tumor types. Monoclonal antibodies  against EGFR (cetuximab and panitumumab) represent a major step in the treatment   of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy  which reveals a potential resistance mechanism to these agents. The last years  immunotherapy appears to be a novel promising strategy for the treatment of  patients with solid tumors, including colorectal cancer. Checkpoint inhibitors,  such as anti-PD1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab)  antibodies have already been developed and applied in mCRC patients with MSI-H  phenotype. The association between mtBRAF and autophagy or MSI status has already  been characterized. In our study, we identify the autophagy initiation through  anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma  cell lines according to microsatellite status. The combination of autophagy  inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy  targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors  appears to be the best treatment approach for microsatellite instability high and  stable colorectal cancer cell lines, respectively. Both combinatorial approaches   reduce cell viability through the induction of apoptotic cell death. The findings  of this study point out the importance of different approach for the treatment of  BRAF mutant metastatic colorectal cancers based on their microsatelite  instability phenotype.
CANIT0001959	30542036	Case report	An elderly case of squamous cell lung cancer	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	An elderly case of squamous-cell lung cancer was treated continuously with pembrolizumab without any decline in the patient's life function.	N/A	N/A	N/A	N/A	N/A	N/A	2018	 [An elderly case of squamous cell lung cancer treated continuously with  pembrolizumab without any decline in the life function].	 Nihon Ronen Igakkai Zasshi	 BACKGROUND: Whether or not immune checkpoint inhibitors are safe and effective  for the elderly remains unclear, even though these drugs were approved two years   ago for the treatment of advanced non-small cell lung cancer in Japan. Older  cancer patients are vulnerable to chemotherapy, so their life function should be   closely monitored before starting, continuing, or discontinuing cancer treatment.  CASE: An 85-year-old man showed a wedge-shaped shadow in the apical portion of  the left lung on chest computed tomography. Unfortunately, repeated bronchoscopy   revealed no malignancy. The shadow progressed over about one year, so a third  bronchoscopy was performed, leading to a diagnosis of squamous-cell carcinoma  (cT3N2M1a, stage IVA). Because PD-L1 immunohistochemical staining was positive  for 80%-90% of the tumor cells, the patient was treated with pembrolizumab as the  first-line therapy, and the tumor dramatically regressed, notably without any  decline in the patient's life functions. CONCLUSION: An elderly case of  squamous-cell lung cancer was treated continuously with pembrolizumab without any  decline in the patient's life function.
CANIT0001960	30572331	Case report	Non-Small Cell Lung Cancer with stage IV adenocarcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Near complete radiological response in patients with decreased carcinoembryonic antigen	Pneumonitis as a serious adverse event	N/A	N/A	Carcinoembryonic antigen (P06731); 	Carcinoembryonic antigen	Gene expression signature on/in tumor cell	2018	 Recurrent Episodes of Nivolumab-Induced Pneumonitis after Nivolumab  Discontinuation and the Time Course of Carcinoembryonic Antigen Levels: A Case of  a 58-Year-Old Woman with Non-Small Cell Lung Cancer.	 Chemotherapy	 INTRODUCTION: The introduction of immune checkpoint inhibitors heralded a new era  in the treatment of non-small cell lung cancer. However, nivolumab, an anti-PD-1   antibody, can cause serious adverse events that are mostly autoimmune related.  CASE PRESENTATION: A 58-year-old woman was treated with nivolumab as second-line   therapy for stage IV adenocarcinoma. The patient developed a nivolumab-induced  recurrent pneumonitis preceding durable clinical remission after seven cycles of   nivolumab. Although high-dose glucocorticosteroids were tapered to conform to  contemporary guidelines, recurring episodes of pneumonitis occurred without  nivolumab rechallenge. In addition, carcinoembryonic antigen (CEA) serum levels  were associated with treatment response, since CEA decline correlated with a near  complete radiological response and, conversely, elevated CEA serum levels were  associated with progressive disease. CONCLUSIONS: In this case, we described  recurrence of nivolumab-induced pneumonitis as a serious adverse event in immune   checkpoint inhibitors. Our case illustrates that immune-related adverse events  may correlate with antitumour activity, even after treatment discontinuation. In   addition, this case suggests the possible clinical utility of CEA serum levels  for the assessment of (durable) effects of immunotherapy.CI  - (c) 2018 S. Karger AG, Basel.
CANIT0001961	30589044	Case report	Metastatic gastric cancer after progression on trastuzumab	Gastric cancer	MONDO:0001056	Stomach	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab plus lapatinib	N/A	Immune checkpoint therapy plus Target therapy	Ipilimumab (DB06186); lapatinib (DB01259); 	1	N/A	Case	Targeted therapy combined with immunotherapy might be a useful option for metastatic gastric.	N/A	N/A	N/A	N/A	N/A	N/A	2018	 Prolonged overall survival in metastatic gastric cancer treated with ipilimumab  and lapatinib.	 J Cancer Res Ther	 Objective: Gastric cancer is one of the most important common tumors in the  world. It remains the second leading cause of cancer-related death worldwide. The  prognosis of patients with unresectable or metastatic gastric cancer remains  poor. New targeted drugs were evaluated in clinic, such as lapatinib. The  potential for making beneficial progress is to investigate innovative therapeutic  strategies, such as immunotherapy. Methods: We used combination therapy including  immunotherapy for treating gastric cancer. We treated a patient of metastatic  gastric cancer for which lapatinib plus ipilimumab was effective after  progression on trastuzumab. Results: The patient has prolonged overall survival  after treatment. Positron emission tomography-computed tomography examination  showed that some of the cervical lymph nodes and retroperitoneal lymph nodes  reduced and glucose metabolism decreased. In blood examination, the tumor marker   (carcinoembryonic antigen) decreased. The patient has been lived for 4 years  after multiple lymph node metastasis. Conclusion: Targeted therapy combined with   immunotherapy might be a useful option for metastatic gastric.
CANIT0001962	31006740	Case report	Primary malignant melanoma of the female urethra	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	The tumor was pathologically confined in the specimen and no lymph node metastasis was found. She received interferone  as adjuvant therapy. However, she developed bilateral adrenal and pulmonary hilar lymph node metastases 1 year after urethrectomy. Although she started to receive nivolumab as salvage therapy, the disease progressed as well as development of interstitial pneumonia (IP) after four cycles. Following improvement of IP with steroid therapy, she started to receive ipilimumab, which resulted in the development of intolerable IP of grade 3. The patient finally died of malignant melanoma 19 months after the initiation of treatment.	Interstitial pneumonia	N/A	N/A	N/A	N/A	N/A	2018	 [PRIMARY MALIGNANT MELANOMA OF THE FEMALE URETHRA: A CASE REPORT].	 Nihon Hinyokika Gakkai Zasshi	 We report a case of primary malignant melanoma (MM) of the female urethra. A  60-year-old female complained bleeding from the urethral meatus. MRI revealed a  mass of 20 mm at the external urethral meatus. Pathological examination of  transurethrally resected specimens revealed MM with stromal invasion. She  underwent total urethrectomy plus cystostomy and sentinel lymph node biopsy. The   tumor was pathologically confined in the specimen and no lymph node metastasis  was found. She received interferone beta as adjuvant therapy. However, she  developed bilateral adrenal and pulmonary hilar lymph node metastases 1 year  after urethrectomy. Although she started to receive nivolumab as salvage therapy,  the disease progressed as well as development of interstitial pneumonia (IP)  after four cycles. Following improvement of IP with steroid therapy, she started   to receive ipilimumab, which resulted in the development of intolerable IP of  grade 3. The patient finally died of MM 19 months after the initiation of  treatment.
CANIT0001963	31006740	Case report	Primary malignant melanoma  of the female urethra	Melanoma	EFO:0000756	Skin	IFNB1 (P01574); 	IFNB1; 	IFNB1	N/A	Immune cytokine	IFNB1 (DB00018); 	1	N/A	Case	The tumor was pathologically confined in the specimen and no lymph node metastasis was found. She received interferone  as adjuvant therapy. However, she developed bilateral adrenal and pulmonary hilar lymph node metastases 1 year after urethrectomy. Although she started to receive nivolumab as salvage therapy, the disease progressed as well as development of interstitial pneumonia (IP) after four cycles. Following improvement of IP with steroid therapy, she started to receive ipilimumab, which resulted in the development of intolerable IP of grade 3. The patient finally died of malignant melanomaM 19 months after the initiation of treatment.	Interstitial pneumonia	N/A	N/A	N/A	N/A	N/A	2018	 [PRIMARY MALIGNANT MELANOMA OF THE FEMALE URETHRA: A CASE REPORT].	 Nihon Hinyokika Gakkai Zasshi	 We report a case of primary malignant melanoma (MM) of the female urethra. A  60-year-old female complained bleeding from the urethral meatus. MRI revealed a  mass of 20 mm at the external urethral meatus. Pathological examination of  transurethrally resected specimens revealed MM with stromal invasion. She  underwent total urethrectomy plus cystostomy and sentinel lymph node biopsy. The   tumor was pathologically confined in the specimen and no lymph node metastasis  was found. She received interferone beta as adjuvant therapy. However, she  developed bilateral adrenal and pulmonary hilar lymph node metastases 1 year  after urethrectomy. Although she started to receive nivolumab as salvage therapy,  the disease progressed as well as development of interstitial pneumonia (IP)  after four cycles. Following improvement of IP with steroid therapy, she started   to receive ipilimumab, which resulted in the development of intolerable IP of  grade 3. The patient finally died of MM 19 months after the initiation of  treatment.
CANIT0001964	31006740	Case report	Primary malignant melanoma  of the female urethra	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The tumor was pathologically confined in the specimen and no lymph node metastasis was found. She received interferone  as adjuvant therapy. However, she developed bilateral adrenal and pulmonary hilar lymph node metastases 1 year after urethrectomy. Although she started to receive nivolumab as salvage therapy, the disease progressed as well as development of interstitial pneumonia (IP) after four cycles. Following improvement of IP with steroid therapy, she started to receive ipilimumab, which resulted in the development of intolerable IP of grade 3. The patient finally died of malignant melanoma 19 months after the initiation of treatment.	Interstitial pneumonia	N/A	N/A	N/A	N/A	N/A	2018	 [PRIMARY MALIGNANT MELANOMA OF THE FEMALE URETHRA: A CASE REPORT].	 Nihon Hinyokika Gakkai Zasshi	 We report a case of primary malignant melanoma (MM) of the female urethra. A  60-year-old female complained bleeding from the urethral meatus. MRI revealed a  mass of 20 mm at the external urethral meatus. Pathological examination of  transurethrally resected specimens revealed MM with stromal invasion. She  underwent total urethrectomy plus cystostomy and sentinel lymph node biopsy. The   tumor was pathologically confined in the specimen and no lymph node metastasis  was found. She received interferone beta as adjuvant therapy. However, she  developed bilateral adrenal and pulmonary hilar lymph node metastases 1 year  after urethrectomy. Although she started to receive nivolumab as salvage therapy,  the disease progressed as well as development of interstitial pneumonia (IP)  after four cycles. Following improvement of IP with steroid therapy, she started   to receive ipilimumab, which resulted in the development of intolerable IP of  grade 3. The patient finally died of MM 19 months after the initiation of  treatment.
CANIT0001965	29207939	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Tocilizumab	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); Tocilizumab (DB06273); 	16	N/A	Retrospective analysis	Tocilizumab may be a therapeutic option for the management of steroid refractory immune-related adverse events secondary to immune checkpoint blockade. There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.	Steroid refractory irAEs secondary to immune checkpoint blockade	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Apr	Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.	 J Oncol Pharm Pract	BACKGROUND: Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid refractory irAEs.METHODS: The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4 mg/kg given IV over one hour. C-reactive protein was drawn at first nivolumab infusion and at q two weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital discharge within seven days.RESULTS: Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1-429). There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1-238.5) at baseline to 109.3 mg/L (21.5-350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25-149) after tocilizumab ( p < 0.00001). Clinical improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a single dose, while 38.2% required two, 8.8% required three and 1 patient required four doses. Twenty-seven doses were given in the inpatient setting (49.1%). Median time to discharge was four days (range 1-27). Seventy-four percent of patients were discharged home. For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 (WAC) during the 18 month study period.CONCLUSIONS: Tocilizumab may be a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.
CANIT0001966	29254746	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	260	N/A	Retrospective analysis	In real life setting, the effectiveness of nivolumab is reasonable yet less prominent than it has been demonstrated in clinical trials. ECOG PS >=2 is associated with poor prognosis.	The nivolumab safety profile was in accordance with the literature data, except for febrile neutropenia and pericarditis (observed in 1 case each).	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2018 Dec	Effectiveness and safety of nivolumab in advanced non-small cell lung cancer: The real-life data.	 Lung Cancer	OBJECTIVES: Nivolumab has recently received regulatory approval as a 2nd-line treatment of non-small cell lung cancer (NSCLC). The data regarding its effectiveness and safety in real life setting is lacking.MATERIALS AND METHODS: 260 consecutive patients with advanced NSCLC treated with nivolumab at five Israeli cancer centers between January 2015 and March 2016 were evaluated for overall survival (OS) and toxicity. OS was analyzed by the Cox proportional-hazards regression model. Overall response rate (ORR) and progression-free survival (PFS) were assessed in 49 patients using RECIST, v.1.1.RESULTS: Median age was 67y (41-99); males 68%; smokers 76%; ECOG PS >=2 46%; non-squamous/squamous/other/NR 70%/23%/6%/1%; brain metastases 21%; liver metastases 21%; treatment line: 1st/2nd/3rd+-line/NR 6%/64%/26%/4%. With median survival follow-up of 18.5 months (range, 12.0-26.9), 155 (60%) patients died; median OS comprised 5.9 months (95% CI 4.7-7.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS. Median OS of patients with ECOG PS 0/1 and ECOG PS >=2 comprised 9.5 months (95% CI, 6.7-NR) and 3.5 months (95% CI, 2.6-4.5), respectively. For 49 patients evaluable for response (median follow-up of 8.4 months (range, 2-16.8), ORR was 35%, median PFS was 2.8 months (95% CI, 1.8-7.7), incidence of pseudo-progression was 9%. The nivolumab safety profile was in accordance with the literature data, except for febrile neutropenia and pericarditis (observed in 1 case each).CONCLUSION: In real life setting, the effectiveness of nivolumab is reasonable yet less prominent than it has been demonstrated in clinical trials. ECOG PS >=2 is associated with poor prognosis.
CANIT0001967	29549485	Clinical research	Urothelial cancer; renal cancer	Renal carcinoma	EFO:0002890	Kidney	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	Meta-analysis	Pseudoprogression (PP)  seems to occur in a non-negligible rate of urothelial (UC) and renal cancer (RCC) (from 1.5 to 17% and from 5 to 15%, respectively).PP and hyperprogression (HP) are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Nov	Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer.	 World J Urol	OBJECTIVES: A small subset of patients treated with immune checkpoint inhibitors manifest atypical patterns of response, the so-called pseudoprogression (PP) and hyperprogression (HP). Their prevalence in urothelial (UC) and renal cancer (RCC) remains, to date, mostly uninvestigated. Therefore, we aimed to provide a summary of the current knowledge about PP and HP during immune checkpoint inhibitor therapy in UC and RCC patients.METHODS AND MATERIALS: A systematic medline/pubmed  literature search was performed. The atypical patterns of response to systemic immunotherapy were reviewed. Endpoints were PP and HP in UC and RCC.RESULTS: Tumors respond differently to immunotherapy compared to systemic chemotherapy. To evaluate response to immunotherapy, new guidelines (iRECIST) have been developed. To date, no studies focused on PP in UC and RCC, and the only way to evaluate its role is to take patients who respond to treatment beyond progression as surrogate for pseudoprogressors. PP seems to occur in a non-negligible rate of UC and RCC (from 1.5 to 17% and from 5 to 15%, respectively). The concept of HP, defined as a rapid progression after treatment, just took the first steps, and therefore, data from ongoing trials are awaited to elucidate its impact in genitourinary cancers.CONCLUSIONS: PP and HP are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.
CANIT0001968	29549485	Clinical research	Urothelial cancer; renal cancer	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	Meta-analysis	Pseudoprogression (PP)  seems to occur in a non-negligible rate of urothelial (UC) and renal cancer (RCC) (from 1.5 to 17% and from 5 to 15%, respectively).PP and hyperprogression (HP) are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Nov	Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer.	 World J Urol	OBJECTIVES: A small subset of patients treated with immune checkpoint inhibitors manifest atypical patterns of response, the so-called pseudoprogression (PP) and hyperprogression (HP). Their prevalence in urothelial (UC) and renal cancer (RCC) remains, to date, mostly uninvestigated. Therefore, we aimed to provide a summary of the current knowledge about PP and HP during immune checkpoint inhibitor therapy in UC and RCC patients.METHODS AND MATERIALS: A systematic medline/pubmed  literature search was performed. The atypical patterns of response to systemic immunotherapy were reviewed. Endpoints were PP and HP in UC and RCC.RESULTS: Tumors respond differently to immunotherapy compared to systemic chemotherapy. To evaluate response to immunotherapy, new guidelines (iRECIST) have been developed. To date, no studies focused on PP in UC and RCC, and the only way to evaluate its role is to take patients who respond to treatment beyond progression as surrogate for pseudoprogressors. PP seems to occur in a non-negligible rate of UC and RCC (from 1.5 to 17% and from 5 to 15%, respectively). The concept of HP, defined as a rapid progression after treatment, just took the first steps, and therefore, data from ongoing trials are awaited to elucidate its impact in genitourinary cancers.CONCLUSIONS: PP and HP are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.
CANIT0001969	29672849	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	Retrospective analysis	Baseline neutrophilia was not associated with response. Among refractory patients, a higher incidence of neutrophilia was observed compared with the overall population.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2018 Oct	Baseline neutrophilia, derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), and outcome in non small cell lung cancer (NSCLC) treated with Nivolumab or Docetaxel.	 J Cell Physiol	Nivolumab is a novel therapeutic option in NSCLC, associated with a significant survival gain compared with Docetaxel. However, predictive biomarkers are lacking. The presence of systemic inflammation has been correlated with poor outcome in many cancer types. We aimed to evaluate whether there is a correlation between some indicators of inflammation and response to Nivolumab or Docetaxel in pre-treated NSCLCs. Data of 62 patients receiving Nivolumab or Docetaxel were analyzed. Baseline neutrophilia and thrombocytosis were not associated with response. High dNLR was associated with no response to Nivolumab, but not with Docetaxel, whereas high PLR correlated with low treatment response in both groups. Among refractory patients, a higher incidence of thrombocytosis, neutrophilia, high PLR, and high dNLR levels were observed compared with the overall population. This is one of the first reports in this field and suggests that indicators of inflammation might be included together with other predictive biomarkers in the baseline evaluation of patients candidate for immunotherapy.
CANIT0001970	29672849	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	Retrospective analysis	High neutrophil-to-lymphocyte ratio (NLR) was associated with no response to Nivolumab, but not with Docetaxel. Among refractory patients, a higher incidence of high NLR levels was observed compared with the overall population.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2018 Oct	Baseline neutrophilia, derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), and outcome in non small cell lung cancer (NSCLC) treated with Nivolumab or Docetaxel.	 J Cell Physiol	Nivolumab is a novel therapeutic option in NSCLC, associated with a significant survival gain compared with Docetaxel. However, predictive biomarkers are lacking. The presence of systemic inflammation has been correlated with poor outcome in many cancer types. We aimed to evaluate whether there is a correlation between some indicators of inflammation and response to Nivolumab or Docetaxel in pre-treated NSCLCs. Data of 62 patients receiving Nivolumab or Docetaxel were analyzed. Baseline neutrophilia and thrombocytosis were not associated with response. High dNLR was associated with no response to Nivolumab, but not with Docetaxel, whereas high PLR correlated with low treatment response in both groups. Among refractory patients, a higher incidence of thrombocytosis, neutrophilia, high PLR, and high dNLR levels were observed compared with the overall population. This is one of the first reports in this field and suggests that indicators of inflammation might be included together with other predictive biomarkers in the baseline evaluation of patients candidate for immunotherapy.
CANIT0001971	29672849	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	Retrospective analysis	High platelet-to-lymphocyte ratios (PLR) correlated with low treatment response in both groups. Among refractory patients, a higher incidence of high PLR levels was observed compared with the overall population.	N/A	N/A	N/A	Platelet-to-lymphocyte ratios (EFO:0008446); 	Platelet-to-lymphocyte ratios	Cell percentage/counts in blood	 2018 Oct	Baseline neutrophilia, derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), and outcome in non small cell lung cancer (NSCLC) treated with Nivolumab or Docetaxel.	 J Cell Physiol	Nivolumab is a novel therapeutic option in NSCLC, associated with a significant survival gain compared with Docetaxel. However, predictive biomarkers are lacking. The presence of systemic inflammation has been correlated with poor outcome in many cancer types. We aimed to evaluate whether there is a correlation between some indicators of inflammation and response to Nivolumab or Docetaxel in pre-treated NSCLCs. Data of 62 patients receiving Nivolumab or Docetaxel were analyzed. Baseline neutrophilia and thrombocytosis were not associated with response. High dNLR was associated with no response to Nivolumab, but not with Docetaxel, whereas high PLR correlated with low treatment response in both groups. Among refractory patients, a higher incidence of thrombocytosis, neutrophilia, high PLR, and high dNLR levels were observed compared with the overall population. This is one of the first reports in this field and suggests that indicators of inflammation might be included together with other predictive biomarkers in the baseline evaluation of patients candidate for immunotherapy.
CANIT0001972	29672849	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	Retrospective analysis	Baseline thrombocytosis was not associated with response. Among refractory patients, a higher incidence of thrombocytosis was observed compared with the overall population.	N/A	N/A	N/A	Thrombocytosis (NCIT:C35530); 	Baseline thrombocytosis	Disease status	 2018 Oct	Baseline neutrophilia, derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), and outcome in non small cell lung cancer (NSCLC) treated with Nivolumab or Docetaxel.	 J Cell Physiol	Nivolumab is a novel therapeutic option in NSCLC, associated with a significant survival gain compared with Docetaxel. However, predictive biomarkers are lacking. The presence of systemic inflammation has been correlated with poor outcome in many cancer types. We aimed to evaluate whether there is a correlation between some indicators of inflammation and response to Nivolumab or Docetaxel in pre-treated NSCLCs. Data of 62 patients receiving Nivolumab or Docetaxel were analyzed. Baseline neutrophilia and thrombocytosis were not associated with response. High dNLR was associated with no response to Nivolumab, but not with Docetaxel, whereas high PLR correlated with low treatment response in both groups. Among refractory patients, a higher incidence of thrombocytosis, neutrophilia, high PLR, and high dNLR levels were observed compared with the overall population. This is one of the first reports in this field and suggests that indicators of inflammation might be included together with other predictive biomarkers in the baseline evaluation of patients candidate for immunotherapy.
CANIT0001973	29714649	Case report	Metastatic gastric linitis plastica	Metastatic gastric linitis plastica	EFO:0000503	Stomach	PD-1 (Q15116); HER2 (P04626); 	PD-1; HER2	Nivolumab plus trastuzumab or pertuzumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); trastuzumab (DB00072); pertuzumab (DB06366); 	1	N/A	Case	The patient received 5-fluorouracil/folinic acid and oxaliplatin combined with trastuzumab/pertuzumab, resulting in disease control for 8 months. Second-line therapy with nivolumab and trastuzumab/pertuzumab was well-tolerated, with macroscopic peritoneal response. Following ovarian progression and surgical resection of ovarian metastases, immunohistochemistry of PD-L1 was negative; proteomics demonstrated normal expression of HER2 and absence of PD-L1, while genomics showed HER2 amplification, suggesting mechanisms of escape to dual HER2 blockade by downregulation of HER2 and to nivolumab by the absence of PD-L1. Based upon this and nonexpression of biomarkers of taxane resistance, therapy was changed to paclitaxel. Two and a half years after diagnosis, the patient is undergoing treatment, with excellent performance status.	Second-line therapy with nivolumab and trastuzumab/pertuzumab was well-tolerated, with macroscopic peritoneal response. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Dec	Personalized therapy based on sequential molecular analysis leads to 30 months of survival in a patient with diffuse unresectable gastric linitis plastica.	 Tumori	INTRODUCTION: Diffuse gastric cancer is associated with poor prognosis. We report a patient with metastatic gastric linitis plastica harboring human epidermal growth factor receptor 2 (HER2) activating mutation and HER2 amplification.CASE DESCRIPTION: The patient received 5-fluorouracil/folinic acid and oxaliplatin combined with trastuzumab/pertuzumab, resulting in disease control for 8 months. Second-line therapy with nivolumab and trastuzumab/pertuzumab was well-tolerated, with macroscopic peritoneal response. Following ovarian progression and surgical resection of ovarian metastases, immunohistochemistry of PD-L1 was negative; proteomics demonstrated normal expression of HER2 and absence of PD-L1, while genomics showed HER2 amplification, suggesting mechanisms of escape to dual HER2 blockade by downregulation of HER2 and to nivolumab by the absence of PD-L1. Based upon this and nonexpression of biomarkers of taxane resistance, therapy was changed to paclitaxel. Two and a half years after diagnosis, the patient is undergoing treatment, with excellent performance status.CONCLUSIONS: Molecular analysis and personalized therapy can help optimize treatment in difficult-to-treat cancers.
CANIT0001974	29847461	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	172	N/A	Retrospective analysis	In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8).	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2018 Oct	Metastatic acral lentiginous melanoma in a tertiary referral center in Switzerland: a systematic analysis.	 Melanoma Res	Acral lentiginous melanoma (ALM) is a unique histopathological subtype of melanoma with a poorer prognosis than other cutaneous melanomas. This study aims to evaluate the clinicopathological characteristics, metastatic pattern, prognostic factors, response to systemic therapy, and overall survival (OS) of ALM in a White population. This is a retrospective study of patients who were diagnosed and/or treated for ALM at the Department of Dermatology of the University Hospital Zurich, Switzerland, from January 2005 to December 2015. Overall, 172 patients with histologically confirmed ALM were included in the study. In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8). In our study, Breslow thickness represents the best prognostic factor for OS. In stage IV ALM patients treated with either immunotherapy or TT, there is a trend for extended mOS compared with ChT.
CANIT0001975	29847461	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	172	N/A	Retrospective analysis	In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8).	N/A	N/A	N/A	Age (NCIT:C25150); 	Status of sentinel lymph node	Personal feature	 2018 Oct	Metastatic acral lentiginous melanoma in a tertiary referral center in Switzerland: a systematic analysis.	 Melanoma Res	Acral lentiginous melanoma (ALM) is a unique histopathological subtype of melanoma with a poorer prognosis than other cutaneous melanomas. This study aims to evaluate the clinicopathological characteristics, metastatic pattern, prognostic factors, response to systemic therapy, and overall survival (OS) of ALM in a White population. This is a retrospective study of patients who were diagnosed and/or treated for ALM at the Department of Dermatology of the University Hospital Zurich, Switzerland, from January 2005 to December 2015. Overall, 172 patients with histologically confirmed ALM were included in the study. In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8). In our study, Breslow thickness represents the best prognostic factor for OS. In stage IV ALM patients treated with either immunotherapy or TT, there is a trend for extended mOS compared with ChT.
CANIT0001976	29847461	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	172	N/A	Retrospective analysis	In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8).	N/A	N/A	N/A	Age (NCIT:C25150); 	Ulceration	Personal feature	 2018 Oct	Metastatic acral lentiginous melanoma in a tertiary referral center in Switzerland: a systematic analysis.	 Melanoma Res	Acral lentiginous melanoma (ALM) is a unique histopathological subtype of melanoma with a poorer prognosis than other cutaneous melanomas. This study aims to evaluate the clinicopathological characteristics, metastatic pattern, prognostic factors, response to systemic therapy, and overall survival (OS) of ALM in a White population. This is a retrospective study of patients who were diagnosed and/or treated for ALM at the Department of Dermatology of the University Hospital Zurich, Switzerland, from January 2005 to December 2015. Overall, 172 patients with histologically confirmed ALM were included in the study. In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8). In our study, Breslow thickness represents the best prognostic factor for OS. In stage IV ALM patients treated with either immunotherapy or TT, there is a trend for extended mOS compared with ChT.
CANIT0001977	29847461	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	172	N/A	Retrospective analysis	In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8).	N/A	N/A	N/A	Breslow thickness (NCIT:C25734); 	Breslow thickness	Disease status	 2018 Oct	Metastatic acral lentiginous melanoma in a tertiary referral center in Switzerland: a systematic analysis.	 Melanoma Res	Acral lentiginous melanoma (ALM) is a unique histopathological subtype of melanoma with a poorer prognosis than other cutaneous melanomas. This study aims to evaluate the clinicopathological characteristics, metastatic pattern, prognostic factors, response to systemic therapy, and overall survival (OS) of ALM in a White population. This is a retrospective study of patients who were diagnosed and/or treated for ALM at the Department of Dermatology of the University Hospital Zurich, Switzerland, from January 2005 to December 2015. Overall, 172 patients with histologically confirmed ALM were included in the study. In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8). In our study, Breslow thickness represents the best prognostic factor for OS. In stage IV ALM patients treated with either immunotherapy or TT, there is a trend for extended mOS compared with ChT.
CANIT0001978	29859006	Clinical research	Metastatic gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	225	N/A	Retrospective analysis	PD-L1 expression on TC, PD-L1 on IC, MMR-deficient (D-MMR), and EBV positivity were identified in 8.4, 65.3, 6.2, and 6.2% cases, respectively. PD-L1 expression in TC was more frequently observed in pts with D-MMR (P < 0.001), PIK3CA mutation (P = 0.020), and KRAS mutation (P = 0.002), and PD-L1 on IC was associated with EBV positivity (P = 0.034), and lymph-node metastasis (P < 0.001). PD-L1 expression on either IC or TC was less frequently observed in pts with peritoneal metastasis and Borrmann Type 4. A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. PD-L1 expression on either TC or IC was not prognostic factor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on immune cells	Gene expression signature on/in immune cell	 2019 Jan	Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer.	 Gastric Cancer	BACKGROUND: Recently, the U.S. Food and Drug Administration approved pembrolizumab for patients (pts) with PD-L1-positive metastatic gastric cancer (MGC) based on 22C3 immunohistochemistry (IHC) assay. However, little is known about detailed clinicopathological features of 22C3 PD-L1 expression in MGC.PATIENTS AND METHODS: Pts with histologically confirmed MGC were eligible for this prospective observational study. PD-L1 expression (22C3) on tumor cell (TC) or immune cell (IC) and mismatch repair (MMR) were analyzed by IHC. Epstein-Barr virus (EBV) was detected by in situ hybridization. The expressions of tyrosine kinase receptors (RTKs) and cancer genome alterations were evaluated by IHC or next-generation sequencing.RESULTS: A total of 225 pts were analyzed in this study. PD-L1 expression on TC, PD-L1 on IC, MMR-deficient (D-MMR), and EBV positivity were identified in 8.4, 65.3, 6.2, and 6.2% cases, respectively. PD-L1 expression in TC was more frequently observed in pts with D-MMR (P < 0.001), PIK3CA mutation (P = 0.020), and KRAS mutation (P = 0.002), and PD-L1 on IC was associated with EBV positivity (P = 0.034), and lymph-node metastasis (P < 0.001). PD-L1 expression on either IC or TC was less frequently observed in pts with peritoneal metastasis and Borrmann Type 4. A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. PD-L1 expression on either TC or IC was not prognostic factor.CONCLUSIONS: 22C3 PD-L1 expression in MGC was associated with distinct clinicopathological features, but was not a prognostic factor.
CANIT0001979	29859006	Clinical research	Metastatic gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	225	N/A	Retrospective analysis	PD-L1 expression on TC, PD-L1 on IC, MMR-deficient (D-MMR), and EBV positivity were identified in 8.4, 65.3, 6.2, and 6.2% cases, respectively. PD-L1 expression in TC was more frequently observed in pts with D-MMR (P < 0.001), PIK3CA mutation (P = 0.020), and KRAS mutation (P = 0.002), and PD-L1 on IC was associated with EBV positivity (P = 0.034), and lymph-node metastasis (P < 0.001). PD-L1 expression on either IC or TC was less frequently observed in pts with peritoneal metastasis and Borrmann Type 4. A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. PD-L1 expression on either TC or IC was not prognostic factor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jan	Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer.	 Gastric Cancer	BACKGROUND: Recently, the U.S. Food and Drug Administration approved pembrolizumab for patients (pts) with PD-L1-positive metastatic gastric cancer (MGC) based on 22C3 immunohistochemistry (IHC) assay. However, little is known about detailed clinicopathological features of 22C3 PD-L1 expression in MGC.PATIENTS AND METHODS: Pts with histologically confirmed MGC were eligible for this prospective observational study. PD-L1 expression (22C3) on tumor cell (TC) or immune cell (IC) and mismatch repair (MMR) were analyzed by IHC. Epstein-Barr virus (EBV) was detected by in situ hybridization. The expressions of tyrosine kinase receptors (RTKs) and cancer genome alterations were evaluated by IHC or next-generation sequencing.RESULTS: A total of 225 pts were analyzed in this study. PD-L1 expression on TC, PD-L1 on IC, MMR-deficient (D-MMR), and EBV positivity were identified in 8.4, 65.3, 6.2, and 6.2% cases, respectively. PD-L1 expression in TC was more frequently observed in pts with D-MMR (P < 0.001), PIK3CA mutation (P = 0.020), and KRAS mutation (P = 0.002), and PD-L1 on IC was associated with EBV positivity (P = 0.034), and lymph-node metastasis (P < 0.001). PD-L1 expression on either IC or TC was less frequently observed in pts with peritoneal metastasis and Borrmann Type 4. A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. PD-L1 expression on either TC or IC was not prognostic factor.CONCLUSIONS: 22C3 PD-L1 expression in MGC was associated with distinct clinicopathological features, but was not a prognostic factor.
CANIT0001980	29889678	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Nivolumab-Associated Guillain-Barre Syndrome in a Patient With Non-Small-Cell Lung Cancer	Nivolumab-Associated Guillain-Barre Syndrome	N/A	N/A	N/A	N/A	N/A	 2018 Nov/Dec	Nivolumab-Associated Guillain-Barre Syndrome in a Patient With Non-Small-Cell Lung Cancer.	 Am J Ther	Unable to provide
CANIT0001981	29927883	Case report	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	3	N/A	Case	Three cancer patients treated with immune checkpoint inhibitors developed orbital inflammation. The first patient was treated with a combination of a cytotoxic T-lymphocyte antigen-4 inhibitor and a programmed cell death protein 1 inhibitor and developed TED-like orbital inflammation with normal thyroid function and antibody levels. The second patient had a previous diagnosis of Graves disease without TED, and developed TED soon after initiating treatment with a programmed cell death protein 1 inhibitor. The third patient developed acute hyperthyroidism with symptomatic TED following treatment with an investigational cytotoxic T-lymphocyte antigen-4 inhibitor agent. All 3 patients were managed with either systemic steroids or observation, with resolution of their symptoms and without the need to halt immune checkpoint inhibitor treatment for their cancer.	Extraocular Muscle Enlargement and Thyroid Eye Disease-like Orbital Inflammation	N/A	N/A	N/A	N/A	N/A	 2019 Jan/Feb	Extraocular Muscle Enlargement and Thyroid Eye Disease-like Orbital Inflammation Associated with Immune Checkpoint Inhibitor Therapy in Cancer Patients.	 Ophthalmic Plast Reconstr Surg	PURPOSE: To describe thyroid eye disease (TED)-like orbital inflammatory syndrome in 3 cancer patients treated with immune checkpoint inhibitors.METHODS: All consecutive patients treated by the senior author who were receiving immune checkpoint inhibitors and developed TED-like orbital inflammation were included.RESULTS: Three cancer patients treated with immune checkpoint inhibitors developed orbital inflammation. The first patient was treated with a combination of a cytotoxic T-lymphocyte antigen-4 inhibitor and a programmed cell death protein 1 inhibitor and developed TED-like orbital inflammation with normal thyroid function and antibody levels. The second patient had a previous diagnosis of Graves disease without TED, and developed TED soon after initiating treatment with a programmed cell death protein 1 inhibitor. The third patient developed acute hyperthyroidism with symptomatic TED following treatment with an investigational cytotoxic T-lymphocyte antigen-4 inhibitor agent. All 3 patients were managed with either systemic steroids or observation, with resolution of their symptoms and without the need to halt immune checkpoint inhibitor treatment for their cancer.DISCUSSION AND CONCLUSIONS: TED-like orbital inflammation may occur as a side effect of immune checkpoint inhibitor therapy with anti-cytotoxic T-lymphocyte antigen-4 or anti-PD-1 inhibitors. To the best of their knowledge, this is the first reported case of TED as a result of programmed cell death protein 1 inhibitor monotherapy. All 3 patients were treated with systemic steroids and responded quickly while continuing treatment with immune checkpoint inhibitors for their cancer. With increasing use of this class of drugs, clinicians should be familiar with the clinical manifestations and treatments for this adverse reaction.
CANIT0001982	29947012	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We experienced a patient with NSCLC with high PD-L1 expression and cervical lymph node metastases, who demonstrated a good clinical response to first line pembrolizumab but suffered from a severe cutaneous adverse event. Both of his skin lesions and cervical metastases showed extensive CD8(+) PD-1(+) T-cell infiltration in immunofluorescence analysis.	Pembrolizumab-induced cutaneous adverse reaction	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Dec	Proliferative CD8(+) PD-1(+) T-cell infiltration in a pembrolizumab-induced cutaneous adverse reaction.	 Invest New Drugs	Pembrolizumab, a humanized monoclonal immunoglobulin (Ig) G4 antibody that is directed against the human cell surface receptor PD-1, is a PD-1 pathway inhibitor that has been approved to treat various malignant diseases, including advanced non-small cell lung cancer (NSCLC). PD-1 is the major inhibitory receptor regulating T-cell exhaustion, and T-cells with high PD-1 expression lose their ability to eliminate cancer. PD-1 pathway blockade by pembrolizumab reinvigorates exhausted T-cells and restores their antitumor immune responses. However, reinvigorated T-cells also evoke immune-related adverse effects (irAEs), which stem from the restored activity. Currently, the pathogenic mechanisms of irAEs have not been sufficiently determined. We experienced a patient with NSCLC with high PD-L1 expression and cervical lymph node metastases, who demonstrated a good clinical response to first line pembrolizumab but suffered from a severe cutaneous adverse event. Both of his skin lesions and cervical metastases showed extensive CD8(+) PD-1(+) T-cell infiltration in immunofluorescence analysis. This finding suggests a possible contribution of reinvigorated CD8(+) PD-1(+) T-cells in anti-PD-1 therapy-induced skin rash. Intriguingly, CD8(+) T-cells in the skin rash showed higher Ki-67 expression, a proliferation marker, than those in the cervical lymph node lesion. This is the first report of an association between proliferative CD8(+) PD-1(+) T-cells and irAEs.
CANIT0001983	29947012	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We experienced a patient with NSCLC with high PD-L1 expression and cervical lymph node metastases, who demonstrated a good clinical response to first line pembrolizumab but suffered from a severe cutaneous adverse event. Both of his skin lesions and cervical metastases showed extensive CD8(+) PD-1(+) T-cell infiltration in immunofluorescence analysis.	Pembrolizumab-induced cutaneous adverse reaction	N/A	N/A	Metastasis (NCIT:C19151); 	Cervical lymph node metastases	Disease status	 2018 Dec	Proliferative CD8(+) PD-1(+) T-cell infiltration in a pembrolizumab-induced cutaneous adverse reaction.	 Invest New Drugs	Pembrolizumab, a humanized monoclonal immunoglobulin (Ig) G4 antibody that is directed against the human cell surface receptor PD-1, is a PD-1 pathway inhibitor that has been approved to treat various malignant diseases, including advanced non-small cell lung cancer (NSCLC). PD-1 is the major inhibitory receptor regulating T-cell exhaustion, and T-cells with high PD-1 expression lose their ability to eliminate cancer. PD-1 pathway blockade by pembrolizumab reinvigorates exhausted T-cells and restores their antitumor immune responses. However, reinvigorated T-cells also evoke immune-related adverse effects (irAEs), which stem from the restored activity. Currently, the pathogenic mechanisms of irAEs have not been sufficiently determined. We experienced a patient with NSCLC with high PD-L1 expression and cervical lymph node metastases, who demonstrated a good clinical response to first line pembrolizumab but suffered from a severe cutaneous adverse event. Both of his skin lesions and cervical metastases showed extensive CD8(+) PD-1(+) T-cell infiltration in immunofluorescence analysis. This finding suggests a possible contribution of reinvigorated CD8(+) PD-1(+) T-cells in anti-PD-1 therapy-induced skin rash. Intriguingly, CD8(+) T-cells in the skin rash showed higher Ki-67 expression, a proliferation marker, than those in the cervical lymph node lesion. This is the first report of an association between proliferative CD8(+) PD-1(+) T-cells and irAEs.
CANIT0001984	29947012	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We experienced a patient with NSCLC with high PD-L1 expression and cervical lymph node metastases, who demonstrated a good clinical response to first line pembrolizumab but suffered from a severe cutaneous adverse event. Both of his skin lesions and cervical metastases showed extensive CD8(+) PD-1(+) T-cell infiltration in immunofluorescence analysis.	Pembrolizumab-induced cutaneous adverse reaction	N/A	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Extensive CD8(+) PD-1(+) T-cell infiltration	Tumor-infiltrating immune cell	 2018 Dec	Proliferative CD8(+) PD-1(+) T-cell infiltration in a pembrolizumab-induced cutaneous adverse reaction.	 Invest New Drugs	Pembrolizumab, a humanized monoclonal immunoglobulin (Ig) G4 antibody that is directed against the human cell surface receptor PD-1, is a PD-1 pathway inhibitor that has been approved to treat various malignant diseases, including advanced non-small cell lung cancer (NSCLC). PD-1 is the major inhibitory receptor regulating T-cell exhaustion, and T-cells with high PD-1 expression lose their ability to eliminate cancer. PD-1 pathway blockade by pembrolizumab reinvigorates exhausted T-cells and restores their antitumor immune responses. However, reinvigorated T-cells also evoke immune-related adverse effects (irAEs), which stem from the restored activity. Currently, the pathogenic mechanisms of irAEs have not been sufficiently determined. We experienced a patient with NSCLC with high PD-L1 expression and cervical lymph node metastases, who demonstrated a good clinical response to first line pembrolizumab but suffered from a severe cutaneous adverse event. Both of his skin lesions and cervical metastases showed extensive CD8(+) PD-1(+) T-cell infiltration in immunofluorescence analysis. This finding suggests a possible contribution of reinvigorated CD8(+) PD-1(+) T-cells in anti-PD-1 therapy-induced skin rash. Intriguingly, CD8(+) T-cells in the skin rash showed higher Ki-67 expression, a proliferation marker, than those in the cervical lymph node lesion. This is the first report of an association between proliferative CD8(+) PD-1(+) T-cells and irAEs.
CANIT0001985	29948974	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	22	N/A	Retrospective analysis	The finding that absolute lymphocyte counts (ALC) at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. The result that the previous radiation is associated with lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2019 Feb	The absolute lymphocyte count can predict the overall survival of patients with non-small cell lung cancer on nivolumab: a clinical study.	 Clin Transl Oncol	INTRODUCTION: The neutrophil-to-lymphocyte (ANC/ALC) ratio is associated with worse prognosis in patients with NSCLC on immunotherapies, but the role of ALC remains unclear. The previous radiation therapy causes lymphopenia, and given approaches of combining radiation with immunotherapies, it is critical to better understand the impact of peripheral lymphocytes.PATIENTS AND METHODS: We evaluated retrospectively 22 patients with advanced NSCLC treated with nivolumab at Boston Medical Center from January 2014 to September 2016 and correlated the peripheral blood counts with the overall survival (OS) and overall time on treatment. We assessed the effect of the previous radiation on peripheral blood counts and clinical outcomes.RESULTS: Baseline ALC and ANC/ALC ratios are positively and negatively correlated, respectively, with the OS on nivolumab. The ALC and ALC/WBC ratios at 6 weeks on treatment are positively associated with the OS. Kaplan-Meier analysis at baseline and at 6 weeks showed significantly increased OS in the group of patients with the highest ALC. The previous radiation therapy was positively correlated with the ANC and negatively correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab.CONCLUSION: Our finding that ALC at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. Our result that the previous radiation is associated with higher ANC and lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.
CANIT0001986	29948974	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	22	N/A	Retrospective analysis	The absolute lymphocyte counts/white blood cell counts (ALC/WBC) ratios at 6 weeks on treatment are positively associated with the OS. The previous radiation therapy was negatively correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab.	N/A	N/A	N/A	Lymphocyte (NCIT:C12535); Surface marker gene (NCIT:C40700); 	Absolute lymphocyte counts/white blood cell counts ratios	Cell percentage/counts in blood	 2019 Feb	The absolute lymphocyte count can predict the overall survival of patients with non-small cell lung cancer on nivolumab: a clinical study.	 Clin Transl Oncol	INTRODUCTION: The neutrophil-to-lymphocyte (ANC/ALC) ratio is associated with worse prognosis in patients with NSCLC on immunotherapies, but the role of ALC remains unclear. The previous radiation therapy causes lymphopenia, and given approaches of combining radiation with immunotherapies, it is critical to better understand the impact of peripheral lymphocytes.PATIENTS AND METHODS: We evaluated retrospectively 22 patients with advanced NSCLC treated with nivolumab at Boston Medical Center from January 2014 to September 2016 and correlated the peripheral blood counts with the overall survival (OS) and overall time on treatment. We assessed the effect of the previous radiation on peripheral blood counts and clinical outcomes.RESULTS: Baseline ALC and ANC/ALC ratios are positively and negatively correlated, respectively, with the OS on nivolumab. The ALC and ALC/WBC ratios at 6 weeks on treatment are positively associated with the OS. Kaplan-Meier analysis at baseline and at 6 weeks showed significantly increased OS in the group of patients with the highest ALC. The previous radiation therapy was positively correlated with the ANC and negatively correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab.CONCLUSION: Our finding that ALC at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. Our result that the previous radiation is associated with higher ANC and lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.
CANIT0001987	29948974	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	22	N/A	Retrospective analysis	The previous radiation therapy was positively correlated with the absolute neutrophil counts (ANC)after the initiation of nivolumab. The result that the previous radiation is associated with higher ANC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2019 Feb	The absolute lymphocyte count can predict the overall survival of patients with non-small cell lung cancer on nivolumab: a clinical study.	 Clin Transl Oncol	INTRODUCTION: The neutrophil-to-lymphocyte (ANC/ALC) ratio is associated with worse prognosis in patients with NSCLC on immunotherapies, but the role of ALC remains unclear. The previous radiation therapy causes lymphopenia, and given approaches of combining radiation with immunotherapies, it is critical to better understand the impact of peripheral lymphocytes.PATIENTS AND METHODS: We evaluated retrospectively 22 patients with advanced NSCLC treated with nivolumab at Boston Medical Center from January 2014 to September 2016 and correlated the peripheral blood counts with the overall survival (OS) and overall time on treatment. We assessed the effect of the previous radiation on peripheral blood counts and clinical outcomes.RESULTS: Baseline ALC and ANC/ALC ratios are positively and negatively correlated, respectively, with the OS on nivolumab. The ALC and ALC/WBC ratios at 6 weeks on treatment are positively associated with the OS. Kaplan-Meier analysis at baseline and at 6 weeks showed significantly increased OS in the group of patients with the highest ALC. The previous radiation therapy was positively correlated with the ANC and negatively correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab.CONCLUSION: Our finding that ALC at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. Our result that the previous radiation is associated with higher ANC and lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.
CANIT0001988	29948974	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	22	N/A	Retrospective analysis	Baseline absolute neutrophil counts/absolute lymphocyte counts (ANC/ALC) ratios are negatively correlated with the OS on nivolumab.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Baseline absolute neutrophil counts/absolute lymphocyte counts ratios	Cell percentage/counts in blood	 2019 Feb	The absolute lymphocyte count can predict the overall survival of patients with non-small cell lung cancer on nivolumab: a clinical study.	 Clin Transl Oncol	INTRODUCTION: The neutrophil-to-lymphocyte (ANC/ALC) ratio is associated with worse prognosis in patients with NSCLC on immunotherapies, but the role of ALC remains unclear. The previous radiation therapy causes lymphopenia, and given approaches of combining radiation with immunotherapies, it is critical to better understand the impact of peripheral lymphocytes.PATIENTS AND METHODS: We evaluated retrospectively 22 patients with advanced NSCLC treated with nivolumab at Boston Medical Center from January 2014 to September 2016 and correlated the peripheral blood counts with the overall survival (OS) and overall time on treatment. We assessed the effect of the previous radiation on peripheral blood counts and clinical outcomes.RESULTS: Baseline ALC and ANC/ALC ratios are positively and negatively correlated, respectively, with the OS on nivolumab. The ALC and ALC/WBC ratios at 6 weeks on treatment are positively associated with the OS. Kaplan-Meier analysis at baseline and at 6 weeks showed significantly increased OS in the group of patients with the highest ALC. The previous radiation therapy was positively correlated with the ANC and negatively correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab.CONCLUSION: Our finding that ALC at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. Our result that the previous radiation is associated with higher ANC and lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.
CANIT0001989	29956884	Clinical research	Metastatic renal cell cancer	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	389	N/A	N/A	The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7-6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus.	The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths.	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Safety and efficacy of nivolumab for metastatic renal cell carcinoma: real-world results from an expanded access programme.	 BJU Int	OBJECTIVE: To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme.PATIENTS AND METHODS: Patients with metastatic renal cell cancer (mRCC) previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Patients included in the analysis had received >=1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.RESULTS: A total of 389 patients were enrolled between July 2015 and April 2016, of whom 18% were aged >=75 years, 6.7% had non-clear cell RCC, 49.6% had bone and 8.2% brain metastases, and 79% had received >=2 previous lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths. The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7-6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus.CONCLUSION: The safety and efficacy observed were consistent with those reported in the pivotal Checkmate 025 trial. Results in patients with non-clear-cell mRCC who were elderly, pretreated with everolimus, and had bone and/or brain metastases encourage the use of nivolumab in these categories of patients.
CANIT0001990	30003574	Clinical research	Urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	115	N/A	N/A	Urothelial bladder cancer patients showed fair agreement of PD-L1 assay outcome in cystectomies and matched TURB or lymph node specimens. PD-L1 expression was discordant more often after neoadjuvant therapy. Therefore, immune-checkpoint inhibitor studies should take into account specimen type and neoadjuvant therapy in assessing the predictive value of PD-L1 expression.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Dec	Concordance of PD-L1 expression in matched urothelial bladder cancer specimens.	 Histopathology	AIMS: Programmed death ligand 1 (PD-L1) expression has predictive value for response to immune-checkpoint inhibitor treatment in urothelial cancer patients. The consistency of PD-L1 expression among different specimen types, however, is unknown. The aim of this study is to compare PD-L1 expression in matched transurethral resections of the bladder (TURB), cystectomy specimens and lymph node metastases of urothelial cancer patients.METHODS AND RESULTS: We performed PD-L1 (SP142) immunohistochemistry on whole tissue slides of 115 urothelial carcinoma patients who had undergone TURB, followed by radical cystectomy and/or pelvic lymph node dissection. The PD-L1 assay was positive if PD-L1 expression in immune cells occupied >=5% of the tumour area. PD-L1 was positive in 15 of 97 (15.5%) TURB, 17 of 98 (17.3%) cystectomies and nine of 49 (18.4%) lymph node metastases. Agreement of PD-L1 assay outcome between cystectomy and TURB (kappa = 0.34; P = 0.002) and cystectomy and lymph node metastasis (kappa = 0.35; P = 0.034) was fair; there was no agreement between TURB and lymph node metastasis (kappa = 0.045; P = 0.82). Discordance of PD-L1 outcome in matched TURB and cystectomy specimens occurred more frequently after neoadjuvant therapy (53.3% versus 25.4%; P = 0.03), and was not associated with other clinicopathological parameters.CONCLUSIONS: Urothelial bladder cancer patients showed fair agreement of PD-L1 assay outcome in cystectomies and matched TURB or lymph node specimens. PD-L1 expression was discordant more often after neoadjuvant therapy. Therefore, immune-checkpoint inhibitor studies should take into account specimen type and neoadjuvant therapy in assessing the predictive value of PD-L1 expression.
CANIT0001991	30054281	Clinical research	Cancer (melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 10))	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab or tremelimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	17	N/A	N/A	Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12479); FOXP3 (Q9BZS1); 	Infiltration of intratumoral CD4(+) T-cells without significantly changing or depleting FOXP3(+) cells	Tumor-infiltrating immune cell	 2019 Feb 15	Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3(+) Regulatory T Cells (Tregs) in Human Cancers.	 Clin Cancer Res	PURPOSE: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two mAbs, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T-cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 mAbs may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3+ cells occurs in patients with cancer treated with anti-CTLA-4 therapies.EXPERIMENTAL DESIGN: Quantitative IHC was used to evaluate the densities of intratumoral CD4+, CD8+, and FOXP3+ cells in stage-matched melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 9) samples treated with ipilimumab and in paired melanoma tumors (n = 18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor-infiltrating cells from paired fresh melanoma tumors (n = 5) treated with ipilimumab.RESULTS: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.CONCLUSIONS: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells.See related commentary by Quezada and Peggs, p. 1130.
CANIT0001992	30054281	Clinical research	Cancer (melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 10))	Prostate cancer	MONDO:0008315	Prostate	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab or tremelimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	17	N/A	N/A	Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12477); FOXP3 (Q9BZS1); 	Infiltration of intratumoral D8(+) T-cells without significantly changing or depleting FOXP3(+) cells	Tumor-infiltrating immune cell	 2019 Feb 15	Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3(+) Regulatory T Cells (Tregs) in Human Cancers.	 Clin Cancer Res	PURPOSE: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two mAbs, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T-cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 mAbs may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3+ cells occurs in patients with cancer treated with anti-CTLA-4 therapies.EXPERIMENTAL DESIGN: Quantitative IHC was used to evaluate the densities of intratumoral CD4+, CD8+, and FOXP3+ cells in stage-matched melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 9) samples treated with ipilimumab and in paired melanoma tumors (n = 18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor-infiltrating cells from paired fresh melanoma tumors (n = 5) treated with ipilimumab.RESULTS: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.CONCLUSIONS: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells.See related commentary by Quezada and Peggs, p. 1130.
CANIT0001993	30054281	Clinical research	Cancer (melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 11))	Bladder cancer	EFO:0000292	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab or tremelimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	N/A	Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12479); FOXP3 (Q9BZS1); 	Infiltration of intratumoral CD4(+) T-cells without significantly changing or depleting FOXP3(+) cells	Tumor-infiltrating immune cell	 2019 Feb 15	Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3(+) Regulatory T Cells (Tregs) in Human Cancers.	 Clin Cancer Res	PURPOSE: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two mAbs, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T-cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 mAbs may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3+ cells occurs in patients with cancer treated with anti-CTLA-4 therapies.EXPERIMENTAL DESIGN: Quantitative IHC was used to evaluate the densities of intratumoral CD4+, CD8+, and FOXP3+ cells in stage-matched melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 9) samples treated with ipilimumab and in paired melanoma tumors (n = 18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor-infiltrating cells from paired fresh melanoma tumors (n = 5) treated with ipilimumab.RESULTS: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.CONCLUSIONS: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells.See related commentary by Quezada and Peggs, p. 1130.
CANIT0001994	30054281	Clinical research	Cancer (melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 11))	Bladder cancer	EFO:0000292	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab or tremelimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	9	N/A	N/A	Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12477); FOXP3 (Q9BZS1); 	Infiltration of intratumoral D8(+) T-cells without significantly changing or depleting FOXP3(+) cells	Tumor-infiltrating immune cell	 2019 Feb 15	Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3(+) Regulatory T Cells (Tregs) in Human Cancers.	 Clin Cancer Res	PURPOSE: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two mAbs, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T-cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 mAbs may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3+ cells occurs in patients with cancer treated with anti-CTLA-4 therapies.EXPERIMENTAL DESIGN: Quantitative IHC was used to evaluate the densities of intratumoral CD4+, CD8+, and FOXP3+ cells in stage-matched melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 9) samples treated with ipilimumab and in paired melanoma tumors (n = 18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor-infiltrating cells from paired fresh melanoma tumors (n = 5) treated with ipilimumab.RESULTS: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.CONCLUSIONS: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells.See related commentary by Quezada and Peggs, p. 1130.
CANIT0001995	30054281	Clinical research	Cancer (melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 9))	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab or tremelimumab	Tremelimumab	Immune checkpoint therapy	Ipilimumab (DB06186); tremelimumab (DB11771); 	19	18	N/A	Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12479); FOXP3 (Q9BZS1); 	Infiltration of intratumoral CD4(+) T-cells without significantly changing or depleting FOXP3(+) cells	Tumor-infiltrating immune cell	 2019 Feb 15	Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3(+) Regulatory T Cells (Tregs) in Human Cancers.	 Clin Cancer Res	PURPOSE: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two mAbs, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T-cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 mAbs may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3+ cells occurs in patients with cancer treated with anti-CTLA-4 therapies.EXPERIMENTAL DESIGN: Quantitative IHC was used to evaluate the densities of intratumoral CD4+, CD8+, and FOXP3+ cells in stage-matched melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 9) samples treated with ipilimumab and in paired melanoma tumors (n = 18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor-infiltrating cells from paired fresh melanoma tumors (n = 5) treated with ipilimumab.RESULTS: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.CONCLUSIONS: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells.See related commentary by Quezada and Peggs, p. 1130.
CANIT0001996	30054281	Clinical research	Cancer (melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 9))	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab or tremelimumab	Tremelimumab	Immune checkpoint therapy	Ipilimumab (DB06186); tremelimumab (DB11771); 	19	18	N/A	Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12477); FOXP3 (Q9BZS1); 	Infiltration of intratumoral D8(+) T-cells without significantly changing or depleting FOXP3(+) cells	Tumor-infiltrating immune cell	 2019 Feb 15	Anti-CTLA-4 Immunotherapy Does Not Deplete FOXP3(+) Regulatory T Cells (Tregs) in Human Cancers.	 Clin Cancer Res	PURPOSE: CTLA-4 was the first inhibitory immune checkpoint to be identified. Two mAbs, ipilimumab (IgG1) and tremelimumab (IgG2), which block the function of CTLA-4, have demonstrated durable clinical activity in a subset of patients with advanced solid malignancies by augmenting effector T-cell-mediated immune responses. Studies in mice suggest that anti-CTLA-4 mAbs may also selectively deplete intratumoral FOXP3+ regulatory T cells via an Fc-dependent mechanism. However, it is unclear whether the depletion of FOXP3+ cells occurs in patients with cancer treated with anti-CTLA-4 therapies.EXPERIMENTAL DESIGN: Quantitative IHC was used to evaluate the densities of intratumoral CD4+, CD8+, and FOXP3+ cells in stage-matched melanoma (n = 19), prostate cancer (n = 17), and bladder cancer (n = 9) samples treated with ipilimumab and in paired melanoma tumors (n = 18) treated with tremelimumab. These findings were corroborated with multiparametric mass cytometry analysis of tumor-infiltrating cells from paired fresh melanoma tumors (n = 5) treated with ipilimumab.RESULTS: Both ipilimumab and tremelimumab increase infiltration of intratumoral CD4+ and CD8+ cells without significantly changing or depleting FOXP3+ cells within the tumor microenvironment.CONCLUSIONS: Anti-CTLA-4 immunotherapy does not deplete FOXP3+ cells in human tumors, which suggests that their efficacy could be enhanced by modifying the Fc portions of the mAbs to enhance Fc-mediated depletion of intratumoral regulatory T cells.See related commentary by Quezada and Peggs, p. 1130.
CANIT0001997	30095468	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	426	N/A	N/A	About 14.6% of all biopsies measured <2 mm creating 2 groups (<2 mm and >=2 mm) whose PD-L1 categories distribution [negative (<1%), low expressor (>=1% and <50%), and positive (>=50%)] were compared. Results were significantly different between both groups (¦Ö test; P=0.0012). To help understand this difference, 1,407,000 in silico simulated biopsies of various sizes were performed on 201 numerical tumors created from digitalized full sections and analyzed. Not only the same results shown in actual biopsies were reproduced, but the model calculated that up to 35% of very small biopsies were misclassified including a mixture of false negative and false positive results. The percentage decreased to 10% with a threshold of 5 mm.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Nov/Dec	Small Biopsies Misclassify up to 35% of PD-L1 Assessments in Advanced Lung Non-Small Cell Lung Carcinomas.	 Appl Immunohistochem Mol Morphol	Pembrolizumab is an FDA-approved immune-checkpoint (IC) inhibitor that targets programmed cell death protein PD-1, and recent phase III trials have demonstrated its superiority over chemotherapy in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Eligibility for treatment with Pembrolizumab is based on demonstration of PD-L1 expression on tumoral cells using the approved companion test 22C3 PharmDx (Dako). Access to the drug depends on a tumor proportion score (TPS) expressing the PD-L1 protein above predetermined cutoffs. The scoring interpretation guide requires a minimum of 100 viable cells to be considered adequate for evaluation. Recent studies have questioned the adequacy of the sampling process when small biopsies are utilized. To further explore this concern, the viable tumor area of 426 consecutive NSCLC biopsies and surgical excisions submitted for PD-L1 assessment was measured and recorded with corresponding PD-L1 expression. About 14.6% of all biopsies measured <2 mm creating 2 groups (<2 mm and >=2 mm) whose PD-L1 categories distribution [negative (<1%), low expressor (>=1% and <50%), and positive (>=50%)] were compared. Results were significantly different between both groups (x test; P=0.0012). To help understand this difference, 1,407,000 in silico simulated biopsies of various sizes were performed on 201 numerical tumors created from digitalized full sections and analyzed. Not only the same results shown in actual biopsies were reproduced, but the model calculated that up to 35% of very small biopsies were misclassified including a mixture of false negative and false positive results. The percentage decreased to 10% with a threshold of 5 mm. In era of precision medicine, appropriate sampling is more than ever critical to achieve accurate assessment of the NSCLC PD-L1. Ignored in most clinical trials, recording of biopsy size would permit refining data analysis and increase predictive accuracy of current and future biomarkers.
CANIT0001998	30100403	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	142	N/A	Multicentre, retrospective analysis	The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Macrophages (NCIT:C12558 ); 	Tumour-associated macrophages	Cell percentage/counts in blood	 2018 Oct	Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.	 Lancet Respir Med	BACKGROUND: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC.METHODS: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival.FINDINGS: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.INTERPRETATION: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies.FUNDING: Obra Social La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.
CANIT0001999	30100403	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	142	N/A	Multicentre, retrospective analysis	The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2018 Oct	Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.	 Lancet Respir Med	BACKGROUND: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC.METHODS: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival.FINDINGS: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.INTERPRETATION: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies.FUNDING: Obra Social La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.
CANIT0002000	30100403	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	142	N/A	Multicentre, retrospective analysis	The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Fibroblasts (NCIT:C12482); 	Cancer-associated fibroblasts	Cell percentage/counts in blood	 2018 Oct	Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.	 Lancet Respir Med	BACKGROUND: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC.METHODS: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival.FINDINGS: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.INTERPRETATION: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies.FUNDING: Obra Social La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.
CANIT0002001	30100403	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	142	N/A	Multicentre, retrospective analysis	The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Endothelial cell (NCIT:C12865); 	Senescent endothelial cells	Cell percentage/counts in blood	 2018 Oct	Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.	 Lancet Respir Med	BACKGROUND: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC.METHODS: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival.FINDINGS: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.INTERPRETATION: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies.FUNDING: Obra Social La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.
CANIT0002002	30100403	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	142	N/A	Multicentre, retrospective analysis	The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	FOXP1 (Q9H334); 	FOXP1 unmethylated status	Gene expression signature on/in tumor cell	 2018 Oct	Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.	 Lancet Respir Med	BACKGROUND: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC.METHODS: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival.FINDINGS: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.INTERPRETATION: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies.FUNDING: Obra Social La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.
CANIT0002003	30100403	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	142	N/A	Multicentre, retrospective analysis	The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Methylation (NCIT:C16848 ); 	Epigenomic profile based on a microarray DNA methylation signature	Gene expression signature on/in tumor cell	 2018 Oct	Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.	 Lancet Respir Med	BACKGROUND: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC.METHODS: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival.FINDINGS: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0.010, 95% CI 3.29 ¡Á 10-4-0.0282; p=0.0067) and overall survival (0.080, 0.017-0.373; p=0.0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0.330, 0.149-0.727; p=0.0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0.415, 0.209-0.802; p=0.0063) and overall survival (0.409, 0.220-0.780; p=0.0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.INTERPRETATION: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies.FUNDING: Obra Social La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.
CANIT0002004	30104119	Case report	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	7	N/A	Case	We report seven cases of immune-mediated hypophysitis in Taiwan. They suffered from various types of advanced cancer and received different regimens of immune checkpoint inhibitors. The time of onset after initiation of immunotherapy ranged from 5 to 36 weeks. All seven subjects were diagnosed of central adrenal insufficiency, while four of them had primary hypothyroidism. There was no typical finding of infiltrative hypophysitis on the pituitary MRI. There was no documented hormone recovery after diagnosis of hypophysitis, and the tumor responses to immunotherapy were variable in these seven patients.	Immune-mediated hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Immune checkpoint inhibitor therapy-induced hypophysitis ¡« a case series of Taiwanese patients.	 J Formos Med Assoc	Immune checkpoint blockade-based immunotherapy is a new modality of cancer treatment with a unique mechanism that has gained increased numbers of indication and is now used in several cancer types. However, immune-related adverse events (irAEs) emerge as a new entity of diseases involving one or multiple organ systems. irAEs could result in interruption of immunotherapy, morbidities or even death. Among various manifestations of irAEs, immune-mediated hypophysitis is rare but important, requiring prompt diagnosis and treatment to avoid life-threatening conditions. We report seven cases of immune-mediated hypophysitis in Taiwan. They suffered from various types of advanced cancer and received different regimens of immune checkpoint inhibitors. The time of onset after initiation of immunotherapy ranged from 5 to 36 weeks. All seven subjects were diagnosed of central adrenal insufficiency, while four of them had primary hypothyroidism. There was no typical finding of infiltrative hypophysitis on the pituitary MRI. There was no documented hormone recovery after diagnosis of hypophysitis, and the tumor responses to immunotherapy were variable in these seven patients. In conclusion, immune-mediated hypophysitis is often irreversible. Fortunately, it can be managed adequately with hormone replacements. Further investigations are warranted to unveil underlying mechanisms and ethnic differences to guide the solutions.
CANIT0002005	30110194	Clinical research	Metastatic esophagogastric cancer	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Nivolumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	101	59	Open-label, two-stage, multicohort, phase I/II trial	Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively. Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer.	Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups of nivolumab 3 mg/kg, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, respectively.	N/A	N/A	N/A	N/A	N/A	 2018 Oct 1	CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer.	 J Clin Oncol	PURPOSE: Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers.PATIENTS AND METHODS: Patients with locally advanced or metastatic chemotherapy-refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated.RESULTS: Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively.CONCLUSION: Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway.
CANIT0002006	30121946	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or Nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1598	N/A	Meta-analysis	Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2019 Jan 1	Impact of clinicopathological characteristics on survival in patients treated with immune checkpoint inhibitors for metastatic melanoma.	 Int J Cancer	Immune checkpoint inhibitors (ICIs) have unprecedented effects on the treatment of metastatic melanoma. However, little is known about the prognostic values of various clinicopathological characteristics. Here, PubMed, Embase and Cochrane database were searched from inception to April 2018 for random controlled trials (RCTs) that compared ICIs with controls. The hazard ratios (HRs) for overall survival (OS) according to gender, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), lactate dehydrogenase (LDH) level and metastasis stage were extracted. Four phase III RCTs involving 1,598 patients with metastatic melanoma were included in this study. Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level. In summary, although immunotherapy significantly prolongs OS in metastatic melanoma, the long-term benefits in women, younger patients (<65 years old) and patients with ECOG PS = 0 were marginal. These results may assist in treatment decision-making, design and interpretation of clinical trials and economic analyses.
CANIT0002007	30121946	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or Nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1598	N/A	Meta-analysis	Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level.	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2019 Jan 1	Impact of clinicopathological characteristics on survival in patients treated with immune checkpoint inhibitors for metastatic melanoma.	 Int J Cancer	Immune checkpoint inhibitors (ICIs) have unprecedented effects on the treatment of metastatic melanoma. However, little is known about the prognostic values of various clinicopathological characteristics. Here, PubMed, Embase and Cochrane database were searched from inception to April 2018 for random controlled trials (RCTs) that compared ICIs with controls. The hazard ratios (HRs) for overall survival (OS) according to gender, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), lactate dehydrogenase (LDH) level and metastasis stage were extracted. Four phase III RCTs involving 1,598 patients with metastatic melanoma were included in this study. Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level. In summary, although immunotherapy significantly prolongs OS in metastatic melanoma, the long-term benefits in women, younger patients (<65 years old) and patients with ECOG PS = 0 were marginal. These results may assist in treatment decision-making, design and interpretation of clinical trials and economic analyses.
CANIT0002008	30121946	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or Nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1598	N/A	Meta-analysis	Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Jan 1	Impact of clinicopathological characteristics on survival in patients treated with immune checkpoint inhibitors for metastatic melanoma.	 Int J Cancer	Immune checkpoint inhibitors (ICIs) have unprecedented effects on the treatment of metastatic melanoma. However, little is known about the prognostic values of various clinicopathological characteristics. Here, PubMed, Embase and Cochrane database were searched from inception to April 2018 for random controlled trials (RCTs) that compared ICIs with controls. The hazard ratios (HRs) for overall survival (OS) according to gender, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), lactate dehydrogenase (LDH) level and metastasis stage were extracted. Four phase III RCTs involving 1,598 patients with metastatic melanoma were included in this study. Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level. In summary, although immunotherapy significantly prolongs OS in metastatic melanoma, the long-term benefits in women, younger patients (<65 years old) and patients with ECOG PS = 0 were marginal. These results may assist in treatment decision-making, design and interpretation of clinical trials and economic analyses.
CANIT0002009	30121946	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or Nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1598	N/A	Meta-analysis	Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Jan 1	Impact of clinicopathological characteristics on survival in patients treated with immune checkpoint inhibitors for metastatic melanoma.	 Int J Cancer	Immune checkpoint inhibitors (ICIs) have unprecedented effects on the treatment of metastatic melanoma. However, little is known about the prognostic values of various clinicopathological characteristics. Here, PubMed, Embase and Cochrane database were searched from inception to April 2018 for random controlled trials (RCTs) that compared ICIs with controls. The hazard ratios (HRs) for overall survival (OS) according to gender, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), lactate dehydrogenase (LDH) level and metastasis stage were extracted. Four phase III RCTs involving 1,598 patients with metastatic melanoma were included in this study. Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level. In summary, although immunotherapy significantly prolongs OS in metastatic melanoma, the long-term benefits in women, younger patients (<65 years old) and patients with ECOG PS = 0 were marginal. These results may assist in treatment decision-making, design and interpretation of clinical trials and economic analyses.
CANIT0002010	30121946	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or Nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1598	N/A	Meta-analysis	Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Metastatic stage	Disease status	 2019 Jan 1	Impact of clinicopathological characteristics on survival in patients treated with immune checkpoint inhibitors for metastatic melanoma.	 Int J Cancer	Immune checkpoint inhibitors (ICIs) have unprecedented effects on the treatment of metastatic melanoma. However, little is known about the prognostic values of various clinicopathological characteristics. Here, PubMed, Embase and Cochrane database were searched from inception to April 2018 for random controlled trials (RCTs) that compared ICIs with controls. The hazard ratios (HRs) for overall survival (OS) according to gender, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), lactate dehydrogenase (LDH) level and metastasis stage were extracted. Four phase III RCTs involving 1,598 patients with metastatic melanoma were included in this study. Compared with conventional agents, ICIs were associated with prolonged OS (HR, 0.67; 95% CI, 0.50-0.88; p = 0.005). The pooled OS HR was 0.60 (95% CI, 0.42-0.84; p = 0.003) in men; 0.84 (95% CI, 0.69-1.01; p = 0.07) in women. The difference in efficacy between men and women was significant (pinteraction = 0.03). The OS HR was 0.59 (95% CI, 0.41-0.83; p = 0.003) in patients >65 years old; 0.74 (95% CI, 0.55-1.01; p = 0.054) in patients <65 years old. The OS HR was 0.75 (95% CI, 0.60-0.94; p = 0.01) in patients with ECOG PS = 1; 0.64 (95% CI, 0.38-1.06; p = 0.08) in patients with ECOG PS = 0. Additionally, the long-term benefits were independent of metastasis stage and LDH level. In summary, although immunotherapy significantly prolongs OS in metastatic melanoma, the long-term benefits in women, younger patients (<65 years old) and patients with ECOG PS = 0 were marginal. These results may assist in treatment decision-making, design and interpretation of clinical trials and economic analyses.
CANIT0002011	30122486	Clinical research	Melanoma, Hematologic tumors, Solid tumors	Cancer	EFO:0000311	Other	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	59	N/A	Retrospective analysis	59 patients included in the database received ipilimumab (Ipi) and 75 received cytokines (Cys). Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in Ipi- and Cy-treated patients than in those who received CHT (12%, 5%, and 2%, respectively).	Acute reactions to iodinated contrast media	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Increased frequency of acute reactions to iodinated contrast media in cancer patients treated with anti-CTLA-4 immunomodulatory antibodies.	 Med Hypotheses	Contrast-enhanced computed tomography (CECT) is an indispensable tool in the management of cancer patients. However, this procedure can be complicated by the development of acute adverse reactions (ARs) to iodinated contrast media (ICM). On the basis of the hypothesis that cancer immunotherapy, in particular with immune checkpoint inhibitors, increases the incidence of allergic-like immediate ARs to ICM with respect to standard cancer chemotherapy/targeted therapy (CHT) we retrospectively evaluated the incidence of CECT-related immediate ARs in cancer patients undergoing cancer treatments. All patients who underwent at least one CECT scan after starting any cancer treatment between 2006 and 2014 were included in a mono-institutional radiological database. The staff of the Radiology Unit recorded any ARs that occurred within 30 min of the ICM injection and classified them as allergic-like or physiologic and graded as mild, moderate, or severe according to the American College of Radiology (ACR) Manual on Contrast Media, version 10.1. Fifty-nine of the 3,521 patients included in the database received ipilimumab (Ipi), 75 received cytokines (Cys), and the remaining 3,387 received non-immunologic agents (CHT). Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in Ipi- and Cy-treated patients than in those who received CHT (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering CECT-related immediate ARs with respect to non-immunologic agents. Although these findings need to be validated in larger prospective studies, they serve as a wake-up call for radiologists to closely monitor patients who have previously received cancer immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies when using ICM in order to reduce the risk of potentially severe immediate ARs.
CANIT0002012	30122486	Clinical research	Melanoma, Hematologic tumors, Solid tumors	Cancer	EFO:0000311	Other	CTLA-4 (P16410); 	CTLA-4; 	Cytokines	N/A	Immune cytokine	Cytokine (); 	75	N/A	Retrospective analysis	59 patients included in the database received ipilimumab (Ipi) and 75 received cytokines (Cys). Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in Ipi- and Cy-treated patients than in those who received CHT (12%, 5%, and 2%, respectively).	Acute reactions to iodinated contrast media	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Increased frequency of acute reactions to iodinated contrast media in cancer patients treated with anti-CTLA-4 immunomodulatory antibodies.	 Med Hypotheses	Contrast-enhanced computed tomography (CECT) is an indispensable tool in the management of cancer patients. However, this procedure can be complicated by the development of acute adverse reactions (ARs) to iodinated contrast media (ICM). On the basis of the hypothesis that cancer immunotherapy, in particular with immune checkpoint inhibitors, increases the incidence of allergic-like immediate ARs to ICM with respect to standard cancer chemotherapy/targeted therapy (CHT) we retrospectively evaluated the incidence of CECT-related immediate ARs in cancer patients undergoing cancer treatments. All patients who underwent at least one CECT scan after starting any cancer treatment between 2006 and 2014 were included in a mono-institutional radiological database. The staff of the Radiology Unit recorded any ARs that occurred within 30 min of the ICM injection and classified them as allergic-like or physiologic and graded as mild, moderate, or severe according to the American College of Radiology (ACR) Manual on Contrast Media, version 10.1. Fifty-nine of the 3,521 patients included in the database received ipilimumab (Ipi), 75 received cytokines (Cys), and the remaining 3,387 received non-immunologic agents (CHT). Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in Ipi- and Cy-treated patients than in those who received CHT (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering CECT-related immediate ARs with respect to non-immunologic agents. Although these findings need to be validated in larger prospective studies, they serve as a wake-up call for radiologists to closely monitor patients who have previously received cancer immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies when using ICM in order to reduce the risk of potentially severe immediate ARs.
CANIT0002013	30131384	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg-suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg-suppressive function. PD-1 blockade also led to IL10 production by T cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL10 production in vitro.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); 	Treg percentages with higher Treg proliferation. 	N/A	 2018 Dec 15	Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.	 Clin Cancer Res	PURPOSE: PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study, we investigated the impact of nivolumab therapy on peripheral blood regulatory T cells (Treg) and its relation to patient outcomes.EXPERIMENTAL DESIGN: Peripheral blood Tregs and conventional CD4+ T cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq. Percentages of circulating Tregs and phosphorylated-STAT3 (pSTAT3) expression levels were assessed by flow cytometry and validated in an independent cohort of active disease patients. Suppressive function of Tregs was assessed in allogeneic mixed lymphocyte reactions.RESULTS: Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg-suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg-suppressive function. PD-1 blockade also led to IL10 production by T cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL10 production in vitro.CONCLUSIONS: These results demonstrate that induction of pSTAT3, reduced suppressive function, and a paradoxical increase in Treg proliferation are novel correlates of patient benefit from PD-1 blockade.
CANIT0002014	30131384	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg-suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg-suppressive function. PD-1 blockade also led to IL10 production by T cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL10 production in vitro.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	STAT3 ( P40763); 	PSTAT3 expression	N/A	 2018 Dec 15	Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.	 Clin Cancer Res	PURPOSE: PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study, we investigated the impact of nivolumab therapy on peripheral blood regulatory T cells (Treg) and its relation to patient outcomes.EXPERIMENTAL DESIGN: Peripheral blood Tregs and conventional CD4+ T cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq. Percentages of circulating Tregs and phosphorylated-STAT3 (pSTAT3) expression levels were assessed by flow cytometry and validated in an independent cohort of active disease patients. Suppressive function of Tregs was assessed in allogeneic mixed lymphocyte reactions.RESULTS: Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg-suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg-suppressive function. PD-1 blockade also led to IL10 production by T cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL10 production in vitro.CONCLUSIONS: These results demonstrate that induction of pSTAT3, reduced suppressive function, and a paradoxical increase in Treg proliferation are novel correlates of patient benefit from PD-1 blockade.
CANIT0002015	30131384	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg-suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg-suppressive function. PD-1 blockade also led to IL10 production by T cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL10 production in vitro.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); 	Reduced Treg-suppressive function	N/A	 2018 Dec 15	Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.	 Clin Cancer Res	PURPOSE: PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study, we investigated the impact of nivolumab therapy on peripheral blood regulatory T cells (Treg) and its relation to patient outcomes.EXPERIMENTAL DESIGN: Peripheral blood Tregs and conventional CD4+ T cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq. Percentages of circulating Tregs and phosphorylated-STAT3 (pSTAT3) expression levels were assessed by flow cytometry and validated in an independent cohort of active disease patients. Suppressive function of Tregs was assessed in allogeneic mixed lymphocyte reactions.RESULTS: Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg-suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg-suppressive function. PD-1 blockade also led to IL10 production by T cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL10 production in vitro.CONCLUSIONS: These results demonstrate that induction of pSTAT3, reduced suppressive function, and a paradoxical increase in Treg proliferation are novel correlates of patient benefit from PD-1 blockade.
CANIT0002016	30131384	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg-suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg-suppressive function. PD-1 blockade also led to IL10 production by T cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL10 production in vitro.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	IL2 (P60568); T-Lymphocyte (NCIT:C12476); 	IL10 expression levels on T-Lymphocyte	N/A	 2018 Dec 15	Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.	 Clin Cancer Res	PURPOSE: PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study, we investigated the impact of nivolumab therapy on peripheral blood regulatory T cells (Treg) and its relation to patient outcomes.EXPERIMENTAL DESIGN: Peripheral blood Tregs and conventional CD4+ T cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq. Percentages of circulating Tregs and phosphorylated-STAT3 (pSTAT3) expression levels were assessed by flow cytometry and validated in an independent cohort of active disease patients. Suppressive function of Tregs was assessed in allogeneic mixed lymphocyte reactions.RESULTS: Tregs from non-relapse patients had increased expression of proliferation associated genes. An increase in the proportion of circulating Tregs and pSTAT3 expression and a reduction in Treg-suppressive capacity were observed in non-relapsing, but not relapsing patient samples 13 weeks after starting treatment. In vitro blockade of PD-1 increased Treg percentages and pSTAT3 expression, and reduced Treg-suppressive function. PD-1 blockade also led to IL10 production by T cells, resulting in higher Treg proliferation. The addition of a STAT3 inhibitor ameliorated the increase in Tregs, enhanced suppressive function, and decreased T-cell IL10 production in vitro.CONCLUSIONS: These results demonstrate that induction of pSTAT3, reduced suppressive function, and a paradoxical increase in Treg proliferation are novel correlates of patient benefit from PD-1 blockade.
CANIT0002017	30132401	Clinical research	Colon cancer patients	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	4	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002018	30132401	Clinical research	Colon cancer patients	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	4	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002019	30132401	Clinical research	Colon cancer patients	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	4	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002020	30132401	Clinical research	Colon cancer patients	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	4	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002021	30132401	Clinical research	Colon cancer patients	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002022	30132401	Clinical research	Glioblastoma multiforme patients	Glioblastoma multiforme	EFO:0000519	Brain	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	3	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002023	30132401	Clinical research	Glioblastoma multiforme patients	Glioblastoma multiforme	EFO:0000519	Brain	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	3	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002024	30132401	Clinical research	Glioblastoma multiforme patients	Glioblastoma multiforme	EFO:0000519	Brain	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	3	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002025	30132401	Clinical research	Glioblastoma multiforme patients	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002026	30132401	Clinical research	Glioblastoma multiforme patients	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002027	30132401	Clinical research	Lung cancer patients	Lung carcinoma	EFO:0001071	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	8	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002028	30132401	Clinical research	Lung cancer patients	Lung carcinoma	EFO:0001071	Lung	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	8	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002029	30132401	Clinical research	Lung cancer patients	Lung carcinoma	EFO:0001071	Lung	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	8	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002030	30132401	Clinical research	Lung cancer patients	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	8	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002031	30132401	Clinical research	Lung cancer patients	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	8	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002032	30132401	Clinical research	Melanoma patients	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	10	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002033	30132401	Clinical research	Melanoma patients	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	10	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002034	30132401	Clinical research	Melanoma patients	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	10	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002035	30132401	Clinical research	Melanoma patients	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002036	30132401	Clinical research	Melanoma patients	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002037	30132401	Clinical research	Non-Hodgkin's lymphoma patients	Non-hodgkins lymphoma	EFO:0005952	Blood and lymph nodes	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002038	30132401	Clinical research	Non-Hodgkin's lymphoma patients	Non-hodgkins lymphoma	EFO:0005952	Blood and lymph nodes	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002039	30132401	Clinical research	Non-Hodgkin's lymphoma patients	Non-hodgkins lymphoma	EFO:0005952	Blood and lymph nodes	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002040	30132401	Clinical research	Non-Hodgkin's lymphoma patients	Non-hodgkins lymphoma	EFO:0005952	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002041	30132401	Clinical research	Non-Hodgkin's lymphoma patients	Non-hodgkins lymphoma	EFO:0005952	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002042	30132401	Clinical research	Ovarian cancer patients	Ovarian carcinoma	EFO:0001075	Ovary	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	2	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002043	30132401	Clinical research	Ovarian cancer patients	Ovarian carcinoma	EFO:0001075	Ovary	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	2	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002044	30132401	Clinical research	Ovarian cancer patients	Ovarian carcinoma	EFO:0001075	Ovary	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	2	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002045	30132401	Clinical research	Ovarian cancer patients	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002046	30132401	Clinical research	Ovarian cancer patients	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002047	30132401	Clinical research	Pancreatic adenocarcinoma patients	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002048	30132401	Clinical research	Pancreatic adenocarcinoma patients	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002049	30132401	Clinical research	Pancreatic adenocarcinoma patients	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002050	30132401	Clinical research	Pancreatic adenocarcinoma patients	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002051	30132401	Clinical research	Pancreatic adenocarcinoma patients	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002052	30132401	Clinical research	Reneal cell carcinoma patients	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	9	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002053	30132401	Clinical research	Reneal cell carcinoma patients	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	9	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002054	30132401	Clinical research	Reneal cell carcinoma patients	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	9	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002055	30132401	Clinical research	Reneal cell carcinoma patients	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	9	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002056	30132401	Clinical research	Reneal cell carcinoma patients	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	9	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002057	30132401	Clinical research	Urothelial carcinoma patients	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	5	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002058	30132401	Clinical research	Urothelial carcinoma patients	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus tremelimumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	5	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002059	30132401	Clinical research	Urothelial carcinoma patients	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	5	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002060	30132401	Clinical research	Urothelial carcinoma patients	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	5	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002061	30132401	Clinical research	Urothelial carcinoma patients	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Retrospective analysis	Immune-related thyroiditis (irT) manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination immune checkpoint inhibitors (ICI). Frequent monitoring of thyroid function tests during ICI is warranted.	Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.	N/A	N/A	N/A	N/A	N/A	 2018 Oct	Immune-Related Thyroiditis with Immune Checkpoint Inhibitors.	 Thyroid	BACKGROUND: Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.METHODS: This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.RESULTS: Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.CONCLUSIONS: IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
CANIT0002062	30138764	Clinical research	Non-small cell lung cancer without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus pemetrexed-carboplatin	Pemetrexed-carboplatin	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); pemetrexed (DB00642); carboplatin (DB00958); 	60	63	Cohort G of KEYNOTE-021 (NCT02039674)	The ORR was 56.7% with pembrolizumab plus pemetrexed-carboplatin (PC) versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9% 42.4%, p = 0.0016]) in patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations. PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33 0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti programmed death 1/anti programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32 0.95, p = 0.0151).	Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events.	N/A	N/A	EGFR/ALK (P00533); 	EGFR/ALK mutational status	Mutational status	 2019 Jan	24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non-Small Cell Lung Cancer.	 J Thorac Oncol	INTRODUCTION: Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42 1.91). Herein, we present an updated analysis.METHODS: A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025).RESULTS: As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9% 42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33 0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti programmed death 1/anti programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32 0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events.CONCLUSIONS: The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC.
CANIT0002063	30151899	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	2092	N/A	Meta-analysis	The pooled HRs of PFS and OS for Neutrophil-to-lymphocyte ratios (NLRs) were 1.81(95% CI 1.36-2.41) and 2.26 (95% CI 1.68-3.03), respectively, suggesting that patients with higher baseline NLRs had significantly poorer PFS and OS. Similar results were detected in sensitivity and subgroup analyses. However, no significant relevance was found between PLR and clinical endpoints in patients treated with ICIs (HR = 1.14, 95% CI 0.88-1.48 for PFS; HR = 1.35, 95% CI 0.86-2.12 for OS).	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2018 Oct	Pretreatment hematological markers predict clinical outcome in cancer patients receiving immune checkpoint inhibitors: A meta-analysis.	 Thorac Cancer	BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the clinical treatment of multiple cancers. Recent studies revealed the potential prognostic value of the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in patients receiving ICIs; however, the results were inconsistent. We conducted a meta-analysis to identify the prognostic significance of baseline NLR and PLR in cancer patients treated with ICIs.METHODS: We conducted a thorough literature search of PubMed, Embase, and Cochrane databases for studies dealing with the prognostic impact of pretreatment NLR and/or PLR levels in cancer patients treated with ICIs. The clinical outcomes were progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and sensitivity and subgroup analyses were performed to investigate heterogeneity.RESULTS: Seventeen articles involving 2092 patients were included in the final analysis. The pooled HRs of PFS and OS for NLR were 1.81(95% CI 1.36-2.41) and 2.26 (95% CI 1.68-3.03), respectively, suggesting that patients with higher baseline NLRs had significantly poorer PFS and OS. Similar results were detected in sensitivity and subgroup analyses. However, no significant relevance was found between PLR and clinical endpoints in patients treated with ICIs (HR = 1.14, 95% CI 0.88-1.48 for PFS; HR = 1.35, 95% CI 0.86-2.12 for OS).CONCLUSION: These results indicate that high pretreatment NLR but not PLR level, as a routinely obtained hematological parameter, is a potential prognostic predictor for poor PFS and OS in cancer patients receiving ICIs.
CANIT0002064	30151899	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	2092	N/A	Meta-analysis	The pooled HRs of PFS and OS for NLR were 1.81(95% CI 1.36-2.41) and 2.26 (95% CI 1.68-3.03), respectively, suggesting that patients with higher baseline NLRs had significantly poorer PFS and OS. Similar results were detected in sensitivity and subgroup analyses. However, no significant relevance was found between platelet-to-lymphocyte ratios (PLRs) and clinical endpoints in patients treated with ICIs (HR = 1.14, 95% CI 0.88-1.48 for PFS; HR = 1.35, 95% CI 0.86-2.12 for OS).	N/A	N/A	N/A	Platelet-to-lymphocyte ratios (EFO:0008446); 	Platelet-to-lymphocyte ratios	Cell percentage/counts in blood	 2018 Oct	Pretreatment hematological markers predict clinical outcome in cancer patients receiving immune checkpoint inhibitors: A meta-analysis.	 Thorac Cancer	BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the clinical treatment of multiple cancers. Recent studies revealed the potential prognostic value of the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in patients receiving ICIs; however, the results were inconsistent. We conducted a meta-analysis to identify the prognostic significance of baseline NLR and PLR in cancer patients treated with ICIs.METHODS: We conducted a thorough literature search of PubMed, Embase, and Cochrane databases for studies dealing with the prognostic impact of pretreatment NLR and/or PLR levels in cancer patients treated with ICIs. The clinical outcomes were progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and sensitivity and subgroup analyses were performed to investigate heterogeneity.RESULTS: Seventeen articles involving 2092 patients were included in the final analysis. The pooled HRs of PFS and OS for NLR were 1.81(95% CI 1.36-2.41) and 2.26 (95% CI 1.68-3.03), respectively, suggesting that patients with higher baseline NLRs had significantly poorer PFS and OS. Similar results were detected in sensitivity and subgroup analyses. However, no significant relevance was found between PLR and clinical endpoints in patients treated with ICIs (HR = 1.14, 95% CI 0.88-1.48 for PFS; HR = 1.35, 95% CI 0.86-2.12 for OS).CONCLUSION: These results indicate that high pretreatment NLR but not PLR level, as a routinely obtained hematological parameter, is a potential prognostic predictor for poor PFS and OS in cancer patients receiving ICIs.
CANIT0002065	30169584	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	15	N/A	Retrospective analysis	Of the 65 eligible patients with Microscopic colitis (MC), 15 cancer patients had exposure to immune checkpoint inhibitor (ICPI), 39 cancer patients had no exposure to ICPI, and 11 had no cancer diagnosis. Among the risk factors, proton pump inhibitor was more frequently used in the ICPI-induced MC cohort (P = 0.040). Furthermore, in this population, mucosal abnormality was the most common endoscopic feature compared with normal findings in the non-ICPI-induced MC groups (P = 0.106). Patients with ICPI-induced MC required more treatments with oral and intravenous steroids and nonsteroidal immunosuppressive agents (all P < 0.001) and had a higher rate of hospitalization (P < 0.001).	Microscopic colitis	N/A	N/A	Mucosal abnormality ()	Mucosal abnormality	Disease status	 2019 Jan 10	Can Immune Checkpoint Inhibitors Induce Microscopic Colitis or a Brand New Entity 	 Inflamm Bowel Dis	BACKGROUND: Microscopic colitis (MC) has been described as 1 pattern of injury in immune checkpoint inhibitor (ICPI)-induced colitis. The main objective of this study was to characterize ICPI-induced MC by exploring the differences in risk factors, colitis treatments, endoscopic features, and clinical outcomes between cancer and noncancer patients with MC with and without exposure to ICPIs.METHODS: A retrospective chart review was conducted among patients diagnosed with MC from our institutional pathology database from January 2012 to January 2018. Patients were categorized into MC in cancer patients with or without ICPI exposure and in noncancer patients. Risk factors (use of tobacco and certain medications), colitis treatments (antidiarrheals and immunosuppressants), endoscopic features (with or without mucosal abnormality), and clinical outcomes (diarrhea recurrence, hospitalization, mortality) were collected and compared among the 3 groups.RESULTS: Of the 65 eligible patients with MC, 15 cancer patients had exposure to ICPI, 39 cancer patients had no exposure to ICPI, and 11 had no cancer diagnosis. Among the risk factors, proton pump inhibitor was more frequently used in the ICPI-induced MC cohort (P = 0.040). Furthermore, in this population, mucosal abnormality was the most common endoscopic feature compared with normal findings in the non-ICPI-induced MC groups (P = 0.106). Patients with ICPI-induced MC required more treatments with oral and intravenous steroids and nonsteroidal immunosuppressive agents (all P < 0.001) and had a higher rate of hospitalization (P < 0.001).CONCLUSION: This study suggests that despite some similarities between MC with and without exposure to ICPIs, ICPI-induced MC has a more aggressive disease course that requires more potent immunosuppressive treatment regimens and greater need for hospitalization. 10.1093/ibd/izy240_video1izy240.video15828223597001.
CANIT0002066	30169584	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	15	N/A	Retrospective analysis	Of the 65 eligible patients with Microscopic colitis (MC), 15 cancer patients had exposure to immune checkpoint inhibitor (ICPI), 39 cancer patients had no exposure to ICPI, and 11 had no cancer diagnosis. Among the risk factors, proton pump inhibitor was more frequently used in the ICPI-induced MC cohort (P = 0.040). Furthermore, in this population, mucosal abnormality was the most common endoscopic feature compared with normal findings in the non-ICPI-induced MC groups (P = 0.106). Patients with ICPI-induced MC required more treatments with oral and intravenous steroids and nonsteroidal immunosuppressive agents (all P < 0.001) and had a higher rate of hospitalization (P < 0.001).	Microscopic colitis	N/A	N/A	Proton Pump Inhibitor (NCIT:C29723); 	Proton pump inhibitor	Exposure factors/status	 2019 Jan 10	Can Immune Checkpoint Inhibitors Induce Microscopic Colitis or a Brand New Entity 	 Inflamm Bowel Dis	BACKGROUND: Microscopic colitis (MC) has been described as 1 pattern of injury in immune checkpoint inhibitor (ICPI)-induced colitis. The main objective of this study was to characterize ICPI-induced MC by exploring the differences in risk factors, colitis treatments, endoscopic features, and clinical outcomes between cancer and noncancer patients with MC with and without exposure to ICPIs.METHODS: A retrospective chart review was conducted among patients diagnosed with MC from our institutional pathology database from January 2012 to January 2018. Patients were categorized into MC in cancer patients with or without ICPI exposure and in noncancer patients. Risk factors (use of tobacco and certain medications), colitis treatments (antidiarrheals and immunosuppressants), endoscopic features (with or without mucosal abnormality), and clinical outcomes (diarrhea recurrence, hospitalization, mortality) were collected and compared among the 3 groups.RESULTS: Of the 65 eligible patients with MC, 15 cancer patients had exposure to ICPI, 39 cancer patients had no exposure to ICPI, and 11 had no cancer diagnosis. Among the risk factors, proton pump inhibitor was more frequently used in the ICPI-induced MC cohort (P = 0.040). Furthermore, in this population, mucosal abnormality was the most common endoscopic feature compared with normal findings in the non-ICPI-induced MC groups (P = 0.106). Patients with ICPI-induced MC required more treatments with oral and intravenous steroids and nonsteroidal immunosuppressive agents (all P < 0.001) and had a higher rate of hospitalization (P < 0.001).CONCLUSION: This study suggests that despite some similarities between MC with and without exposure to ICPIs, ICPI-induced MC has a more aggressive disease course that requires more potent immunosuppressive treatment regimens and greater need for hospitalization. 10.1093/ibd/izy240_video1izy240.video15828223597001.
CANIT0002067	30171269	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	52	N/A	Retrospective analysis	Involved organs had target-lesions in the lung (42%), liver (25%), lymph nodes (56%) and soft tissue (13%) and non-target lesions in the bones (23%). ORR and disease control rate (DCR) were 20% and 45%, respectively. Median overall survival, progression-free survival and duration of response were 11.9, 2.3 and 10.3 months. OSRR and organ-specific DCR (OSDCR) were 28% and 90% in lymph nodes, 8% and 54 in the liver, and 9% and 55% in lung metastases. Nine out of 12 patients with bone metastases had progressive lesions. The cumulative incidence probability of organ-specific progression at 6 months was 14% in lymph nodes, 42% in the liver, 36% in lung metastases and 26% in the primary tumor, 29% in soft tissue and 33% in adrenal metastases.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Dec	Organ-specific response to nivolumab in patients with non-small cell lung cancer (NSCLC).	 Cancer Immunol Immunother	BACKGROUND: Response to immune checkpoint inhibitors depends on tumor intrinsic properties and also on host factors in the tumour microenvironment including the presence of immune cells (IC). We hypothesized that nivolumab efficacy varies across different metastatic sites.METHODS: We retrospectively analyzed computed tomography scans of patients with metastatic non-small cell lung carcinoma (NSCLC) receiving nivolumab. RECIST 1.1 criteria were applied to assess the overall response rate (ORR) and organ-specific response rate (OSRR).RESULTS: We analyzed 52 patients including 44% females, 58% adenocarcinoma and 8% never smokers. Involved organs had target-lesions in the lung (42%), liver (25%), lymph nodes (56%) and soft tissue (13%) and non-target lesions in the bones (23%). ORR and disease control rate (DCR) were 20% and 45%, respectively. Median overall survival, progression-free survival and duration of response were 11.9, 2.3 and 10.3 months. OSRR and organ-specific DCR (OSDCR) were 28% and 90% in lymph nodes, 8% and 54 in the liver, and 9% and 55% in lung metastases. Nine out of 12 patients with bone metastases had progressive lesions. The cumulative incidence probability of organ-specific progression at 6 months was 14% in lymph nodes, 42% in the liver, 36% in lung metastases and 26% in the primary tumor, 29% in soft tissue and 33% in adrenal metastases.CONCLUSION: In conclusion, the efficacy of immunotherapy is dependent on the metastatic location. Treatment appears more active in lymph nodes compared to other organ sites such as liver, adrenals and bone. Future strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit.
CANIT0002068	30188231	Clinical research	Non-squamous, NSCLC	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus platinum and pemetrexed chemotherapy	Platinum and pemetrexed chemotherapy	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	N/A	N/A	Retrospective analysis	In the full non-squamous population, pembrolizumab + chemotherapy is projected to increase life expectancy by 2.04 years vs chemotherapy (3.96 vs 1.92), for an approximate doubling of life years. Resultant incremental cost-effectiveness ratios (ICERs) are $104,823/QALY and $87,242/life year. In patients with PD-L1 >= 50% and 1-49%, life expectancy is more than doubled (4.53 vs 1.88 years) and (4.87 vs 2.01 years), with a 32% (2.60 vs 1.97 years) increase in PD-L1 < 1% patients. Corresponding incremental costs/quality-adjusted life year (QALY) are $103,402, $66,837, and $183,529 for PD-L1 >= 50%, 1-49%, and <1% groups, respectively. Versus pembrolizumab monotherapy in PD-L1 >= 50% patients, representing current standard of care, pembrolizumab + chemotherapy increases life expectancy by 65% (4.53 vs 2.74 years) at an ICER of $147,365/QALY.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Dec	Cost-effectiveness of pembrolizumab in combination with chemotherapy in the 1st line treatment of non-squamous NSCLC in the US.	 J Med Econ	AIMS: To describe cost-effectiveness of pembrolizumab plus platinum and pemetrexed chemotherapy in metastatic, non-squamous, NSCLC patients in the US.MATERIALS AND METHODS: A model is developed utilizing partitioned survival analysis to estimate the cost-effectiveness of KEYNOTE-189 trial comparators pembrolizumab + chemotherapy (carboplatin/cisplatin + pemetrexed) vs chemotherapy alone. Clinical efficacy, treatment utilization, health utility, and safety data are derived from the trial and projected over 20 years. For extrapolating survival beyond the trial, a novel SEER population-data approach is applied (primary analysis), with separate estimation via traditional parametric extrapolation methods. Costs for drugs and non-drug disease management are also incorporated. Based on an indirect treatment comparison, cost-effectiveness of pembrolizumab + chemotherapy vs pembrolizumab monotherapy is evaluated for patients with programmed death-ligand 1 (PD-L1) >= 50%.RESULTS: In the full non-squamous population, pembrolizumab + chemotherapy is projected to increase life expectancy by 2.04 years vs chemotherapy (3.96 vs 1.92), for an approximate doubling of life years. Resultant incremental cost-effectiveness ratios (ICERs) are $104,823/QALY and $87,242/life year. In patients with PD-L1 >= 50% and 1-49%, life expectancy is more than doubled (4.53 vs 1.88 years) and (4.87 vs 2.01 years), with a 32% (2.60 vs 1.97 years) increase in PD-L1 < 1% patients. Corresponding incremental costs/quality-adjusted life year (QALY) are $103,402, $66,837, and $183,529 for PD-L1 >= 50%, 1-49%, and <1% groups, respectively. Versus pembrolizumab monotherapy in PD-L1 >= 50% patients, representing current standard of care, pembrolizumab + chemotherapy increases life expectancy by 65% (4.53 vs 2.74 years) at an ICER of $147,365/QALY.LIMITATIONS AND CONCLUSIONS: The addition of pembrolizumab to chemotherapy is projected to extend life expectancy to a point not previously seen in previously untreated metastatic non-squamous NSCLC. Although ICERs vary by sub-group and comparator, results suggest pembrolizumab + chemotherapy yields ICERs near, or in most cases, well below a 3-times US per capita GDP threshold of $180,000/QALY, and may be a cost-effective first-line treatment for metastatic non-squamous NSCLC patients.
CANIT0002069	30197259	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	91	N/A	N/A	The median overall survival (OS) for patients with immune-related adverse events was longer than that for patients without (24.3 vs. 5.3 months; hazard ratio, 2.75; 95% confidence interval, 1.54-4.92; P < .001). However, a landmark analysis of patients after 3 months of treatment revealed no difference in OS between patients with and without immune-related adverse events. No increased risk of pneumonitis was seen in patients with previous thoracic radiotherapy, although these patients had shorter survival (4.2 vs. 9.7 months; P = .004). Radiotherapy after the initiation of immunotherapy (n = 15) did not increase the risk of immune-related adverse events or pneumonitis; however, these patients had improved OS (17.3 vs. 6.0 months; P = .016).	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Previous thoracic radiotherapy	Disease status	 2018 Nov	Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer.	 Clin Lung Cancer	BACKGROUND: The risk factors for immune-related adverse events (irAEs) remain undefined. Recently, a correlation between irAEs and clinical benefit was suggested. We examined the risk factors for irAEs and their effect on survival in patients with non-small-cell lung cancer (NSCLC) who had received immunotherapy.PATIENTS AND METHODS: We performed a retrospective review of patients with NSCLC treated with single-agent immunotherapy at our institution. irAEs were determined by treating physician diagnosis. A landmark analysis was performed at 3 months using log-rank tests and the Bonferroni method.RESULTS: irAEs occurred in 27 of 91 patients (30%). The median overall survival (OS) for patients with irAEs was longer than that for patients without (24.3 vs. 5.3 months; hazard ratio, 2.75; 95% confidence interval, 1.54-4.92; P < .001). However, a landmark analysis of patients after 3 months of treatment revealed no difference in OS between patients with and without irAEs. No increased risk of pneumonitis was seen in patients with previous thoracic radiotherapy, although these patients had shorter survival (4.2 vs. 9.7 months; P = .004). Radiotherapy after the initiation of immunotherapy (n = 15) did not increase the risk of irAEs or pneumonitis; however, these patients had improved OS (17.3 vs. 6.0 months; P = .016).CONCLUSION: The development of irAEs did not significantly correlate with survival when controlling for the duration of therapy in a landmark analysis. We found no increased risk of pneumonitis or irAEs in patients who had received radiotherapy. Radiotherapy before immunotherapy was associated with shorter survival, and radiotherapy after immunotherapy was associated with improved survival.
CANIT0002070	30197259	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	91	N/A	N/A	The median overall survival (OS) for patients with immune-related adverse events was longer than that for patients without (24.3 vs. 5.3 months; hazard ratio, 2.75; 95% confidence interval, 1.54-4.92; P < .001). However, a landmark analysis of patients after 3 months of treatment revealed no difference in OS between patients with and without immune-related adverse events. No increased risk of pneumonitis was seen in patients with previous thoracic radiotherapy, although these patients had shorter survival (4.2 vs. 9.7 months; P = .004). Radiotherapy after the initiation of immunotherapy (n = 15) did not increase the risk of immune-related adverse events or pneumonitis; however, these patients had improved OS (17.3 vs. 6.0 months; P = .016).	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2018 Nov	Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer.	 Clin Lung Cancer	BACKGROUND: The risk factors for immune-related adverse events (irAEs) remain undefined. Recently, a correlation between irAEs and clinical benefit was suggested. We examined the risk factors for irAEs and their effect on survival in patients with non-small-cell lung cancer (NSCLC) who had received immunotherapy.PATIENTS AND METHODS: We performed a retrospective review of patients with NSCLC treated with single-agent immunotherapy at our institution. irAEs were determined by treating physician diagnosis. A landmark analysis was performed at 3 months using log-rank tests and the Bonferroni method.RESULTS: irAEs occurred in 27 of 91 patients (30%). The median overall survival (OS) for patients with irAEs was longer than that for patients without (24.3 vs. 5.3 months; hazard ratio, 2.75; 95% confidence interval, 1.54-4.92; P < .001). However, a landmark analysis of patients after 3 months of treatment revealed no difference in OS between patients with and without irAEs. No increased risk of pneumonitis was seen in patients with previous thoracic radiotherapy, although these patients had shorter survival (4.2 vs. 9.7 months; P = .004). Radiotherapy after the initiation of immunotherapy (n = 15) did not increase the risk of irAEs or pneumonitis; however, these patients had improved OS (17.3 vs. 6.0 months; P = .016).CONCLUSION: The development of irAEs did not significantly correlate with survival when controlling for the duration of therapy in a landmark analysis. We found no increased risk of pneumonitis or irAEs in patients who had received radiotherapy. Radiotherapy before immunotherapy was associated with shorter survival, and radiotherapy after immunotherapy was associated with improved survival.
CANIT0002071	30201371	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	216	N/A	Retrospective analysis	The developed software supported the generation of BReC plots and diagnostic validation of biomarker response-based medical tests by generating the sensitivity, specificity and predictive values. Obtained BReC plots showed a clear relationship between clinical outcome and CEA and Cyfra 21.1 responses. Furthermore, using BReC plots, CEA and Cyfra 21.1 based medical tests were designed with a sensitivity for detection of treatment failure of 0.34 and 0.35 and a specificity of 0.96.	N/A	N/A	N/A	CEA (P06731); 	Serial carcinoembryonic antigen	Gene expression signature on/in tumor cell	 2018 Dec	Diagnostic validation and interpretation of longitudinal circulating biomarkers using a biomarker response characteristic plot.	 Clin Chim Acta	BACKGROUND: Serum-based tumor biomarkers are used to monitor cancer treatment, while clear guidance on the clinical usage is often lacking. We describe a graphical presentation to support diagnostic accuracy studies and clinical interpretation of longitudinal biomarker data.METHODS: A biomarker response characteristic (BReC) plot was designed. To allow demonstration of the BReC plot application, software was developed that supported 1) dynamic generation of BReC plots, and 2) diagnostic accuracy studies of biomarker response-based medical tests. The BReC plot application was demonstrated using serial carcinoembryonic antigen (CEA) and Cyfra 21.1 results from 216 patients with metastasized non-small cell lung cancer, treated with Nivolumab in routine clinical practice.RESULTS: The developed software supported the generation of BReC plots and diagnostic validation of biomarker response-based medical tests by generating the sensitivity, specificity and predictive values. Obtained BReC plots showed a clear relationship between clinical outcome and CEA and Cyfra 21.1 responses. Furthermore, using BReC plots, CEA and Cyfra 21.1 based medical tests were designed with a sensitivity for detection of treatment failure of 0.34 and 0.35 and a specificity of 0.96.CONCLUSIONS: The BReC plot appears to support diagnostic validation studies and the interpretation of longitudinal biomarkers though further validation is warranted.
CANIT0002072	30205166	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab or ipilimumab or pembrolizumab or nivolumab plus crizotinib	Crizotinib	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); crizotinib (DB08865); 	11	442	N/A	We identified 453 patients who had NSCLC with an oncogenic alteration in ALK receptor tyrosine kinase gene (ALK), ROS1, or MET proto-oncogene, receptor tyrosine kinase gene (MET) and were treated with crizotinib (11 with and 442 without prior ICI therapy). Among the 11 patients treated with an ICI followed by crizotinib, five (cumulative incidence 45.5% [95% confidence interval (CI): 14.9-72.2]) experienced development of a grade 3 or 4 increase in alanine transaminase level and four (cumulative incidence 36.4% [95% CI: 10.0-64.2]) experienced development of a grade 3 or 4 increase in aspartate transaminase level. In comparison, among the 442 patients who received crizotinib only, a grade 3 or 4 increase in alanine transaminase level occurred in 34 patients (cumulative incidence 8.1% [95% CI: 5.7-11.0, p < 0.0001]) and a grade 3 or 4 increase in aspartate transaminase level occurred in 14 (cumulative incidence 3.4% [95% CI: 1.9-5.5, p < 0.0001]). There were no grade 5 transaminitis events. All cases of hepatotoxicity after sequential ICI and crizotinib use were reversible and nonfatal, and no case met the Hy's law criteria.	Hepatotoxicity	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non-Small Cell Lung Cancer.	 J Thorac Oncol	INTRODUCTION: Immune checkpoint inhibitors (ICIs) are standard therapies in advanced NSCLC. Although genotype-directed tyrosine kinase inhibitors represent the standard of care for subsets of oncogene-driven NSCLC, patients may receive ICIs during their disease course. The impact of sequential ICI and tyrosine kinase inhibitor therapy on the risk of hepatotoxicity has not been described.METHODS: Patients with advanced ALK receptor tyrosine kinase (ALK)-driven, ROS1-driven, or MET proto-oncogene, receptor tyrosine kinase (MET)-driven NSCLC treated with crizotinib, with or without preceding ICI therapy, were identified. The cumulative incidences of crizotinib-associated grade 3 or higher increases in transaminase level (per the Common Terminology Criteria for Adverse Events, version 4.0) were compared.RESULTS: We identified 453 patients who had NSCLC with an oncogenic alteration in ALK receptor tyrosine kinase gene (ALK), ROS1, or MET proto-oncogene, receptor tyrosine kinase gene (MET) and were treated with crizotinib (11 with and 442 without prior ICI therapy). Among the 11 patients treated with an ICI followed by crizotinib, five (cumulative incidence 45.5% [95% confidence interval (CI): 14.9-72.2]) experienced development of a grade 3 or 4 increase in alanine transaminase level and four (cumulative incidence 36.4% [95% CI: 10.0-64.2]) experienced development of a grade 3 or 4 increase in aspartate transaminase level. In comparison, among the 442 patients who received crizotinib only, a grade 3 or 4 increase in alanine transaminase level occurred in 34 patients (cumulative incidence 8.1% [95% CI: 5.7-11.0, p < 0.0001]) and a grade 3 or 4 increase in aspartate transaminase level occurred in 14 (cumulative incidence 3.4% [95% CI: 1.9-5.5, p < 0.0001]). There were no grade 5 transaminitis events. All cases of hepatotoxicity after sequential ICI and crizotinib use were reversible and nonfatal, and no case met the Hy's law criteria.CONCLUSIONS: Sequential ICI and crizotinib treatment is associated with a significantly increased risk of hepatotoxicity. Careful consideration and monitoring for hepatotoxicity may be warranted in patients treated with crizotinib after ICI therapy.
CANIT0002073	30206764	Clinical research	Diffuse intrinsic pontine glioma	Diffuse intrinsic pontine glioma	EFO:1000026	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Reirradiation	Reirradiation	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); 	8	4	Retrospective analysis	Patients who received reirradiation (reRT) had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4 months-reRT alone; 8.3 months-no reRT; p < 0.0001). Patients who received reRT with nivolumab vs. reRT only had slightly prolonged OS from diagnosis and from reRT (22.9 vs. 20.4 months for time from diagnosis; 6.8 vs. 6.0 months for time from reRT).	All patients receiving reRT with or without nivolumab tolerated the therapy without acute or late toxicity.	N/A	N/A	N/A	N/A	N/A	 2018 Dec	Reirradiation and PD-1 inhibition with nivolumab for the treatment of recurrent diffuse intrinsic pontine glioma: a single-institution experience.	 J Neurooncol	BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive brain tumor with no known cure. Reirradiation (reRT) at recurrence can prolong survival. The impact of irradiation may be heightened when combined with PD-1 inhibition. We describe our experience using reRT, with or without PD-1 inhibition, in a cohort of patients with recurrent DIPG.METHODS: We performed a retrospective cohort analysis of children who received reRT with or without concomitant PD-1 inhibition for recurrent DIPG at a single institution between 2005 and 2016. We compared progression-free (PFS) and overall survival (OS) between those who received reRT alone or in combination with PD-1 inhibition. We then compared reRT to a cohort of patients who did not receive reRT.RESULTS: Thirty-one patients were included (8-reRT with nivolumab; 4-reRT alone; 19-no reRT). Patients who received reRT had prolonged OS compared to no reRT (22.9 months-reRT with nivolumab; 20.4 months-reRT alone; 8.3 months-no reRT; p < 0.0001). Patients who received reRT with nivolumab vs. reRT only had slightly prolonged OS from diagnosis and from reRT (22.9 vs. 20.4 months for time from diagnosis; 6.8 vs. 6.0 months for time from reRT). All patients receiving reRT with or without nivolumab tolerated the therapy without acute or late toxicity.CONCLUSIONS: Our experience demonstrates the tolerability of reRT with concurrent PD-1 inhibition for recurrent DIPG and suggests that combination therapy may offer survival benefit. Future prospective studies are needed to confirm the benefits of this combination therapy.
CANIT0002074	30220316	Clinical research	Advanced head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	N/A	100	N/A	Retrospective analysis	HPV+ disease and increased total mutational burden were associated with distant disease in the absence of locoregional disease (p < 0.01 and p = 0.03, respectively). Forty patients (40%) demonstrated clinical benefit to ICPi, and the median overall survival (OS) on PD-1 therapy was 4.5 months. A lower tumor burden at baseline was associated with clinical benefit (p = 0.03) and improved OS (p < 0.01, HR 2.33). There was only one instance of pseudoprogression; indeed any increase in TB on first interval scan was associated with poor OS (p = 0.02, HR 2.39).	N/A	N/A	N/A	HPV (NCIT:C1951 ); 	HPV-positive	Microbiota	 2018 Oct	Radiologic predictors of immune checkpoint inhibitor response in advanced head and neck squamous cell carcinoma.	 Oral Oncol	Radiologic predictors of response to immune checkpoint blockade (ICPi) in advanced head and neck squamous cell carcinoma (HNSCC) patients could help guide patient selection and management. We analyzed a large institutional cohort of 100 consecutive HNSCC patients treated with ICPi to investigate associations between molecular and radiologic phenotype and assess radiologic predictors of response and survival. Of particular interest was the impact of increased total tumor burden (TB), calculated as the sum of the largest diameter of all measurable lesions according to RECIST 1.1, and early radiologic indicators of response versus progression. Within our cohort, 42% of patients had HPV+ associated disease, 64% had persistent/recurrent head and neck lesions, and 77% had distant metastases. Median TB was 5.4 cm. HPV+ disease and increased total mutational burden were associated with distant disease in the absence of locoregional disease (p < 0.01 and p = 0.03, respectively). Forty patients (40%) demonstrated clinical benefit to ICPi, and the median overall survival (OS) on PD-1 therapy was 4.5 months. A lower tumor burden at baseline was associated with clinical benefit (p = 0.03) and improved OS (p < 0.01, HR 2.33). There was only one instance of pseudoprogression; indeed any increase in TB on first interval scan was associated with poor OS (p = 0.02, HR 2.39). These data suggest that HNSCC patients who benefit from ICPi are more likely to have lower tumor burden at the onset of treatment and minimal increase in tumor burden while on treatment.
CANIT0002075	30220316	Clinical research	Advanced head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	N/A	100	N/A	Retrospective analysis	HPV+ disease and increased total mutational burden were associated with distant disease in the absence of locoregional disease (p < 0.01 and p = 0.03, respectively). Forty patients (40%) demonstrated clinical benefit to ICPi, and the median overall survival (OS) on PD-1 therapy was 4.5 months. A lower tumor burden at baseline was associated with clinical benefit (p = 0.03) and improved OS (p < 0.01, HR 2.33). There was only one instance of pseudoprogression; indeed any increase in TB on first interval scan was associated with poor OS (p = 0.02, HR 2.39).	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2018 Oct	Radiologic predictors of immune checkpoint inhibitor response in advanced head and neck squamous cell carcinoma.	 Oral Oncol	Radiologic predictors of response to immune checkpoint blockade (ICPi) in advanced head and neck squamous cell carcinoma (HNSCC) patients could help guide patient selection and management. We analyzed a large institutional cohort of 100 consecutive HNSCC patients treated with ICPi to investigate associations between molecular and radiologic phenotype and assess radiologic predictors of response and survival. Of particular interest was the impact of increased total tumor burden (TB), calculated as the sum of the largest diameter of all measurable lesions according to RECIST 1.1, and early radiologic indicators of response versus progression. Within our cohort, 42% of patients had HPV+ associated disease, 64% had persistent/recurrent head and neck lesions, and 77% had distant metastases. Median TB was 5.4 cm. HPV+ disease and increased total mutational burden were associated with distant disease in the absence of locoregional disease (p < 0.01 and p = 0.03, respectively). Forty patients (40%) demonstrated clinical benefit to ICPi, and the median overall survival (OS) on PD-1 therapy was 4.5 months. A lower tumor burden at baseline was associated with clinical benefit (p = 0.03) and improved OS (p < 0.01, HR 2.33). There was only one instance of pseudoprogression; indeed any increase in TB on first interval scan was associated with poor OS (p = 0.02, HR 2.39). These data suggest that HNSCC patients who benefit from ICPi are more likely to have lower tumor burden at the onset of treatment and minimal increase in tumor burden while on treatment.
CANIT0002076	30230649	Clinical research	Advanced solid tumors	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	168	N/A	N/A	Twenty-three (14%) of a total of 168 patients developed thyroid dysfunction (TD), including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53-23.9). In multivariate analysis, elevated thyroid-stimulating hormone (TSH) and antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb) at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66-32.7) and 26.5 (95% CI, 8.18-85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre-existing TgAb and elevated TSH at baseline are at high risk of TD.	Thyroid dysfunction induced by nivolumab	N/A	N/A	Thyroid-stimulating hormone (NCIT:C2280); 	Thyroid-stimulating hormone levels	Gene expression signature in serum	 2018 Nov	Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab.	 Cancer Sci	Thyroid dysfunction (TD) induced by immune checkpoint inhibitors is not sufficiently understood. The purpose of this retrospective observational study was to identify risk factors and the clinical course of TD induced by nivolumab. Patients with advanced solid tumors who were treated with nivolumab from March 2009 through to March 2016 at the National Cancer Center Hospital (Tokyo, Japan) were included. Thyroid function and antithyroid Abs from serum samples among all patients were evaluated at baseline and during nivolumab treatment. Overt hypothyroidism was defined as low serum-free T4 together with elevated thyroid-stimulating hormone (TSH) >10 ¦ÌIU/mL. Thyrotoxicosis was defined as low TSH with elevated free T4 and/or free T3. We defined thyroid autoimmunity as the presence of antithyroid Abs at baseline, including antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb). Twenty-three (14%) of a total of 168 patients developed TD, including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53-23.9). In multivariate analysis, elevated TSH and TgAb at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66-32.7) and 26.5 (95% CI, 8.18-85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre-existing TgAb and elevated TSH at baseline are at high risk of TD.
CANIT0002077	30230649	Clinical research	Advanced solid tumors	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	168	N/A	N/A	Twenty-three (14%) of a total of 168 patients developed thyroid dysfunction (TD), including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53-23.9). In multivariate analysis, elevated thyroid-stimulating hormone (TSH) and antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb) at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66-32.7) and 26.5 (95% CI, 8.18-85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre-existing TgAb and elevated TSH at baseline are at high risk of TD.	Thyroid dysfunction induced by nivolumab	N/A	N/A	Thyroid Antithyroglobulin Antibody levels (NCIT:C81992); 	Thyroid Antithyroglobulin Antibody levels	Gene expression signature in serum	 2018 Nov	Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab.	 Cancer Sci	Thyroid dysfunction (TD) induced by immune checkpoint inhibitors is not sufficiently understood. The purpose of this retrospective observational study was to identify risk factors and the clinical course of TD induced by nivolumab. Patients with advanced solid tumors who were treated with nivolumab from March 2009 through to March 2016 at the National Cancer Center Hospital (Tokyo, Japan) were included. Thyroid function and antithyroid Abs from serum samples among all patients were evaluated at baseline and during nivolumab treatment. Overt hypothyroidism was defined as low serum-free T4 together with elevated thyroid-stimulating hormone (TSH) >10 ¦ÌIU/mL. Thyrotoxicosis was defined as low TSH with elevated free T4 and/or free T3. We defined thyroid autoimmunity as the presence of antithyroid Abs at baseline, including antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb). Twenty-three (14%) of a total of 168 patients developed TD, including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53-23.9). In multivariate analysis, elevated TSH and TgAb at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66-32.7) and 26.5 (95% CI, 8.18-85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre-existing TgAb and elevated TSH at baseline are at high risk of TD.
CANIT0002078	30242316	Clinical research	More than 16 000 000 adverse drug reactions in World Health Organization (WHO) pharmacovigilance database (Vigilyze), 3545 patients treated with ICIs from 7 academic centers, a meta-analysis of 112 trials involving 19 217 patients	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Ipilimumab or tremelimumab or nivolumab, pembrolizumab or atezolizumab or avelumab or durvalumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); avelumab (DB11945); durvalumab (DB11714); ipilimumab (DB06186); nivolumab (DB09035); pembrolizumab (DB09037); tremelimumab (DB11771); 	16 000 000	N/A	Meta-analysis	In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen.	Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes.	N/A	N/A	N/A	N/A	N/A	2018 Dec 1	Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.	JAMA Oncol. 	Importance: Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.Objective: To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.Design, setting, and participants: We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally.Exposures: Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab).Main outcomes and measures: Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects.Results: Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4).Conclusions and relevance: In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.
CANIT0002079	30248181	Basic research	Glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); LAG3 (Q61790); 	PD-1; LAG3	Anti-LAG-3 plus nivolumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	We show that LAG-3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG-3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG-3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG-3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG-3 in the treatment of glioblastoma.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	LAG3 (Q61790); 	LAG3 expression levels 	Gene expression signature on/in tumor cell	 2018 Dec 15	Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma.	 Int J Cancer	Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti-PD-1 or CTLA4. We here investigate the expression and efficacy of a novel immune-checkpoint inhibitor, called LAG-3. We show that LAG-3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG-3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG-3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG-3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG-3 in the treatment of glioblastoma.
CANIT0002080	30253080	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	51	N/A	Retrospective analysis	The overall response rate was 21.6% (11/51). The response rate was significantly lower in patients with pleural or pericardial metastasis than in patients without pleural or pericardial metastasis (4.3% vs. 35.7%; P = 0.007). 	Patients with pleural or pericardial metastasis had a significantly higher rate of adverse events of any grade (91.3% vs. 50.0%; P = 0.002) and grade 3-5 adverse events (52.2% vs. 25.0%; P = 0.046).	N/A	N/A	Metastasis (NCIT:C19151); 	Pleural or pericardial metastasis	Disease status	 2018 Nov	Pleural or pericardial metastasis: A significant factor affecting efficacy and adverse events in lung cancer patients treated with PD-1/PD-L1 inhibitors.	 Thorac Cancer	BACKGROUND: Immunotherapy is a new paradigm for the treatment of non-small-cell lung cancer (NSCLC), and targeting the PD-1 or PD-L1 pathway is a promising therapeutic option. Although PD-1/PD-L1 inhibitors are more effective than standard chemotherapy in lung cancer, clinicians are afraid to actively use them because of hyperprogression and pseudoprogression. The aim of this study was to investigate the factors associated with tumor response and serious outcomes.METHODS: We retrospectively collected the medical records of 51 patients with advanced NSCLC who received PD-1/PD-L1 inhibitors between January 2016 and February 2018.RESULTS: The mean patient age was 63.9 years, and 72.5% (37/51) were male. Most (92.2%, 47/51) had received previous systemic treatment. The overall response rate was 21.6% (11/51). The response rate was significantly lower in patients with pleural or pericardial metastasis than in patients without pleural or pericardial metastasis (4.3% vs. 35.7%; P = 0.007). Patients with pleural or pericardial metastasis had a significantly higher rate of adverse events of any grade (91.3% vs. 50.0%; P = 0.002) and grade 3-5 adverse events (52.2% vs. 25.0%; P = 0.046).CONCLUSION: Pleural or pericardial metastasis is a significant factor affecting the efficacy and rate of adverse events in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinicians should pay attention to the use of immune checkpoint inhibitors in lung cancer patients with pleural or pericardial metastasis.
CANIT0002081	30253992	Case report	Glioblastoma multiforme	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Pembrolizumab plus bevacizumab followed by imatinib	N/A	Immune checkpoint therapy plus Target therapy followed by Chemotherapy	Pembrolizumab (DB09037); bevacizumab (DB00112); imatinib (DB00619); 	1	N/A	Case	In a 45-year-old man without focal neurologic deficit, a right temporal GBM, IDH-wildtype (biomarkers MGMT promoter methylation negative, Ki-67 proliferation rate 70%) was diagnosed. Gross tumor resection followed by concomitant and adjuvant radiotherapy and chemotherapy with temozolomide was performed. Routine follow-up imaging 8 months later showed a right parietal meningeal tumor. Resection confirmed a distant GBM, and next-generation sequencing revealed high tumor mutational burden, high-frequency microsatellite instability, and a pharmacologically targetable KIT mutation. Complete neuraxis imaging revealed multiple contrast-enhancing tumors in the craniocervical junction and levels C7, Th8-Th11, and S1. The craniocervical tumors and the cervical spine from C1-C2 were irradiated as palliative care, and second-line combined chemotherapy and antiangiogenic therapy with irinotecan and bevacizumab was initiated, which was later changed to an immune-checkpoint blockade with pembrolizumab in combination with bevacizumab owing to tumor progression. Tumor growth was slowed, but the patient eventually developed a progressive paraparesis. Subsequent KIT-targeting tyrosine kinase inhibitor therapy with imatinib was administered for a short time. The patient died 13.8 months after initial diagnosis.	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2018 Dec	Extensive Leptomeningeal Intracranial and Spinal Metastases in a Patient with a Supratentorial Glioblastoma Multiforme, IDH-Wildtype.	 World Neurosurg	BACKGROUND: Glioblastoma multiforme (GBM) is usually characterized by diffuse, infiltrative growth and local tumor progression. Extensive leptomeningeal metastases are rarely observed. It is unclear which GBMs are prone to this specific growth pattern and progression, and standardized salvage treatment protocols are unavailable.CASE DESCRIPTION: In a 45-year-old man without focal neurologic deficit, a right temporal GBM, IDH-wildtype (biomarkers MGMT promoter methylation negative, Ki-67 proliferation rate 70%) was diagnosed. Gross tumor resection followed by concomitant and adjuvant radiotherapy and chemotherapy with temozolomide was performed. Routine follow-up imaging 8 months later showed a right parietal meningeal tumor. Resection confirmed a distant GBM, and next-generation sequencing revealed high tumor mutational burden, high-frequency microsatellite instability, and a pharmacologically targetable KIT mutation. Complete neuraxis imaging revealed multiple contrast-enhancing tumors in the craniocervical junction and levels C7, Th8-Th11, and S1. The craniocervical tumors and the cervical spine from C1-C2 were irradiated as palliative care, and second-line combined chemotherapy and antiangiogenic therapy with irinotecan and bevacizumab was initiated, which was later changed to an immune-checkpoint blockade with pembrolizumab in combination with bevacizumab owing to tumor progression. Tumor growth was slowed, but the patient eventually developed a progressive paraparesis. Subsequent KIT-targeting tyrosine kinase inhibitor therapy with imatinib was administered for a short time. The patient died 13.8 months after initial diagnosis.CONCLUSIONS: High-risk genetic profiles for GBMs prone to develop extensive leptomeningeal metastases need to be identified. Guidelines on preemptive, complete neuraxis imaging in certain patients with GBM as well as treatment guidelines need to be developed.
CANIT0002082	30253992	Case report	Glioblastoma multiforme	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Pembrolizumab plus bevacizumab followed by imatinib	N/A	Immune checkpoint therapy plus Target therapy followed by Chemotherapy	Pembrolizumab (DB09037); bevacizumab (DB00112); imatinib (DB00619); 	1	N/A	Case	In a 45-year-old man without focal neurologic deficit, a right temporal GBM, IDH-wildtype (biomarkers MGMT promoter methylation negative, Ki-67 proliferation rate 70%) was diagnosed. Gross tumor resection followed by concomitant and adjuvant radiotherapy and chemotherapy with temozolomide was performed. Routine follow-up imaging 8 months later showed a right parietal meningeal tumor. Resection confirmed a distant GBM, and next-generation sequencing revealed high tumor mutational burden, high-frequency microsatellite instability, and a pharmacologically targetable KIT mutation. Complete neuraxis imaging revealed multiple contrast-enhancing tumors in the craniocervical junction and levels C7, Th8-Th11, and S1. The craniocervical tumors and the cervical spine from C1-C2 were irradiated as palliative care, and second-line combined chemotherapy and antiangiogenic therapy with irinotecan and bevacizumab was initiated, which was later changed to an immune-checkpoint blockade with pembrolizumab in combination with bevacizumab owing to tumor progression. Tumor growth was slowed, but the patient eventually developed a progressive paraparesis. Subsequent KIT-targeting tyrosine kinase inhibitor therapy with imatinib was administered for a short time. The patient died 13.8 months after initial diagnosis.	N/A	N/A	N/A	Microsatellite instability (NCIT:C36318); 	Microsatellite instability	Mutational status	 2018 Dec	Extensive Leptomeningeal Intracranial and Spinal Metastases in a Patient with a Supratentorial Glioblastoma Multiforme, IDH-Wildtype.	 World Neurosurg	BACKGROUND: Glioblastoma multiforme (GBM) is usually characterized by diffuse, infiltrative growth and local tumor progression. Extensive leptomeningeal metastases are rarely observed. It is unclear which GBMs are prone to this specific growth pattern and progression, and standardized salvage treatment protocols are unavailable.CASE DESCRIPTION: In a 45-year-old man without focal neurologic deficit, a right temporal GBM, IDH-wildtype (biomarkers MGMT promoter methylation negative, Ki-67 proliferation rate 70%) was diagnosed. Gross tumor resection followed by concomitant and adjuvant radiotherapy and chemotherapy with temozolomide was performed. Routine follow-up imaging 8 months later showed a right parietal meningeal tumor. Resection confirmed a distant GBM, and next-generation sequencing revealed high tumor mutational burden, high-frequency microsatellite instability, and a pharmacologically targetable KIT mutation. Complete neuraxis imaging revealed multiple contrast-enhancing tumors in the craniocervical junction and levels C7, Th8-Th11, and S1. The craniocervical tumors and the cervical spine from C1-C2 were irradiated as palliative care, and second-line combined chemotherapy and antiangiogenic therapy with irinotecan and bevacizumab was initiated, which was later changed to an immune-checkpoint blockade with pembrolizumab in combination with bevacizumab owing to tumor progression. Tumor growth was slowed, but the patient eventually developed a progressive paraparesis. Subsequent KIT-targeting tyrosine kinase inhibitor therapy with imatinib was administered for a short time. The patient died 13.8 months after initial diagnosis.CONCLUSIONS: High-risk genetic profiles for GBMs prone to develop extensive leptomeningeal metastases need to be identified. Guidelines on preemptive, complete neuraxis imaging in certain patients with GBM as well as treatment guidelines need to be developed.
CANIT0002083	30253992	Case report	Glioblastoma multiforme	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Pembrolizumab plus bevacizumab followed by imatinib	N/A	Immune checkpoint therapy plus Target therapy followed by Chemotherapy	Pembrolizumab (DB09037); bevacizumab (DB00112); imatinib (DB00619); 	1	N/A	Case	In a 45-year-old man without focal neurologic deficit, a right temporal GBM, IDH-wildtype (biomarkers MGMT promoter methylation negative, Ki-67 proliferation rate 70%) was diagnosed. Gross tumor resection followed by concomitant and adjuvant radiotherapy and chemotherapy with temozolomide was performed. Routine follow-up imaging 8 months later showed a right parietal meningeal tumor. Resection confirmed a distant GBM, and next-generation sequencing revealed high tumor mutational burden, high-frequency microsatellite instability, and a pharmacologically targetable KIT mutation. Complete neuraxis imaging revealed multiple contrast-enhancing tumors in the craniocervical junction and levels C7, Th8-Th11, and S1. The craniocervical tumors and the cervical spine from C1-C2 were irradiated as palliative care, and second-line combined chemotherapy and antiangiogenic therapy with irinotecan and bevacizumab was initiated, which was later changed to an immune-checkpoint blockade with pembrolizumab in combination with bevacizumab owing to tumor progression. Tumor growth was slowed, but the patient eventually developed a progressive paraparesis. Subsequent KIT-targeting tyrosine kinase inhibitor therapy with imatinib was administered for a short time. The patient died 13.8 months after initial diagnosis.	N/A	N/A	N/A	KIT (P10721); 	A pharmacologically targetable KIT mutation	Mutational status	 2018 Dec	Extensive Leptomeningeal Intracranial and Spinal Metastases in a Patient with a Supratentorial Glioblastoma Multiforme, IDH-Wildtype.	 World Neurosurg	BACKGROUND: Glioblastoma multiforme (GBM) is usually characterized by diffuse, infiltrative growth and local tumor progression. Extensive leptomeningeal metastases are rarely observed. It is unclear which GBMs are prone to this specific growth pattern and progression, and standardized salvage treatment protocols are unavailable.CASE DESCRIPTION: In a 45-year-old man without focal neurologic deficit, a right temporal GBM, IDH-wildtype (biomarkers MGMT promoter methylation negative, Ki-67 proliferation rate 70%) was diagnosed. Gross tumor resection followed by concomitant and adjuvant radiotherapy and chemotherapy with temozolomide was performed. Routine follow-up imaging 8 months later showed a right parietal meningeal tumor. Resection confirmed a distant GBM, and next-generation sequencing revealed high tumor mutational burden, high-frequency microsatellite instability, and a pharmacologically targetable KIT mutation. Complete neuraxis imaging revealed multiple contrast-enhancing tumors in the craniocervical junction and levels C7, Th8-Th11, and S1. The craniocervical tumors and the cervical spine from C1-C2 were irradiated as palliative care, and second-line combined chemotherapy and antiangiogenic therapy with irinotecan and bevacizumab was initiated, which was later changed to an immune-checkpoint blockade with pembrolizumab in combination with bevacizumab owing to tumor progression. Tumor growth was slowed, but the patient eventually developed a progressive paraparesis. Subsequent KIT-targeting tyrosine kinase inhibitor therapy with imatinib was administered for a short time. The patient died 13.8 months after initial diagnosis.CONCLUSIONS: High-risk genetic profiles for GBMs prone to develop extensive leptomeningeal metastases need to be identified. Guidelines on preemptive, complete neuraxis imaging in certain patients with GBM as well as treatment guidelines need to be developed.
CANIT0002084	30267032	Clinical research	Recurrent human papilloma virus (HPV)-driven cancer	Human papilloma virus-driven cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	Single-arm, single-center phase 2 clinical trial	Of the 24 patients (4 women and 20 men; 22 with oropharyngeal cancer; median age, 60 years [range, 36-73 years]), the overall response rate was 33% (8 patients; 90% CI, 19%-50%). Median duration of response was 10.3 months (95% CI, 10.3 months to inestimable). Five of 8 patients remain in response. Median progression-free survival was 2.7 months (95% CI, 2.5-9.4 months). Median overall survival was 17.5 months (95% CI, 17.5 months to inestimable).	Grades 3 to 4 toxicity occurred in 2 patients (asymptomatic grade 3 transaminase level elevation in 1 patient and grade 4 lipase elevation in 1 patient), requiring discontinuation of nivolumab therapy.	N/A	N/A	N/A	N/A	N/A	 2019 Jan 1	Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16-Related Cancer: A Phase 2 Clinical Trial.	 JAMA Oncol	IMPORTANCE: In recurrent human papilloma virus (HPV)-driven cancer, immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies produces tumor regression in only a minority of patients. Therapeutic HPV vaccines have produced strong immune responses to HPV-16, but vaccination alone has been ineffective for invasive cancer.OBJECTIVE: To determine whether the efficacy of nivolumab, an anti-PD-1 immune checkpoint antibody, is amplified through treatment with ISA 101, a synthetic long-peptide HPV-16 vaccine inducing HPV-specific T cells, in patients with incurable HPV-16-positive cancer.DESIGN, SETTING, AND PARTICIPANTS: In this single-arm, single-center phase 2 clinical trial, 24 patients with incurable HPV-16-positive cancer were enrolled from December 23, 2015, to December 12, 2016. Duration of follow-up for censored patients was 12.2 months through August 31, 2017.INTERVENTIONS: The vaccine ISA101, 100 ¦Ìg/peptide, was given subcutaneously on days 1, 22, and 50. Nivolumab, 3 mg/kg, was given intravenously every 2 weeks beginning day 8 for up to 1 year.MAIN OUTCOMES AND MEASURES: Assessment of efficacy reflected in the overall response rate (per Response Evaluation Criteria in Solid Tumors, version 1.1).RESULTS: Of the 24 patients (4 women and 20 men; 22 with oropharyngeal cancer; median age, 60 years [range, 36-73 years]), the overall response rate was 33% (8 patients; 90% CI, 19%-50%). Median duration of response was 10.3 months (95% CI, 10.3 months to inestimable). Five of 8 patients remain in response. Median progression-free survival was 2.7 months (95% CI, 2.5-9.4 months). Median overall survival was 17.5 months (95% CI, 17.5 months to inestimable). Grades 3 to 4 toxicity occurred in 2 patients (asymptomatic grade 3 transaminase level elevation in 1 patient and grade 4 lipase elevation in 1 patient), requiring discontinuation of nivolumab therapy.CONCLUSIONS AND RELEVANCE: The overall response rate of 33% and median overall survival of 17.5 months is promising compared with PD-1 inhibition alone in similar patients. A randomized clinical trial to confirm the contribution of HPV-16 vaccination to tumoricidal effects of PD-1 inhibition is warranted for further study.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02426892.
CANIT0002085	30267842	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	205	N/A	Retrospective analysis	The results demonstrate a higher incidence of  Checkpoint inhibitor pneumonitis (CIP) (19%) than previously reported in clinical trials (3%-5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher-grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life-threatening complication of ICI therapy.	Pneumonitis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors.	 J Thorac Oncol	Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that can occur after initiation of anti-programmed death 1/programmed death ligand 1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including NSCLC. However, the incidence of CIP has not been previously examined in a population that included both trial-enrolled and non-trial-enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence, and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti-programmed death 1/programmed death ligand 1 ICIs. Our results demonstrate a higher incidence of CIP (19%) than previously reported in clinical trials (3%-5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher-grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life-threatening complication of ICI therapy.
CANIT0002086	30268458	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	87	N/A	Retrospective analysis	In the discovery cohort, increase (>=10%) of the lymphocyte-to-monocyte ratios (LMR) at 4 weeks after the start of nivolumab monotherapy relative to the pretreatment LMR was positively correlated with an objective response (objective response rate (ORR); 39.4% vs 11.8%, p = 0.0065). When this cutoff value of >=10% was used, increase of the LMR was significantly associated with a prolonged progression-free survival (PFS) (median PFS [mPFS]; 7.3 months vs 2.5 months, p = 0.0049) and overall survival (OS) (median survival time; 15.6 months vs 8.9 months, p = 0.014). In the validation cohort also, increase of the LMR was significantly associated with higher ORR (50.0% vs 20.0%, p = 0.015) and prolonged PFS (mPFS; not reached vs 3.1 months, p = 0.0092). On the other hand, no such correlation was observed among patients treated with docetaxel.	N/A	N/A	N/A	Lymphocyte-to-monocyte ratios (EFO:0004587); 	Lymphocyte-to-monocyte ratios	Cell percentage/counts in blood	 2018 Oct	Change in the lymphocyte-to-monocyte ratio is an early surrogate marker of the efficacy of nivolumab monotherapy in advanced non-small-cell lung cancer.	 Lung Cancer	OBJECTIVES: Nivolumab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, has been shown to yield a durable response and significant prolongation of the survival in some patients with non-small-cell lung cancer (NSCLC). However, identification of patients who are likely to respond to nivolumab remains difficult at present.MATERIALS AND METHODS: We conducted a retrospective analysis of the clinical data of 87 consecutive patients with advanced NSCLC seen in clinical practice who received nivolumab monotherapy at the National Cancer Center Hospital in Japan between January 2016 and July 2016 (discovery cohort). In addition, we also collected the clinical data of 75 patients who were administered nivolumab monotherapy between August 2016 and March 2017 (validation cohort). For this study, we focused on the changes in the lymphocyte-to-monocyte ratio (LMR) observed after nivolumab monotherapy.RESULTS: In the discovery cohort, increase (>=10%) of the LMR at 4 weeks after the start of nivolumab monotherapy relative to the pretreatment LMR was positively correlated with an objective response (objective response rate (ORR); 39.4% vs 11.8%, p = 0.0065). When this cutoff value of >=10% was used, increase of the LMR was significantly associated with a prolonged progression-free survival (PFS) (median PFS [mPFS]; 7.3 months vs 2.5 months, p = 0.0049) and overall survival (OS) (median survival time; 15.6 months vs 8.9 months, p = 0.014). In the validation cohort also, increase of the LMR was significantly associated with higher ORR (50.0% vs 20.0%, p = 0.015) and prolonged PFS (mPFS; not reached vs 3.1 months, p = 0.0092). On the other hand, no such correlation was observed among patients treated with docetaxel.CONCLUSION: A rapid increase of the LMR was significantly associated with the effects of nivolumab monotherapy in our study cohort. Therefore, early change of the LMR may be used as a novel effective surrogate marker to decide on continuation of anti-PD-1 therapy.
CANIT0002087	30268469	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Chemotherapy	Immune checkpoint therapy	Pembrolizumab (DB09037); 	N/A	N/A	A randomized, open-label, phase III trial	Patients treated with pembrolizumab accumulated 1.80 quality-adjusted life-years (QALYs) (95% CrI 1.56-1.89), for moderate dependency between outcomes, compared to 1.06 QALYs (0.94-1.13) with chemotherapy. From a British National Health System (NHS) perspective, the incremental cost-effectiveness ratios (ICERs) was $52k ($43k-$69k) per end-of-life (EoL) adjusted QALY gained, above the 42k USD threshold, while from a US cost perspective, the ICER was $49k ($40k-67k) per EoL adjusted QALY, below the hypothetical 100k USD threshold.	N/A	N/A	N/A	EGFR/ALK (P00533); 	EGFR/ALK mutational status	Mutational status	 2018 Oct	Cost-effectiveness of pembrolizumab as first-line therapy for advanced non-small cell lung cancer.	 Lung Cancer	BACKGROUND: Anti-PD-1 immunotherapy has dramatically shifted therapeutic perspectives for advanced non-small cell lung cancer (NSCLC). We assessed cost-effectiveness of anti-PD-1 antibody pembrolizumab compared to platinum-doublet chemotherapy as first-line therapy for advanced NSCLC.METHODS: We retrieved survival, progression, and safety data comparing first-line pembrolizumab to platinum-doublets for advanced NSCLC patients with PD-L1 expression >=50%, non-mutated EGFR, and non-translocated ALK, from KEYNOTE-024. Published United Kingdom (UK) and United States (US) costs informed incremental cost-effectiveness ratios (ICERs). Our analysis was based on a Bayesian Markov model of disease with full lifetime horizon. We estimated costs in USD and summarized effectiveness as quality-adjusted life-years (QALYs).RESULTS: Patients treated with pembrolizumab accumulated 1.80 QALYs (95% CrI 1.56-1.89), for moderate dependency between outcomes, compared to 1.06 QALYs (0.94-1.13) with chemotherapy. From a British National Health System (NHS) perspective, the ICER was $52k ($43k-$69k) per end-of-life (EoL) adjusted QALY gained, above the 42k USD threshold, while from a US cost perspective, the ICER was $49k ($40k-67k) per EoL adjusted QALY, below the hypothetical 100k USD threshold.CONCLUSIONS: Evidence suggests first-line pembrolizumab for NSCLC may be cost-effective in the US but not the UK, in spite of very similar ICER values in both countries.
CANIT0002088	30275274	Clinical research	Metastatic melanoma, non-small cell lung carcinoma, or head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	403	N/A	N/A	Thirty-one patients (7.7%) developed pancreatic atrophy (PA) compared with 41 matched controls (P = 0.006). Four patients developed exocrine pancreatic insufficiency (EPI), all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029).	Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors	N/A	N/A	N/A	N/A	N/A	 2018 Dec	Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case-Control Study.	 Cancer Immunol Res	Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients (n = 403) treated with anti-PD-1 (n = 356) or anti-CTLA-4 (n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls (P = 0.006). Four patients developed EPI, all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements.
CANIT0002089	30275274	Clinical research	Metastatic melanoma, non-small cell lung carcinoma, or head and neck squamous cell carcinoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	403	N/A	N/A	Thirty-one patients (7.7%) developed pancreatic atrophy (PA) compared with 41 matched controls (P = 0.006). Four patients developed exocrine pancreatic insufficiency (EPI), all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029).	Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors	N/A	N/A	N/A	N/A	N/A	 2018 Dec	Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case-Control Study.	 Cancer Immunol Res	Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients (n = 403) treated with anti-PD-1 (n = 356) or anti-CTLA-4 (n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls (P = 0.006). Four patients developed EPI, all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements.
CANIT0002090	30275274	Clinical research	Metastatic melanoma, non-small cell lung carcinoma, or head and neck squamous cell carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	403	N/A	N/A	Thirty-one patients (7.7%) developed pancreatic atrophy (PA) compared with 41 matched controls (P = 0.006). Four patients developed exocrine pancreatic insufficiency (EPI), all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029).	Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors	N/A	N/A	N/A	N/A	N/A	 2018 Dec	Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case-Control Study.	 Cancer Immunol Res	Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients (n = 403) treated with anti-PD-1 (n = 356) or anti-CTLA-4 (n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls (P = 0.006). Four patients developed EPI, all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements.
CANIT0002091	30280635	Clinical research	Metastatic, squamous non-small-cell lung cancer	Non-small cell squamous lung carcinoma	MONDO:0056806	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus Chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	278	281	Double-blind, phase 3 trial	After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001).	Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Nov 22	Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.	 N Engl J Med	BACKGROUND: Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on >=50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC.METHODS: In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival.RESULTS: After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%).CONCLUSIONS: In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).
CANIT0002092	30285770	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Nivolumab or atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); nivolumab (DB09035); 	19	N/A	Multicenter retrospective study	The median number of treatment cycles was 7 (range, 1-70), and the median duration of treatment was 2.8 months (range, 1 day-32.9 months). The overall response rate with confirmation during treatment was 21.1%. The median progression-free survival (PFS) was 10.2 months (95% confidence interval [CI] = 3.2-17.1 months) and 5.6 months (95% CI = 0-12.2 months) from the initiation and the discontinuation of PD-1/PD-L1 treatment, respectively. The median PFS after discontinuation according to the confirmed response during administration was not reached for partial response (PR) and 4.9 months (95% CI, 3.7-6.0) for stable disease (SD) patients (P = 0.02).	Approximately half of AEs were interstitial pneumonia. Fourteen patients (73.7%) were treated with steroid therapy.	N/A	N/A	N/A	N/A	N/A	 2018 Oct 3	Efficacy of anti-PD-1/PD-L1 antibodies after discontinuation due to adverse events in non-small cell lung cancer patients (HANSHIN 0316).	 BMC Cancer	BACKGROUND: Immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic agents in non-small cell lung cancer (NSCLC). However, the duration for which ICIs should be continued remains a clinical problem.METHODS: We examined the efficacy of anti-PD-1/PD-L1 inhibitors after the discontinuation of antibodies due to adverse events (AEs) in patients with NSCLC. This was a multicenter retrospective study that analyzed NSCLC patients who were treated with PD-1/PD-L1 inhibitors by August 2016.RESULTS: The patients with NSCLC were 18 males and 1 female at a median 67 years of age (range: 49-80 years). Eighteen of 19 patients were treated with nivolumab, one was with atezolizumab. Approximately half of AEs were interstitial pneumonia. Fourteen patients (73.7%) were treated with steroid therapy. The median number of treatment cycles was 7 (range, 1-70), and the median duration of treatment was 2.8 months (range, 1 day-32.9 months). The overall response rate with confirmation during treatment was 21.1%. The median progression-free survival (PFS) was 10.2 months (95% confidence interval [CI] = 3.2-17.1 months) and 5.6 months (95% CI = 0-12.2 months) from the initiation and the discontinuation of PD-1/PD-L1 treatment, respectively. The median PFS after discontinuation according to the confirmed response during administration was not reached for partial response (PR) and 4.9 months (95% CI, 3.7-6.0) for stable disease (SD) patients (P = 0.02).CONCLUSION: The PFS of the PR patients was completely different from that of the SD patients. The cases with PR prior to the onset of AE tended to show a durable response after the discontinuation of PD-1/PD-L1 inhibitors.
CANIT0002093	30286225	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	A black man in his 30s presented for evaluation of papules and plaques on his bilateral lower extremities. Nine months before the current presentation, he was treated with intramuscular penicillin for syphilis. His medical history was also significant for HIV, for which he was receiving highly active antiretroviral therapy, and metastatic programmed cell death ligand 1¨Cpositive squamous non¨Csmall cell lung cancer. Four months before the current presentation, the patient had started pembrolizumab monotherapy as a first-line treatment for his cancer. One month before this presentation, multiple ulcers developed on his buccal mucosa, as well as a nonpainful shallow penile ulcer and pruritic, mildly painful, hyperpigmented papules and plaques on the bilateral soles of his feet in a pattern identical to previous syphilitic eruption. The patient denied fever, chills, and weight loss. Physical examination revealed multiple hyperpigmented papules and plaques with violaceous borders on his bilateral soles and lateral feet (Figure, A) and scattered, violaceous papules and nodules with overlying scale on his bilateral lower extremities. He was referred to the dermatology service, and a punch biopsy specimen was obtained from the right medial sole (Figure, B).	Bilateral Lower Extremity Skin Eruptions	N/A	N/A	N/A	N/A	N/A	 2019 Feb 1	Bilateral Lower Extremity Skin Eruptions in an HIV-Positive Man Receiving Pembrolizumab Monotherapy for Non-Small Cell Lung Cancer.	 JAMA Oncol	Unable to provide
CANIT0002094	30297909	Clinical research	High-risk resectable melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Nivolumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	12	11	A randomized phase 2 study	Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3  treatment-related adverse events (trAEs)), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3  treatment-related adverse events (trAEs)). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers	Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	Clonal and diverse T-cell infiltrate	Tumor-infiltrating immune cell	 2018 Nov	Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.	 Nat Med	Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment1; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma ( NCT02519322 ). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.
CANIT0002095	30297909	Clinical research	High-risk resectable melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Nivolumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	12	11	A randomized phase 2 study	Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3  treatment-related adverse events (trAEs)), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3  treatment-related adverse events (trAEs)). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers	Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Tumor infiltrate (NCIT:C12546); Immune responses (NCIT:C17930); 	Lymphoid infiltrates	Personal feature	 2018 Nov	Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.	 Nat Med	Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses compared with adjuvant treatment1; however, optimal regimens have not been defined. Here we report results from a randomized phase 2 study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma ( NCT02519322 ). RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs) and immune correlates of response were assessed. Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs). Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy. These results describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.
CANIT0002096	30297911	Clinical research	Stage III melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Neoadjuvant ipilimumab plus nivolumab	Adjuvant ipilimumab plus nivolumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	10	10	Randomized controlled trial	Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity.	However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	Tumor-infiltrating T-cell 	Immune response	 2018 Nov	Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.	 Nat Med	Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients1,2. In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy3. Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy4. To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg-1 and nivolumab 1 mg kg-1, as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity.
CANIT0002097	30306202	Clinical research	Advanced breast, ovarian, or gastric cancers	Breast cancer	MONDO:0007254	Breast	WT1 (P19544); 	WT1; 	DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides	N/A	Tumor vaccine	WT1 vaccine (NCIT:C104738); 	10	N/A	Phase I/II study	The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFNG assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood.	All of the adverse events to DC vaccinations were tolerable under an adjuvant setting.	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); T-Lymphocyte (NCIT:C12476); 	Monocytic myeloid-derived suppressor cells counts	Cell percentage/counts in blood	 2019 Jan	Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer.	 Cancer Immunol Immunother	Dendritic cell (DC)-based immunotherapies have been created for a broad expanse of cancers, and DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides have shown great therapeutic efficacy in these diseases. In this paper, we report the results of a phase I/II study of a DC-based vaccination for advanced breast, ovarian, and gastric cancers, and we offer evidence that patients can be effectively vaccinated with autologous DCs pulsed with WT1 peptide. There were ten patients who took part in this clinical study; they were treated biweekly with a WT1 peptide-pulsed DC vaccination, with toxicity and clinical and immunological responses as the principal endpoints. All of the adverse events to DC vaccinations were tolerable under an adjuvant setting. The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFN-¦Ã assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood. These outcomes offered initial clinical evidence that the WT1 peptide-pulsed DC vaccination is a potential treatment for advanced cancer.
CANIT0002098	30306202	Clinical research	Advanced breast, ovarian, or gastric cancers	Gastric cancer	MONDO:0001056	Stomach	WT1 (P19544); 	WT1; 	DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides	N/A	Tumor vaccine	WT1 vaccine (NCIT:C104738); 	10	N/A	Phase I/II study	The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFNG assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood.	All of the adverse events to DC vaccinations were tolerable under an adjuvant setting.	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); T-Lymphocyte (NCIT:C12476); 	Monocytic myeloid-derived suppressor cells counts	Cell percentage/counts in blood	 2019 Jan	Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer.	 Cancer Immunol Immunother	Dendritic cell (DC)-based immunotherapies have been created for a broad expanse of cancers, and DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides have shown great therapeutic efficacy in these diseases. In this paper, we report the results of a phase I/II study of a DC-based vaccination for advanced breast, ovarian, and gastric cancers, and we offer evidence that patients can be effectively vaccinated with autologous DCs pulsed with WT1 peptide. There were ten patients who took part in this clinical study; they were treated biweekly with a WT1 peptide-pulsed DC vaccination, with toxicity and clinical and immunological responses as the principal endpoints. All of the adverse events to DC vaccinations were tolerable under an adjuvant setting. The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFN-¦Ã assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood. These outcomes offered initial clinical evidence that the WT1 peptide-pulsed DC vaccination is a potential treatment for advanced cancer.
CANIT0002099	30306202	Clinical research	Advanced breast, ovarian, or gastric cancers	Ovarian carcinoma	EFO:0001075	Ovary	WT1 (P19544); 	WT1; 	DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides	N/A	Tumor vaccine	WT1 vaccine (NCIT:C104738); 	10	N/A	Phase I/II study	The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFNG assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood.	All of the adverse events to DC vaccinations were tolerable under an adjuvant setting.	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); T-Lymphocyte (NCIT:C12476); 	Monocytic myeloid-derived suppressor cells counts	Cell percentage/counts in blood	 2019 Jan	Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer.	 Cancer Immunol Immunother	Dendritic cell (DC)-based immunotherapies have been created for a broad expanse of cancers, and DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides have shown great therapeutic efficacy in these diseases. In this paper, we report the results of a phase I/II study of a DC-based vaccination for advanced breast, ovarian, and gastric cancers, and we offer evidence that patients can be effectively vaccinated with autologous DCs pulsed with WT1 peptide. There were ten patients who took part in this clinical study; they were treated biweekly with a WT1 peptide-pulsed DC vaccination, with toxicity and clinical and immunological responses as the principal endpoints. All of the adverse events to DC vaccinations were tolerable under an adjuvant setting. The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFN-¦Ã assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood. These outcomes offered initial clinical evidence that the WT1 peptide-pulsed DC vaccination is a potential treatment for advanced cancer.
CANIT0002100	30307035	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	77	N/A	N/A	In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNA2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.	N/A	N/A	N/A	Chitinase 3-like-1	Serum chitinase 3-like-1 before treatment	Gene expression signature in serum	 2019 Mar 1	Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor.	 Int J Cancer	Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNa2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.
CANIT0002101	30307035	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	77	N/A	N/A	In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNA2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.	N/A	N/A	N/A	CXCL2 (P19875); 	Serum CXCL2 levels after treatment 	Gene expression signature in serum	 2019 Mar 1	Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor.	 Int J Cancer	Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNa2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.
CANIT0002102	30307035	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	77	N/A	N/A	In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNA2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.	N/A	N/A	N/A	GM-CSF (P04141); 	Serum GM-CSF levels before treatment	Gene expression signature in serum	 2019 Mar 1	Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor.	 Int J Cancer	Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNa2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.
CANIT0002103	30307035	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	77	N/A	N/A	In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNA2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.	N/A	N/A	N/A	IFNA (P48551); 	Serum IFNa2 levels after treatment 	Gene expression signature in serum	 2019 Mar 1	Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor.	 Int J Cancer	Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNa2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.
CANIT0002104	30307035	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	77	N/A	N/A	In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNA2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.	N/A	N/A	N/A	MMP2 (P08253); 	Serum MMP2 levels after treatment 	Gene expression signature in serum	 2019 Mar 1	Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor.	 Int J Cancer	Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNa2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.
CANIT0002105	30307035	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	77	N/A	N/A	In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNA2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.	N/A	N/A	N/A	VEGF (P15692); 	Serum VEGF expression levels	Gene expression signature in serum	 2019 Mar 1	Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor.	 Int J Cancer	Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNa2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.
CANIT0002106	30309915	Clinical research	Tumor	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	>300	N/A	Retrospective analysis	Tumor mutational burden and T cell-inflamed gene expression profile (GEP) were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology.	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	T-cell -inflamed gene expression profile	Gene expression signature on/in immune cell	 2018 Oct 12	Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.	 Science	Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
CANIT0002107	30309915	Clinical research	Tumor	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	>300	N/A	Retrospective analysis	Tumor mutational burden and T cell-inflamed gene expression profile (GEP) were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology.	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2018 Oct 12	Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.	 Science	Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
CANIT0002108	30311027	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	113	N/A	N/A	A remarkable association between sCTLA-4 levels and best overall response (BOR) was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during ipilimumab (IPI) treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any immune-related adverse events (irAEs) (p value = 0.029), in particular immune-related adverse events of the digestive tract (p value = 0.041).	N/A	N/A	N/A	CTLA-4 (P16410); 	Serum CTLA-4 levels	Gene expression signature in serum	 2019 Jan	Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study.	 Cancer Immunol Immunother	CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.
CANIT0002109	30311424	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	Nivolumab	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	104	N/A	Retrospective analysis	Respective 1- and 2-year OS rates were 48.8% and 29.1%, while 1- and 2-year progression-free survival (PFS) rates were 20.9% and 10.1%. PFS was significantly better for patients with least one grade 3/4 immune-related AE (IRAE) (P = 0.038) than those without and a trend toward better OS (P = 0.06). Delivering radiation before or during/after nivolumab administration was not associated with better OS or PFS.	Any-grade adverse events (AEs) were observed in 62 (59.6%), with 10 (9.6%) experiencing at least one grade 3/4 toxicity and 9 (8.7%) at least one grade 3/4 immune-related AE (IRAE).	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Least one grade 3/4 immune-related AE	Adverse events	 2018 Nov	Safety of combined PD-1 pathway inhibition and radiation therapy for non-small-cell lung cancer: A multicentric retrospective study from the GFPC.	 Cancer Med	INTRODUCTION: Randomized prospective studies on patients with metastatic non-small-cell lung cancers (NSCLCs) showed that anti-programmed death-1 (PD-1) agents notably improved 2-year overall survival (OS) rates, compared to docetaxel. NSCLC patients now receive nivolumab and irradiation, concurrently or not. However, little is known about the safety of this combination, even though the preclinical model suggested a possible synergic effect. We analyzed NSCLC patients treated with radiotherapy and nivolumab according to former's timing.METHODS: We retrospectively reviewed records of a large series of metastatic NSCLC patients from three French centers, irradiated during the 6 months preceding, concomitantly, or 3 months after nivolumab administration to assess nivolumab tolerance and outcomes.RESULTS: Among 104 patients included (37 women; 67 men; median age 60.3 years; 67% with performance status <2; 93.2% were current or past smokers) and their 144 intra- or extracranial irradiation courses, any-grade adverse events (AEs) were observed in 62 (59.6%), with 10 (9.6%) experiencing at least one grade 3/4 toxicity and 9 (8.7%) at least one grade 3/4 immune-related AE (IRAE). Respective 1- and 2-year OS rates were 48.8% and 29.1%, while 1- and 2-year progression-free survival (PFS) rates were 20.9% and 10.1%. PFS was significantly better for patients with IRAE(s) (P = 0.038) than those without and a trend toward better OS (P = 0.06). Delivering radiation before or during/after nivolumab administration was not associated with better OS or PFS.CONCLUSION: Radiotherapy delivered during the 6 months before, during, or the three months following nivolumab for NSCLCs was not associated with an increased risk of severe or unexpected toxicities.
CANIT0002110	30318169	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	29	N/A	N/A	Among the 29 recruited patients, the non-responders displayed higher serum concentrations of HGF than the responders (P = 0.00124). Patients with low serum concentrations of HGF showed longer overall survival (N = 28, P = 0.039; HR 0.3125, 95% CI 0.1036-0.9427) and progression-free survival (N = 24, P = 0.0068; HR 0.2087, 95% CI 0.06525-0.6676) than those with high concentrations of HGF. We observed a significant correlation between the serum concentration of HGF and immunohistochemical-positive staining (P = 0.000663). In a flow cytometry analysis of PBMCs from healthy donors, HGF was found to downregulate perforin secretion. Furthermore, the addition of capmatinib, a specific inhibitor of c-MET, increased the expression of perforin in CD8+ T cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	HGF (P08581); 	Serum HGF levels	Gene expression signature in serum	 2019 Jan	Serum concentrations of HGF are correlated with response to anti-PD-1 antibody therapy in patients with metastatic melanoma.	 J Dermatol Sci	BACKGROUND: Anti-programmed cell death protein (PD)-1 antibody treatment is associated with a notable improvement in only 30%-40% of patients. Thus, a predictive and easily measured marker of the clinical benefit of anti-PD-1 antibody treatment is necessary; therefore, in this study, we focused on the serum concentration of hepatocyte growth factor (HGF).OBJECTIVES: To evaluate whether the serum concentration of HGF can be used as a biomarker for the clinical response to anti-PD-1 antibody therapy.METHODS: This study included 29 metastatic melanoma patients receiving nivolumab or pembrolizumab. Nine patients responded to anti-PD-1 antibody treatment, whereas the other 20 patients did not. The serum concentrations of HGF were analyzed by using ELISA. In 28 patients, immunohistochemical analysis of the HGF protein in patients' cancer tissues was also performed. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with an anti-CD3 antibody in the presence or absence of HGF and c-MET inhibitor. The expression of perforin in CD8+ T cells were evaluated by using flow cytometry.RESULTS: Among the 29 recruited patients, the non-responders displayed higher serum concentrations of HGF than the responders (P =  0.00124). Patients with low serum concentrations of HGF showed longer overall survival (N = 28, P =  0.039; HR 0.3125, 95% CI 0.1036-0.9427) and progression-free survival (N = 24, P =  0.0068; HR 0.2087, 95% CI 0.06525-0.6676) than those with high concentrations of HGF. We observed a significant correlation between the serum concentration of HGF and immunohistochemical-positive staining (P =  0.000663). In a flow cytometry analysis of PBMCs from healthy donors, HGF was found to downregulate perforin secretion. Furthermore, the addition of capmatinib, a specific inhibitor of c-MET, increased the expression of perforin in CD8+ T cells.CONCLUSIONS: HGF concentration represents a valid biomarker that can be further developed for the evaluation of anti-PD-1 therapy. Our results suggested that c-MET inhibition promotes perforin expression in CD8+ T cells. Therefore, c-MET inhibitors can activate the immune system and may play an important role in combined immunotherapy.
CANIT0002111	30318515	Clinical research	Unresectable pancreatic cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	TGFB1 (P01137); TGFR1 (P36897); 	TGFB1; TGFR1	Galunisertib plus gemcitabine	Gemcitabine	Immune checkpoint therapy plus Chemotherapy	Galunisertib (DB11911); gemcitabine (DB00441); 	104	52	Two-part, multinational study	Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59-1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-A (CCL3) and interferonG-induced protein 10 were associated with galunisertib benefit.	N/A	N/A	N/A	CCL3 (P10147); 	Serum CCL3 expression levels	Gene expression signature in serum	 2018 Nov	Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer.	 Br J Cancer	BACKGROUND: Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined.METHODS: This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib-gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers.RESULTS: Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59-1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit.CONCLUSIONS: Galunisertib-gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.
CANIT0002112	30318515	Clinical research	Unresectable pancreatic cancer	Pancreatic carcinoma	EFO:0002618	Pancreas	TGFB1 (P01137); TGFR1 (P36897); 	TGFB1; TGFR1	Galunisertib plus gemcitabine	Gemcitabine	Immune checkpoint therapy plus Chemotherapy	Galunisertib (DB11911); gemcitabine (DB00441); 	104	52	Two-part, multinational study	Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59-1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-A and interferonG-induced protein 10 (IP10) were associated with galunisertib benefit.	N/A	N/A	N/A	IP10 (P02778); 	Baseline levels of IP10	Gene expression signature in serum	 2018 Nov	Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer.	 Br J Cancer	BACKGROUND: Galunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined.METHODS: This was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib-gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers.RESULTS: Dose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59-1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit.CONCLUSIONS: Galunisertib-gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.
CANIT0002113	30337059	Clinical research	Prostate cancer	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	13	N/A	Retrospective analysis	Prostate cancers with mismatch repair gene mutations have aggressive clinical and pathological features; however, these are very sensitive to standard and novel hormonal therapies, and also demonstrate anecdotal sensitivity to PD-1 inhibitors such as pembrolizumab.	N/A	N/A	N/A	Mismatch-repair status (NCIT:C20639); 	DNA mismatch repair-deficient	Mutational status	 2019 Mar	Clinical Features and Therapeutic Outcomes in Men with Advanced Prostate Cancer and DNA Mismatch Repair Gene Mutations.	 Eur Urol	Mismatch repair (MMR) gene mutations are rare in prostate cancer, and their histological and clinical characteristics are largely unknown. We conducted a retrospective study to explore disease characteristics and treatment outcomes of men with metastatic prostate cancer harboring germline and/or somatic MMR mutations detected using clinical-grade genomic assays. Thirteen patients with a deleterious MMR gene mutation were identified. Median age was 64 yr, 75% had grade group 5 (Gleason sum 9 or 10), 23% had intraductal histology, 46% had metastatic disease at initial diagnosis, and 31% had visceral metastases. Most patients (46%) had MSH6 mutations, 73% demonstrated microsatellite instability, and median tumor mutational load was 18/Mb (range, 3-165 mutations/Mb). Surprisingly, responses to standard hormonal therapies were very durable (median progression-free survival [PFS] of 67 mo to initial androgen deprivation and median PFS of 26 mo to abiraterone/enzalutamide). Two of four men receiving PD-1 inhibitors achieved a >=50% prostate-specific antigen response at 12 wk, with a median PFS duration in these four men of 9 mo. Despite aggressive clinical and pathological features, patients with MMR-mutated advanced prostate cancer appear to have particular sensitivity to hormonal therapies, as well as anecdotal responses to PD-1 inhibitors. Certain histological features (grade group 5, intraductal carcinoma) should prompt evaluation for MMR deficiency. These data are only hypothesis generating. PATIENT SUMMARY: Prostate cancers with mismatch repair gene mutations have aggressive clinical and pathological features; however, these are very sensitive to standard and novel hormonal therapies, and also demonstrate anecdotal sensitivity to PD-1 inhibitors such as pembrolizumab.
CANIT0002114	30339560	Case report	Metastatic hypopharyngeal cancer	Hypopharyngeal cancer	EFO:0007321	Throat	PD-1 (Q15116); 	PD-1; 	Nivolumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); 	1	N/A	Case	We present the case of a metastatic hypopharyngeal cancer patient who after progressing clinically and radiologically to PD-L1-based IO and then to second-line cetuximab-based chemotherapy, achieved a partial response to third-line nivolumab. Our case shows that PD(L)1 rechallenge after interval chemotherapy may be worth considering in SCCHN.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Response to immunotherapy rechallenge after interval chemotherapy in a patient with head and neck cancer.	 Anticancer Drugs	Patients with metastatic squamous cell cancer of the head and neck (SCCHN) have a poor prognosis, with most patients surviving less than a year. Immunotherapy (IO) is changing the natural history of the disease and programmed death-ligand 1 (PD-L1) inhibitors are showing notable improvements in survival with a more favourable toxicity profile than chemotherapy. To our knowledge, there are no data regarding how checkpoint blockade inhibitors may behave at rechallenge in SCCHN. We present the case of a metastatic hypopharyngeal cancer patient who after progressing clinically and radiologically to PD-L1-based IO and then to second-line cetuximab-based chemotherapy, achieved a partial response to third-line nivolumab. Our case shows that PD(L)1 rechallenge after interval chemotherapy may be worth considering in SCCHN. Studies should try to address which is the optimal treatment sequence in the era of IO in SCCHN.
CANIT0002115	30347977	Basic research	Cancer	Cancer	EFO:0000311	Other	IDO1 (P14902); 	IDO1; 	Linrodostat	N/A	Immune checkpoint therapy	Linrodostat (DB14986); 	Cell lines	N/A	Basic research	Here, we report three crystal structures of hIDO1-BMS complexes that define the complete binding trajectory of the inhibitor. BMS first binds in a solvent exposed surface cleft near the active site in an extended conformation. The initial binding partially unfolds the active site, which triggers heme release, thereby exposing a new binding pocket. The inhibitor then undergoes a large scale movement to this new binding pocket, where it binds by adopting a high energy kinked conformation. Finally, the inhibitor relaxes to a bent conformation, via an additional large scale rearrangement, culminating in the energy minimum state.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2018 Nov 7	Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3-Dioxygenase 1.	 J Am Chem Soc	Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an important heme-containing enzyme that is a key drug target for cancer immunotherapy. Several hIDO1 inhibitors have entered clinical trials, among which BMS-986205 (BMS) stands out as the only suicide inhibitor. Despite its best-in-class activity, the action mechanism of BMS remains elusive. Here, we report three crystal structures of hIDO1-BMS complexes that define the complete binding trajectory of the inhibitor. BMS first binds in a solvent exposed surface cleft near the active site in an extended conformation. The initial binding partially unfolds the active site, which triggers heme release, thereby exposing a new binding pocket. The inhibitor then undergoes a large scale movement to this new binding pocket, where it binds by adopting a high energy kinked conformation. Finally, the inhibitor relaxes to a bent conformation, via an additional large scale rearrangement, culminating in the energy minimum state. The structural data offer a molecular explanation for the remarkable efficacy and suicide inhibition activity of the inhibitor. They also suggest a novel strategy that can be applied for drug development targeting hIDO1 and related enzymes.
CANIT0002116	30348216	Clinical research	Advanced or metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus pazopanib	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); pazopanib (DB06589)	20	N/A	Open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study	Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months. The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.	Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%).	N/A	N/A	N/A	N/A	N/A	 2018 Oct 22	Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study.	 J Immunother Cancer	BACKGROUND: Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented.METHODS: Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint.RESULTS: Arm N + S enrolled 33 patients, 19 of whom were treatment-na ve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had >=1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months.CONCLUSIONS: The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01472081 . Registered 16 November 2011.
CANIT0002117	30348216	Clinical research	Advanced or metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus sunitinib	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); 	33	N/A	Open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study	Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.	Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%).	N/A	N/A	N/A	N/A	N/A	 2018 Oct 22	Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study.	 J Immunother Cancer	BACKGROUND: Combination treatment with immune checkpoint inhibitors and antiangiogenic drugs has shown encouraging preliminary antitumor activity across various tumor types including advanced or metastatic renal cell carcinoma (aRCC). The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of nivolumab in combination with antiangiogenic tyrosine kinase inhibitors or ipilimumab. Long-term outcomes from this study for the combination of nivolumab plus sunitinib or pazopanib in aRCC are presented.METHODS: Patients with aRCC received nivolumab plus either sunitinib (50 mg/day, 4 weeks on/2 weeks off; N + S) or pazopanib (800 mg/day; N + P) until progression/unacceptable toxicity. The nivolumab starting dose was 2 mg/kg every 3 weeks, with planned escalation to 5 mg/kg every 3 weeks. Primary endpoints were safety and tolerability; antitumor activity was a secondary endpoint.RESULTS: Arm N + S enrolled 33 patients, 19 of whom were treatment-na ve; this arm advanced to the expansion phase. Median follow-up was 50.0 months. Patients experienced high frequencies of adverse events (AEs) including treatment-related AEs (100%), grade 3/4 treatment-related AEs (82%), and treatment-related AEs leading to discontinuation (39%). Investigator-assessed objective response rate (ORR) was 55% (18/33) and median progression-free survival (PFS) was 12.7 months. Median overall survival (OS) was not reached. Arm N + P enrolled 20 patients, all had >=1 prior systemic therapy; this arm was closed due to dose-limiting toxicities and did not proceed to expansion. Median follow-up was 27.1 months. Patients treated with N + P experienced high frequencies of AEs including treatment-related AEs (100%), grade 3/4 treatment-related AEs (70%), and treatment-related AEs leading to discontinuation (25%). Investigator-assessed ORR was 45% (9/20) and median PFS was 7.2 months. Median OS was 27.9 months.CONCLUSIONS: The addition of standard doses of sunitinib or pazopanib to nivolumab resulted in a high incidence of high-grade toxicities limiting future development of either combination regimen. While there was no adverse impact on response and the OS outcome was notable, the findings suggest that the success of combination regimens based on immune checkpoint inhibitors and antiangiogenic drugs may be dependent on careful selection of the antiangiogenic component and dose.TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01472081 . Registered 16 November 2011.
CANIT0002118	30361162	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	115	N/A	N/A	The median OS was 11.4 months {CI95%: 11.1-11.7}, with a 1-year survival of 44%, in line with clinical trial data. Median PFS was 5.4 months {CI95%: 2.8-7.9}. Treatment was discontinued in 82 cases, most frequently due to disease progression.	There were 38 cases of Adverse Drug Reaction (ADRs) documented in the patient medical chart, 21 of which led to treatment discontinuation.	N/A	N/A	N/A	N/A	N/A	 2019 Jan-Feb	The cancer registry as an ally in monitoring treatment effectiveness.	 Pulmonology	OBJECTIVE: To evaluate if the cancer registry database can be used to monitor treatment effectiveness using nivolumab treatment of non-small cell lung cancer (NSCLC) as an example.METHOD: An observational inception cohort was used, where all registered cases of NSCLC with authorisation to initiate treatment with nivolumab were monitored retrospectively to evaluate disease characteristics and response to prior treatments. Current exposure to nivolumab was prospectively characterised and treatment outcomes classified based on the clinical information registered in the patient medical record. The main outcome measure used to assess treatment effectiveness was overall survival (OS). Secondary outcomes considered were progression free survival (PFS) as a measure of effectiveness and occurrence of Adverse Drug Reaction (ADRs) as a measure of safety. Data were analysed using SPSS, version 24.RESULTS: A total of 115 patients received treatment with nivolumab for NSCLC, between November 1st 2015 and July 31st 2016, and were registered in the database. The majority were non-squamous type (n=107). The median OS was 11.4 months {CI95%: 11.1-11.7}, with a 1-year survival of 44%, in line with clinical trial data. Median PFS was 5.4 months {CI95%: 2.8-7.9}. Treatment was discontinued in 82 cases, most frequently due to disease progression. There were 38 cases of ADRs documented in the patient medical chart, 21 of which led to treatment discontinuation.CONCLUSION: The analysed data suggest that the cancer registry is a powerful tool to monitor treatment effectiveness, although considerable investment is needed to improve the medical culture of recording treatment exposure, particularly documentation of ADRs.
CANIT0002119	30361170	Clinical research	Previously untreated, unresectable, stage III or stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	314	315	A multicentre, randomised, phase 3 trial	At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p<0.0001) and for nivolumab versus ipilimumab was 0.65 (0.53-0.79; p<0.0001). Median progression-free survival was 11.5 months (95% CI 8.7-19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1-10.2) in the nivolumab group, and 2.9 months (2.8-3.2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0.42 (95% CI 0.35-0.51; p<0.0001) and for nivolumab versus ipilimumab was 0.53 (0.44-0.64; p<0.0001). In an analysis of overall survival by BRAF mutation status, 4-year overall survival for patients with BRAF-mutated tumours was 62% (95% CI 52 71) in the combination group, 50% (39 59) in the nivolumab group, and 33% (24 42) in the ipilimumab group, whereas these results for patients with wild-type BRAF were 49% (42 55), 45% (38 52), and 28% (22 35), respectively.	Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2018 Nov	Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.	 Lancet Oncol	BACKGROUND: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.METHODS: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.FINDINGS: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46.9 months (IQR 10.9-51.8) in the nivolumab plus ipilimumab group, 36.0 months (10.5-51.4) in the nivolumab group, and 18.6 months (7.6-49.5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p<0.0001) and for nivolumab versus ipilimumab was 0.65 (0.53-0.79; p<0.0001). Median progression-free survival was 11.5 months (95% CI 8.7-19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1-10.2) in the nivolumab group, and 2.9 months (2.8-3.2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0.42 (95% CI 0.35-0.51; p<0.0001) and for nivolumab versus ipilimumab was 0.53 (0.44-0.64; p<0.0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.INTERPRETATION: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.FUNDING: Bristol-Myers Squibb.
CANIT0002120	30361170	Clinical research	Previously untreated, unresectable, stage III or stage IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	314	315	A multicentre, randomised, phase 3 trial	At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p<0.0001) and for nivolumab versus ipilimumab was 0.65 (0.53-0.79; p<0.0001). Median progression-free survival was 11.5 months (95% CI 8.7-19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1-10.2) in the nivolumab group, and 2.9 months (2.8-3.2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0.42 (95% CI 0.35-0.51; p<0.0001) and for nivolumab versus ipilimumab was 0.53 (0.44-0.64; p<0.0001). In another analysis, using a 5% cutoff for tumour PD-L1 expression (the percentage used as a study stratification factor), in patients with less than 5% PD-L1 expression, 4-year overall survival was 52% (95% CI 45¨C58) in the combination group, 45% (38¨C52) in the nivolumab group, and 28% (22¨C35) in the ipilimumab group, whereas in patients with 5% or more PD-L1 expression these values were 61% (48¨C71), 54% (42¨C64), and 36% (25¨C47), respectively. For all PD-L1 expression levels evaluated, both progression-free survival and overall survival in the combination group were significantly improved versus ipilimumab monotherapy .	Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Nov	Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.	 Lancet Oncol	BACKGROUND: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.METHODS: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.FINDINGS: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46.9 months (IQR 10.9-51.8) in the nivolumab plus ipilimumab group, 36.0 months (10.5-51.4) in the nivolumab group, and 18.6 months (7.6-49.5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p<0.0001) and for nivolumab versus ipilimumab was 0.65 (0.53-0.79; p<0.0001). Median progression-free survival was 11.5 months (95% CI 8.7-19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1-10.2) in the nivolumab group, and 2.9 months (2.8-3.2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0.42 (95% CI 0.35-0.51; p<0.0001) and for nivolumab versus ipilimumab was 0.53 (0.44-0.64; p<0.0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.INTERPRETATION: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.FUNDING: Bristol-Myers Squibb.
CANIT0002121	30361170	Clinical research	Previously untreated, unresectable, stage III or stage IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	316	315	A multicentre, randomised, phase 3 trial	At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p<0.0001) and for nivolumab versus ipilimumab was 0.65 (0.53-0.79; p<0.0001). Median progression-free survival was 11.5 months (95% CI 8.7-19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1-10.2) in the nivolumab group, and 2.9 months (2.8-3.2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0.42 (95% CI 0.35-0.51; p<0.0001) and for nivolumab versus ipilimumab was 0.53 (0.44-0.64; p<0.0001). In an analysis of overall survival by BRAF mutation status, 4-year overall survival for patients with BRAF-mutated tumours was 62% (95% CI 52 71) in the combination group, 50% (39 59) in the nivolumab group, and 33% (24 42) in the ipilimumab group, whereas these results for patients with wild-type BRAF were 49% (42 55), 45% (38 52), and 28% (22 35), respectively.	Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2018 Nov	Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.	 Lancet Oncol	BACKGROUND: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.METHODS: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.FINDINGS: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46.9 months (IQR 10.9-51.8) in the nivolumab plus ipilimumab group, 36.0 months (10.5-51.4) in the nivolumab group, and 18.6 months (7.6-49.5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p<0.0001) and for nivolumab versus ipilimumab was 0.65 (0.53-0.79; p<0.0001). Median progression-free survival was 11.5 months (95% CI 8.7-19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1-10.2) in the nivolumab group, and 2.9 months (2.8-3.2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0.42 (95% CI 0.35-0.51; p<0.0001) and for nivolumab versus ipilimumab was 0.53 (0.44-0.64; p<0.0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.INTERPRETATION: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.FUNDING: Bristol-Myers Squibb.
CANIT0002122	30361170	Clinical research	Previously untreated, unresectable, stage III or stage IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	316	315	A multicentre, randomised, phase 3 trial	At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p<0.0001) and for nivolumab versus ipilimumab was 0.65 (0.53-0.79; p<0.0001). Median progression-free survival was 11.5 months (95% CI 8.7-19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1-10.2) in the nivolumab group, and 2.9 months (2.8-3.2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0.42 (95% CI 0.35-0.51; p<0.0001) and for nivolumab versus ipilimumab was 0.53 (0.44-0.64; p<0.0001). In another analysis, using a 5% cutoff for tumour PD-L1 expression (the percentage used as a study stratification factor), in patients with less than 5% PD-L1 expression, 4-year overall survival was 52% (95% CI 45¨C58) in the combination group, 45% (38¨C52) in the nivolumab group, and 28% (22¨C35) in the ipilimumab group, whereas in patients with 5% or more PD-L1 expression these values were 61% (48¨C71), 54% (42¨C64), and 36% (25¨C47), respectively. For all PD-L1 expression levels evaluated, both progression-free survival and overall survival in the combination group were significantly improved versus ipilimumab monotherapy .	Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Nov	Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.	 Lancet Oncol	BACKGROUND: Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.METHODS: In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.FINDINGS: Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46.9 months (IQR 10.9-51.8) in the nivolumab plus ipilimumab group, 36.0 months (10.5-51.4) in the nivolumab group, and 18.6 months (7.6-49.5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p<0.0001) and for nivolumab versus ipilimumab was 0.65 (0.53-0.79; p<0.0001). Median progression-free survival was 11.5 months (95% CI 8.7-19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1-10.2) in the nivolumab group, and 2.9 months (2.8-3.2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0.42 (95% CI 0.35-0.51; p<0.0001) and for nivolumab versus ipilimumab was 0.53 (0.44-0.64; p<0.0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.INTERPRETATION: The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.FUNDING: Bristol-Myers Squibb.
CANIT0002123	30368069	Clinical research	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus influenza vaccination	Nivolumab	Immune checkpoint therapy plus Tumor vaccine 	Nivolumab (DB09035); 	42	85	N/A	Influenza vaccination in patients with lung cancer receiving anti-PD-1 immunotherapy does not induce immune-related adverse events in our cohort. With this result, influenza vaccination should not be deterred from this group of patients.	In vaccinated and non-vaccinated patients, the incidence of irAEs was 26% and 22%, respectively, rate ratio 1.20 (95% confidence interval [CI] 0.51-2.65). The incidence of serious irAEs was 7% and 4%, respectively, rate ratio 2.07 (95% CI 0.28-15.43). Influenza vaccination while receiving nivolumab did not result in significant differences in the rates of discontinuation, death, clinical deterioration or tumour response between the groups.	N/A	N/A	N/A	N/A	N/A	 2018 Nov	Influenza vaccination in patients with lung cancer receiving anti-programmed death receptor 1 immunotherapy does not induce immune-related adverse events.	 Eur J Cancer	BACKGROUND: Influenza vaccination is recommended in patients with cancer to reduce influenza-related complications. Recently, more immune-related adverse events (irAEs) were demonstrated in patients with lung cancer who were vaccinated with the trivalent seasonal influenza vaccine during anti-programmed death receptor 1 (PD-1) immunotherapy. Confirmation of these findings is essential before recommendations on influenza vaccination may be revoked.METHODS: In this cohort study in patients with lung cancer receiving nivolumab 3 mg/kg every 2 weeks during two influenza seasons (2015/16-2016/17), irAEs have been monitored. Incidence, timing and severity of irAEs were compared between vaccinated patients and non-vaccinated patients.FINDINGS: In a compassionate use programme, 127 patients with lung cancer had been treated with at least one dose of nivolumab during two national influenza vaccination campaigns from September until December of 2015 and 2016. Forty-two patients had received the influenza vaccine, and 85 patients were not vaccinated. Median follow-up period was 118 days (interquartile range 106-119). Mean age was 64 years (range 46-83). In vaccinated and non-vaccinated patients, the incidence of irAEs was 26% and 22%, respectively, rate ratio 1.20 (95% confidence interval [CI] 0.51-2.65). The incidence of serious irAEs was 7% and 4%, respectively, rate ratio 2.07 (95% CI 0.28-15.43). Influenza vaccination while receiving nivolumab did not result in significant differences in the rates of discontinuation, death, clinical deterioration or tumour response between the groups.INTERPRETATION: Influenza vaccination in patients with lung cancer receiving anti-PD-1 immunotherapy does not induce irAEs in our cohort. With this result, influenza vaccination should not be deterred from this group of patients.
CANIT0002124	30377342	Clinical research	Advanced NSCLC harbouring KRAS mutations	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	530	N/A	N/A	Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01).	The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively.	N/A	N/A	KRAS (P01116); 	KRAS mutational status	Mutational status	 2019 Jan	Efficacy of nivolumab in pre-treated non-small-cell lung cancer patients harbouring KRAS mutations.	 Br J Cancer	BACKGROUND: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations.METHODS: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events.RESULTS: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively.CONCLUSIONS: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.
CANIT0002125	30382051	Basic research	Rectal cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	We investigated whether hyperthermia enhanced the efficacy of immune check point inhibitor therapy. The LLC tumor inoculated in mouse was heated and immunostained, which showed increase in PD-L1 staining post-heating. PD-L1 and HLA class I staining increased after heating samples derived from a case of analinvasion of rectalcancer associated with Lynch syndrome.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2018 Oct	[Enhancing Antitumor Effects Using Hyperthermia(Including Immune Checkpoint Inhibitor)].	 Gan To Kagaku Ryoho	Hyperthermia enhances the efficacies of radiotherapy, chemotherapy, immunotherapy, and molecular targeted therapy. In this study, we investigated whether hyperthermia enhanced the efficacy of immune check point inhibitor therapy. The LLC tumor inoculated in mouse was heated and immunostained, which showed increase in PD-L1 staining post-heating. PD-L1 and HLA class I staining increased after heating samples derived from a case of analinvasion of rectalcancer associated with Lynch syndrome.
CANIT0002126	30383184	Clinical research	Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus Tremelimumab followed by Durvalumab	Durvalumab	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	133	65	Phase 2, randomized, open-label study	Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively.In patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression, all 3 regimens (durvalumab,tremelimumab,and durvalumab plus tremelimumab) exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way.	Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial.	 JAMA Oncol	IMPORTANCE: Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression.OBJECTIVE: To assess safety and objective response rate of durvalumab combined with tremelimumab.DESIGN, SETTING, AND PARTICIPANTS: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific.INTERVENTIONS: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy.MAIN OUTCOMES AND MEASURES: Safety and tolerability and efficacy measured by objective response rate.RESULTS: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively.CONCLUSIONS AND RELEVANCE: In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02319044.
CANIT0002127	30383184	Clinical research	Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Durvalumab plus Tremelimumab followed by Durvalumab	Tremelimumab	Immune checkpoint therapy	Durvalumab (DB11714); tremelimumab (DB11771); 	133	65	Phase 2, randomized, open-label study	Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively.In patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression, all 3 regimens (durvalumab,tremelimumab,and durvalumab plus tremelimumab) exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 4 study is under way.	Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial.	 JAMA Oncol	IMPORTANCE: Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression.OBJECTIVE: To assess safety and objective response rate of durvalumab combined with tremelimumab.DESIGN, SETTING, AND PARTICIPANTS: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific.INTERVENTIONS: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy.MAIN OUTCOMES AND MEASURES: Safety and tolerability and efficacy measured by objective response rate.RESULTS: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively.CONCLUSIONS AND RELEVANCE: In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02319044.
CANIT0002128	30395075	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	13	N/A	N/A	Thirteen patients developed high-grade combination Immune checkpoint inhibitor (IO)-induced colitis; 11 were managed with the combination of high-dose corticosteroid and MMF. Median patient age was 59 (range: 28-73) years. Four (36%) developed flare of colitis; flares occurred at a median of 11 (interquartile range: 4.5-16.75) days. All colitis flares responded fully to infliximab (5 mg/kg). The remaining seven patients did not develop colitis flare during corticosteroid wean. All patients were successfully weaned from corticosteroids and none had a resurgence of colitis at 8 weeks following discontinuation of MMF. Concomitant enteric-coated MMF alongside high-dose corticosteroids may hasten the improvement of high-grade colitis to normal bowel habit and reduce the incidence of colitis flare.	Immune checkpoint inhibitor (IO) induced colitis	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Mycophenolate mofetil alongside high-dose corticosteroids: optimizing the management of combination immune checkpoint inhibitor-induced colitis.	 Melanoma Res	Immune checkpoint inhibitor (IO) induced colitis is primarily managed with corticosteroids. Most patients have a rapid resolution of symptoms and do not require additional immunosuppressants. Many patients, however, require prolonged corticosteroid courses to maintain control of toxicity. Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid; which in turn directly inhibits activated T and B lymphocytes. MMF, in addition to corticosteroids, may enable reduction of corticosteroids without precipitating resurgence of colitis. Metastatic melanoma patients between 1 January 2017 and 31 December 2017 with combination IO-induced colitis were managed with a novel treatment algorithm: upfront oral enteric-coated MMF alongside high-dose corticosteroids. Outcome measures included incidence of colitis flare, time to grade 1 colitis, time to patient-reported normal bowel habit and overall cumulative corticosteroid exposure. Thirteen patients developed high-grade combination IO-induced colitis; 11 were managed with the combination of high-dose corticosteroid and MMF. Median patient age was 59 (range: 28-73) years. Four (36%) developed flare of colitis; flares occurred at a median of 11 (interquartile range: 4.5-16.75) days. All colitis flares responded fully to infliximab (5 mg/kg). The remaining seven patients did not develop colitis flare during corticosteroid wean. All patients were successfully weaned from corticosteroids and none had a resurgence of colitis at 8 weeks following discontinuation of MMF. Concomitant enteric-coated MMF alongside high-dose corticosteroids may hasten the improvement of high-grade colitis to normal bowel habit and reduce the incidence of colitis flare.
CANIT0002129	30399387	Clinical research	Cancers	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	98	N/A	Retrospective analysis	In total, 98 patients (51 men, 47 women) treated with checkpoint inhibitors developed 103 inflammatory eruptions, with a range of mean latency of 0.2-17.7 months. A minority of patients (25/103; 24.3%) required immunotherapy interruption; most of these cases involved immunobullous (7/8; 87.5%), lichenoid (8/26; 30.8%), maculopapular (6/18; 33.3%), and Stevens-Johnson syndrome-like (2/2, 100%) reactions. Only 3 of 16 (18.8%) patients who had their immunotherapy interrupted had a grade 2 or 3 flare on rechallenge. Most reactions (93/103; 90.3%) responded to dermatologic therapy or immunotherapy interruption.	Distinct inflammatory eruptions associated with checkpoint inhibitors	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Inflammatory eruptions associated with immune checkpoint inhibitor therapy: A single-institution retrospective analysis with stratification of reactions by toxicity and implications for management.	 J Am Acad Dermatol	BACKGROUND: There is increasing recognition of distinct inflammatory eruptions associated with checkpoint inhibitors. A better understanding of their severity, therapeutic response, and impact on cancer treatment is needed.OBJECTIVE: To analyze the different rashes associated with immunotherapy referred to our institution's oncodermatology clinic and inpatient consultative service and to evaluate their therapeutic response and impact on immunotherapy.METHODS: We retrospectively reviewed the medical records of patients referred to the oncodermatology clinic or inpatient dermatology service during 2016-2018 at Yale-New Haven Hospital for eruptions that developed during immunotherapy.RESULTS: In total, 98 patients (51 men, 47 women) treated with checkpoint inhibitors developed 103 inflammatory eruptions, with a range of mean latency of 0.2-17.7 months. A minority of patients (25/103; 24.3%) required immunotherapy interruption; most of these cases involved immunobullous (7/8; 87.5%), lichenoid (8/26; 30.8%), maculopapular (6/18; 33.3%), and Stevens-Johnson syndrome-like (2/2, 100%) reactions. Only 3 of 16 (18.8%) patients who had their immunotherapy interrupted had a grade 2 or 3 flare on rechallenge. Most reactions (93/103; 90.3%) responded to dermatologic therapy or immunotherapy interruption.LIMITATIONS: This was a retrospective study from a single tertiary care center.CONCLUSION: A variety of inflammatory reactions might occur from immunotherapy with differing degrees of severity. While most rashes responded to topical treatment, immunobullous and exfoliative presentations frequently interrupted immunotherapy. Increased awareness and early recognition could reduce the need for unnecessary immunotherapy interruption.
CANIT0002130	30408065	Clinical research	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4868	N/A	Retrospective analysis	Of 4,868 evaluable tests, 3,799 (78%), 195 (4%), 165 (3%), and 709 (15%) used the Agilent 22C3 pharmDx, Agilent 28-8 pharmDx, Ventana PD-L1 (SP142) Assay, and laboratory-developed tests (LDTs, including SP263), respectively. The percentages of tests scoring PD-L1 tumor expression of >=50% were 33%, 32%, 10%, and 23%, respectively. Measured PD-L1 tumor expression varied across the four assay types (¦Ö2 p < 0.001) and across three assay types excluding SP142 (p < 0.001), with no significant difference between 22C3 and 28-8 assays (p = 0.96). The PD-L1 testing rate increased from 18% in the fourth quarter of 2015 to 71% in the fourth quarter of 2017.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2018 Nov 8	Real-world PD-L1 testing and distribution of PD-L1 tumor expression by immunohistochemistry assay type among patients with metastatic non-small cell lung cancer in the United States.	 PLoS One	BACKGROUND: The anti-programmed death receptor-1 (anti-PD-1) pembrolizumab is approved as first-line monotherapy for metastatic non-small cell lung cancer (mNSCLC) with PD-ligand 1 (PD-L1) tumor expression >=50%. Most studies comparing PD-L1 results by immunohistochemistry (IHC) assay type have been conducted by prespecified and, in most cases, highly experienced, trained pathologists; however, knowledge is limited regarding the current use and concordance of PD-L1 assays in the real-world clinical setting. Our aim was to study the distribution of PD-L1 tumor expression by IHC assay type among patients with mNSCLC in US oncology practices.METHODS: This retrospective observational study utilized de-identified, longitudinal data from a large US electronic medical record database. Eligible patients were adults (>=18 years) with histologically/cytologically confirmed initial diagnosis of metastatic or recurrent NSCLC from October 2015 through December 2017. We determined PD-L1 testing trends and distribution of PD-L1 tumor expression (percentage of tumor cells staining for PD-L1) by IHC assay type.RESULTS: The 12,574 eligible patients (mean age, 69 years) included 6,620 (53%) men and 86% with positive smoking history. Of 4,868 evaluable tests, 3,799 (78%), 195 (4%), 165 (3%), and 709 (15%) used the Agilent 22C3 pharmDx, Agilent 28-8 pharmDx, Ventana PD-L1 (SP142) Assay, and laboratory-developed tests (LDTs, including SP263), respectively. The percentages of tests scoring PD-L1 tumor expression of >=50% were 33%, 32%, 10%, and 23%, respectively. Measured PD-L1 tumor expression varied across the four assay types (x2 p < 0.001) and across three assay types excluding SP142 (p < 0.001), with no significant difference between 22C3 and 28-8 assays (p = 0.96). The PD-L1 testing rate increased from 18% in the fourth quarter of 2015 to 71% in the fourth quarter of 2017.CONCLUSIONS: In the real-world clinical setting, we observed that measured PD-L1 tumor expression is concordant using the 22C3 and 28-8 assays; however, the SP142 assay and LDTs appear discordant and could underestimate high PD-L1 positivity. Further study is needed to evaluate the association between PD-L1 tumor expression and response to therapy.
CANIT0002131	30409415	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	29	N/A	Retrospective analysis	Eighteen patients had confirmed toxicity including inflammatory arthritis (n = 12) and PMR (n = 6). Twelve patients had de novo toxicity and six had a flare of a pre-existing rheumatic condition. The onset of de novo toxicity occurred late into treatment (median 38 weeks), while patients with pre-existing rheumatic disease flared soon after initiation of ICI treatment (median 4.6 weeks). Management often required systemic or intra-articular steroids, with initiation of disease modifying anti-rheumatic drug (DMARD) therapy in those unable to wean off steroids.	Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: A single center experience.	 Semin Arthritis Rheum	BACKGROUND: The use of immune checkpoint inhibition (ICI) has revolutionized cancer treatment. However, these medications are associated with significant and potentially debilitating immune-related adverse events (irAEs). While certain toxicities have been well studied, rheumatic complications have been less widely recognized and characterized.METHODS: We report our experience of patients who were evaluated by rheumatology after the development of a suspected rheumatic irAE following ICI treatment. Cases of rheumatic irAEs were included if active rheumatic signs or symptoms developed during or after ICI treatment and were confirmed by a treating rheumatologist.RESULTS: Twenty-nine patients were evaluated by rheumatology for suspected rheumatic irAEs. Eighteen patients had confirmed toxicity including inflammatory arthritis (n = 12) and PMR (n = 6). Twelve patients had de novo toxicity and six had a flare of a pre-existing rheumatic condition. The onset of de novo toxicity occurred late into treatment (median 38 weeks), while patients with pre-existing rheumatic disease flared soon after initiation of ICI treatment (median 4.6 weeks). Management often required systemic or intra-articular steroids, with initiation of disease modifying anti-rheumatic drug (DMARD) therapy in those unable to wean off steroids.CONCLUSION: De novo rheumatic irAEs are generally delayed in onset after ICI initiation, while flares of pre-existing rheumatic conditions occur shortly after ICI initiation. Effective management often requires systemic corticosteroids as well as DMARDs in a subset of patients. Future prospective studies are needed to accurately describe the incidence and spectrum of rheumatic irAEs and to identify the most effective management strategies.
CANIT0002132	30409776	Clinical research	Acute myeloid leukemia	Acute myeloid leukemia	EFO:0000222	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab plus azacitidine	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); azacitidine (DB00928); 	70	N/A	Single-arm trial	The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)-na ve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-na ve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, 	Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Pretherapy CD3(+) bone marrow infiltrate T-cell	Tumor-infiltrating immune cell	 2019 Mar	Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study.	 Cancer Discov	Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFN¦Ã signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22-90) and the median number of prior therapies received was 2 (range, 1-7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)-na ve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-na ve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-na ve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, p. 305.
CANIT0002133	30426665	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab followed by nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	45	N/A	Real-world data	In this study, responses to combination immunotherapy were lower than reported. Patients treated with prior immunotherapy had similar responses as treatment-na ve patients (pts). The toxicity profile seen in this study is similar to those reported in clinical trials. The disease control rate (DCR) was 54% and objective response rate (ORR) was 29%. Of pts treated with prior immune checkpoint inhibitors, the DCR and ORR were 50% and 33%, respectively. Intracranial responses were observed in 18% (n = 2). The median progression-free survival (PFS) was 5.8 months (95% Confidence interval (CI), 2.9-14.1 months). PFS was higher in treatment na ve patients compared to those who had prior immunotherapy (6.2 months vs 4.9 months, P = 0.59). The median OS was 17.4 months (95% CI, 7.1-NR). pts requiring corticosteroids had a shorter PFS (4.9 months vs 6.8 months) and OS (7.1 months vs NR, P = 0.01).	Treatment-related adverse events of any grade were experienced by 88% of pts, with 54% having grade 3-4 adverse events. Treatment discontinuation due to adverse events occurred in 44% of pts.	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma.	 Asia Pac J Clin Oncol	BACKGROUND: There is limited real-world data on the efficacy and safety of combination programmed cell death protein-1 (PD-1) inhibitor, nivolumab and the cytotoxic T-lymphocyte antigen (CTLA-4) inhibitor ipilimumab.METHOD: We retrospectively identified patients (pts) with metastatic melanoma treated with three-weekly nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) for four cycles followed by nivolumab monotherapy (3 mg/kg) fortnightly. Patient demographics and treatment parameters were collected and outcomes determined.RESULTS: A total of 45 pts received combination treatment with a median follow up of 8.7 months (range 0.33-25.9 months). A total of 67% were male, and BRAF V600 mutations detected in 38%. At treatment commencement, 14 (31%) pts had brain metastases, 51% had an elevated LDH and 18 (40%) were treatment-naive. Almost a third (30%) required corticosteroids for symptom control or management of prior toxicities. Nineteen (42%) patients had prior anti-PD-1 therapy. The disease control rate (DCR) was 54% and objective response rate (ORR) was 29%. Of pts treated with prior immune checkpoint inhibitors, the DCR and ORR were 50% and 33%, respectively. Intracranial responses were observed in 18% (n = 2). The median progression-free survival (PFS) was 5.8 months (95% Confidence interval (CI), 2.9-14.1 months). PFS was higher in treatment na ve patients compared to those who had prior immunotherapy (6.2 months vs 4.9 months, P = 0.59). The median OS was 17.4 months (95% CI, 7.1-NR). pts requiring corticosteroids had a shorter PFS (4.9 months vs 6.8 months) and OS (7.1 months vs NR, P = 0.01).Treatment-related adverse events of any grade were experienced by 88% of pts, with 54% having grade 3-4 adverse events. Treatment discontinuation due to adverse events occurred in 44% of pts.CONCLUSION: In this study, responses to combination immunotherapy were lower than reported. Patients treated with prior immunotherapy had similar responses as treatment-na ve pts. The toxicity profile seen in this study is similar to those reported in clinical trials.
CANIT0002134	30429014	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	167	N/A	Retrospective analysis	The incidences of all-grade and grade 3-4 pneumonitis were 13.2% and 4.2%, respectively. The presence of preexisting interstitial lung disease [odd ratio (OR), 6.03; 95% confidence interval (CI), 1.19-30.45; P = 0.030] was associated with a higher incidence of ICI-related pneumonitis. The presence of extrathoracic metastasis [OR, 0.34; 95% CI, 0.13-0.92; P = 0.034] was associated with a lower incidence of ICI-related pneumonitis. The dominant radiologic pattern (72.7%) of ICI-related pneumonitis was organizing pneumonia. Half of the patients with pneumonitis completely recovered or improved; however, the mortality rate was 18.2%.	Immune checkpoint inhibitor-related pneumonitis	N/A	N/A	Interstitial lung disease (NCIT:C27006); 	Pre-existing interstitial lung disease	Disease status	 2018 Nov	Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer.	 Lung Cancer	OBJECTIVES: Immune checkpoint inhibitors (ICIs) can cause pneumonitis in lung cancer patients. We aimed to identify the clinical and radiologic characteristics, incidence, and risk factors of ICI-related pneumonitis in patients with non-small cell lung cancer (NSCLC).MATERIALS AND METHODS: Medical records and chest computed tomography scans of NSCLC patients treated with an ICI over a 5-year period at a tertiary hospital were retrospectively analyzed. Clinical characteristics were compared between patients with and without ICI-related pneumonitis to identify risk factors.RESULTS: Data from 167 eligible patients were analyzed. The incidences of all-grade and grade 3-4 pneumonitis were 13.2% and 4.2%, respectively. The presence of preexisting interstitial lung disease [odd ratio (OR), 6.03; 95% confidence interval (CI), 1.19-30.45; P = 0.030] was associated with a higher incidence of ICI-related pneumonitis. The presence of extrathoracic metastasis [OR, 0.34; 95% CI, 0.13-0.92; P = 0.034] was associated with a lower incidence of ICI-related pneumonitis. The dominant radiologic pattern (72.7%) of ICI-related pneumonitis was organizing pneumonia. Half of the patients with pneumonitis completely recovered or improved; however, the mortality rate was 18.2%.CONCLUSION: ICIs should be used with caution when treating lung cancer patients who have underlying chronic lung disease, especially interstitial lung disease.
CANIT0002135	30429014	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	167	N/A	Retrospective analysis	The incidences of all-grade and grade 3-4 pneumonitis were 13.2% and 4.2%, respectively. The presence of preexisting interstitial lung disease [odd ratio (OR), 6.03; 95% confidence interval (CI), 1.19-30.45; P = 0.030] was associated with a higher incidence of ICI-related pneumonitis. The presence of extrathoracic metastasis [OR, 0.34; 95% CI, 0.13-0.92; P = 0.034] was associated with a lower incidence of ICI-related pneumonitis. The dominant radiologic pattern (72.7%) of ICI-related pneumonitis was organizing pneumonia. Half of the patients with pneumonitis completely recovered or improved; however, the mortality rate was 18.2%.	Immune checkpoint inhibitor-related pneumonitis	N/A	N/A	Metastasis (NCIT:C19151); 	Extrathoracic metastasis	Disease status	 2018 Nov	Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer.	 Lung Cancer	OBJECTIVES: Immune checkpoint inhibitors (ICIs) can cause pneumonitis in lung cancer patients. We aimed to identify the clinical and radiologic characteristics, incidence, and risk factors of ICI-related pneumonitis in patients with non-small cell lung cancer (NSCLC).MATERIALS AND METHODS: Medical records and chest computed tomography scans of NSCLC patients treated with an ICI over a 5-year period at a tertiary hospital were retrospectively analyzed. Clinical characteristics were compared between patients with and without ICI-related pneumonitis to identify risk factors.RESULTS: Data from 167 eligible patients were analyzed. The incidences of all-grade and grade 3-4 pneumonitis were 13.2% and 4.2%, respectively. The presence of preexisting interstitial lung disease [odd ratio (OR), 6.03; 95% confidence interval (CI), 1.19-30.45; P = 0.030] was associated with a higher incidence of ICI-related pneumonitis. The presence of extrathoracic metastasis [OR, 0.34; 95% CI, 0.13-0.92; P = 0.034] was associated with a lower incidence of ICI-related pneumonitis. The dominant radiologic pattern (72.7%) of ICI-related pneumonitis was organizing pneumonia. Half of the patients with pneumonitis completely recovered or improved; however, the mortality rate was 18.2%.CONCLUSION: ICIs should be used with caution when treating lung cancer patients who have underlying chronic lung disease, especially interstitial lung disease.
CANIT0002136	30439628	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	36	N/A	Retrospective analysis	This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic immune-related adverse events (n = 24). Thirty-four of the 36 patients sustained rheumatic immune-related adverse events (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup.	Rheumatic immune-related adverse events	N/A	N/A	N/A	N/A	N/A	 2018 Dec	Rheumatic immune-related adverse events secondary to anti-programmed death-1 antibodies and preliminary analysis on the impact of corticosteroids on anti-tumour response: A case series.	 Eur J Cancer	IMPORTANCE: Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs.OBJECTIVE: The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy.METHODS: Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated.RESULTS: This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup.CONCLUSIONS: Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.
CANIT0002137	30448924	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	N/A	PD-L1 upregulation in a pN+ cohort correlates with improved prognosis, which is similar to that in patients without nodal metastasis. Moreover, this study verified that PD-L1 and IFNG were upregulated by neoCRT treatment in LARC patients and demonstrated that neoCRT may be useful not only for immune checkpoint inhibitor treatment but also for reinvigorating preexisting anti-cancer immunity.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Feb	Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers.	 Cancer Immunol Immunother	The expression of programmed cell death 1 ligand 1 (PD-L1) and interferon-¦Ã (IFN-¦Ã) is of great interest for the development of chemoradiotherapy and immune checkpoint inhibitor treatments. Patients with nodal metastasis (pN+) tend to have a poor prognosis, even after neoadjuvant chemoradiotherapy (neoCRT) and surgical treatment. In this study, we examined the roles of tumor PD-L1 and IFN-¦Ã before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 expression (p < 0.001). Furthermore, in the pN+ population, patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year DFS and OS. PD-L1 and IFN-¦Ã upregulation increased in tumor tissues after neoCRT, and patients with high PD-L1 and high IFN-¦Ã exhibit improved 5-year DFS and OS (p = 0.04 and p = 0.001, respectively). To the best of our knowledge, this study is the first to demonstrate that PD-L1 upregulation in a pN+ cohort correlates with improved prognosis, which is similar to that in patients without nodal metastasis. Moreover, this study verified that PD-L1 and IFN-¦Ã were upregulated by neoCRT treatment in LARC patients and demonstrated that neoCRT may be useful not only for immune checkpoint inhibitor treatment but also for reinvigorating preexisting anti-cancer immunity.
CANIT0002138	30452494	Clinical research	Metastatic colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	38	N/A	Post hoc analysis	Primary resistance of metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR) to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient	Mutational status	 2019 Apr 1	Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status.	 JAMA Oncol	IMPORTANCE: Primary resistance to immune checkpoint inhibitors is observed in 10% to 40% of patients with metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR).OBJECTIVE: To investigate possible mechanisms underlying primary resistance to immune checkpoint inhibitors of mCRC displaying MSI or dMMR.DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of a single-center, prospective cohort included 38 patients with mCRC diagnosed as MSI or dMMR by local laboratories and entered into trials of immune checkpoint inhibitors between January 1, 2015, and December 31, 2016. The accuracy of MSI or dMMR status was also assessed in a retrospective cohort comprising 93 cases of mCRC that were diagnosed as MSI or dMMR between January 1, 1998, and December 31, 2016, in 6 French hospitals. Primary resistance of mCRC was defined as progressive disease according to Response Evaluation Criteria in Solid Tumors criteria, 6 to 8 weeks after initiation of immune checkpoint inhibitors, without pseudo-progression. All tumor samples were reassessed for dMMR status using immunohistochemistry with antibodies directed against MLH1, MSH2, MSH6, and PMS2, and for MSI using polymerase chain reaction with pentaplex markers and with the HSP110 T17 (HT17) repeat.MAIN OUTCOMES AND MEASURES: The primary outcome was positive predictive value.RESULTS: Among the 38 patients (15 women and 23 men; mean [SD] age, 55.6 [13.7] years) in the study with mCRC displaying MSI or dMMR, primary resistance to immune checkpoint inhibitors was observed in 5 individuals (13%). Reassessment of the status of MSI or dMMR revealed that 3 (60%) of these 5 resistant tumors were microsatellite stable or displayed proficient mismatch repair. The positive predictive value of MSI or dMMR status assessed by local laboratories was therefore 92.1% (95% CI, 78.5%-98.0%). In the retrospective cohort of 93 patients (44 women and 49 men; mean [SD] age, 56.8 [18.3] years) without immune checkpoint inhibitor treatment, misdiagnosis of the MSI or dMMR status by local assessment was 10% (n = 9), with a positive predictive value of 90.3% (95% CI, 82.4%-95.0%). Testing for MSI with the HT17 assay confirmed the MSI or dMMR status in 2 of 4 cases showing discrepant results between immunohistochemistry and pentaplex polymerase chain reaction (ie, dMMR but microsatellite stable).CONCLUSIONS AND RELEVANCE: Primary resistance of mCRC displaying MSI or dMMR to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors.
CANIT0002139	30452494	Clinical research	Metastatic colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	38	N/A	Post hoc analysis	Primary resistance of mCRC displaying MSI or dMMR to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	Microsatellite instability	Mutational status	 2019 Apr 1	Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status.	 JAMA Oncol	IMPORTANCE: Primary resistance to immune checkpoint inhibitors is observed in 10% to 40% of patients with metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR).OBJECTIVE: To investigate possible mechanisms underlying primary resistance to immune checkpoint inhibitors of mCRC displaying MSI or dMMR.DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of a single-center, prospective cohort included 38 patients with mCRC diagnosed as MSI or dMMR by local laboratories and entered into trials of immune checkpoint inhibitors between January 1, 2015, and December 31, 2016. The accuracy of MSI or dMMR status was also assessed in a retrospective cohort comprising 93 cases of mCRC that were diagnosed as MSI or dMMR between January 1, 1998, and December 31, 2016, in 6 French hospitals. Primary resistance of mCRC was defined as progressive disease according to Response Evaluation Criteria in Solid Tumors criteria, 6 to 8 weeks after initiation of immune checkpoint inhibitors, without pseudo-progression. All tumor samples were reassessed for dMMR status using immunohistochemistry with antibodies directed against MLH1, MSH2, MSH6, and PMS2, and for MSI using polymerase chain reaction with pentaplex markers and with the HSP110 T17 (HT17) repeat.MAIN OUTCOMES AND MEASURES: The primary outcome was positive predictive value.RESULTS: Among the 38 patients (15 women and 23 men; mean [SD] age, 55.6 [13.7] years) in the study with mCRC displaying MSI or dMMR, primary resistance to immune checkpoint inhibitors was observed in 5 individuals (13%). Reassessment of the status of MSI or dMMR revealed that 3 (60%) of these 5 resistant tumors were microsatellite stable or displayed proficient mismatch repair. The positive predictive value of MSI or dMMR status assessed by local laboratories was therefore 92.1% (95% CI, 78.5%-98.0%). In the retrospective cohort of 93 patients (44 women and 49 men; mean [SD] age, 56.8 [18.3] years) without immune checkpoint inhibitor treatment, misdiagnosis of the MSI or dMMR status by local assessment was 10% (n = 9), with a positive predictive value of 90.3% (95% CI, 82.4%-95.0%). Testing for MSI with the HT17 assay confirmed the MSI or dMMR status in 2 of 4 cases showing discrepant results between immunohistochemistry and pentaplex polymerase chain reaction (ie, dMMR but microsatellite stable).CONCLUSIONS AND RELEVANCE: Primary resistance of mCRC displaying MSI or dMMR to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors.
CANIT0002140	30452687	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus stereotactic radiation therapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); stereotactic ablative radiotherapy (NCIT:C157991); 	6	N/A	N/A	One complete response and two partial responses were achieved. Four patients had measurable lesions outside the irradiated area, of whom three patients responded to the treatment. The initial progression sites were mainly outside the irradiated field, including one brain metastasis.	Grade 3 pneumonitis occurred in one patient, but no other serious adverse events were reported for the other patients.	N/A	N/A	N/A	N/A	N/A	 2019 Feb 1	Nivolumab and stereotactic radiation therapy for the treatment of patients with Stage IV non-small-cell lung cancer.	 Jpn J Clin Oncol	BACKGROUND: Radiation therapy might modify the cancer immune environment to enhance the antitumor effect of immune checkpoint inhibitors. We performed a feasibility study of nivolumab following stereotactic radiation therapy for chemotherapy pretreated advanced non-small-cell lung cancer.PATIENTS AND METHODS: Pretreated advanced/recurrent non-small-cell lung cancer patients received stereotactic radiation therapy to one of the disease sites. Nivolumab at a dose of 3 mg/kg was given within 2 weeks after the completion of stereotactic radiation therapy and continued every 2 weeks thereafter until disease progression or unacceptable toxicities. The primary endpoint was the occurrence rate of Grade 3 pneumonitis (within 12 weeks) or other non-hematological toxicity (within 8 weeks).RESULTS: From September 2016 to September 2017, six patients were enrolled. Five received stereotactic radiation therapy to their primary lesions. All patients received nivolumab on the following day after stereotactic radiation therapy completion. Grade 3 pneumonitis occurred in one patient, but no other serious adverse events were reported for the other patients. One complete response and two partial responses were achieved. Four patients had measurable lesions outside the irradiated area, of whom three patients responded to the treatment. The initial progression sites were mainly outside the irradiated field, including one brain metastasis.CONCLUSIONS: Nivolumab therapy immediately following stereotactic radiation therapy was well tolerated. This sequential combination warrants further study.
CANIT0002141	30453170	Clinical research	Metastatic skin cancer	Skin carcinoma	EFO:0009259	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	38	N/A	N/A	Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.	Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors.	 Eur J Cancer	AIM: To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy.METHODS: The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised.RESULTS: Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.CONCLUSION: Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.
CANIT0002142	30453170	Clinical research	Metastatic skin cancer	Skin carcinoma	EFO:0009259	Skin	CTLA-4 (P16410); 	CTLA-4; 	Tremelimumab	N/A	Immune checkpoint therapy	Tremelimumab (DB11771); 	38	N/A	N/A	Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.	Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors.	 Eur J Cancer	AIM: To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy.METHODS: The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised.RESULTS: Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.CONCLUSION: Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.
CANIT0002143	30453170	Clinical research	Metastatic skin cancer	Skin carcinoma	EFO:0009259	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.	Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors.	 Eur J Cancer	AIM: To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy.METHODS: The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised.RESULTS: Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.CONCLUSION: Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.
CANIT0002144	30453170	Clinical research	Metastatic skin cancer	Skin carcinoma	EFO:0009259	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	38	N/A	N/A	Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.	Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors.	 Eur J Cancer	AIM: To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy.METHODS: The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised.RESULTS: Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases.CONCLUSION: Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.
CANIT0002145	30461210	Case report	Lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A 62-year-old man was diagnosed with lung adenocarcinoma and nivolumab was selected as the third-line regimen. After three cycles of nivolumab treatment, chest computed tomography revealed pulmonary infiltrates in both lungs. The patient was diagnosed with acute eosinophilic pneumonia (AEP) based on the diagnostic criteria for AEP. Nivolumab was suspended and the patient was started on oral prednisolone. His symptoms and radiological findings had rapidly improved.	Acute eosinophilic pneumonia	N/A	N/A	N/A	N/A	N/A	 2019 Mar	A potential mechanism of the onset of acute eosinophilic pneumonia triggered by an anti-PD-1 immune checkpoint antibody in a lung cancer patient.	 Immun Inflamm Dis	INTRODUCTION: The impact of immune checkpoint blockade on immunity in cancer patients is not completely elucidated due to the complexity of the immune network. Recent studies have revealed a significant role of programed cell death-ligand 2 (PD-L2) in negatively controlling the production of CD4+ T helper type 2 (Th2) cytokines and airway hypersensitiveness, suggesting hypo-responsive Th2 cells via the PD-1/PD-L2 inhibitory pathway in lung could be reawaken by PD-1 blockade therapy.METHODS: We describe the first report of acute eosinophilic pneumonia (AEP), which is known as Th2-associated pulmonary disease, triggered by nivolumab, an anti-PD-1 antibody, in an advanced non-small cell lung cancer patient. Based on the current case report and literature, the present study proposes a potential mechanism of the onset of AEP as an immune-related adverse event (irAE).RESULTS: A 62-year-old man was diagnosed with lung adenocarcinoma and nivolumab was selected as the third-line regimen. After three cycles of nivolumab treatment, chest computed tomography revealed pulmonary infiltrates in both lungs. The patient was diagnosed with AEP based on the diagnostic criteria for AEP. Nivolumab was suspended and the patient was started on oral prednisolone. His symptoms and radiological findings had rapidly improved.CONCLUSIONS: Given the increasing frequency of the use of anti-PD-1 antibodies, clinicians should be aware of the risk of AEP as a potential irAE. This study may improve our understanding of the pathophysiology underlying Th2-associated irAEs and AEP.
CANIT0002146	30470260	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	157	N/A	Retrospective analysis	At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline absolute neutrophil count,absolute monocyte count, absolute neutrophil count: absolute lymphocyte count ratio and absolute monocyte count: absolute lymphocyte count ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baselineabsolute neutrophil count: absolute lymphocyte count ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline absolute monocyte count: absolute lymphocyte count ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2018 Nov 23	Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung Cancer patients treated with anti-PD-1 antibodies.	 J Immunother Cancer	BACKGROUND: Anti-programmed cell death 1 (PD-1) antibodies have demonstrated improved overall survival (OS) and progression-free survival (PFS) in a subset of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). To date, no blood biomarkers have been identified in NSCLC to predict clinical outcomes of treatment with anti-PD-1 antibodies.PATIENT AND METHODS: We performed an analysis of retrospectively registered data of 157 patients with advanced NSCLC treated with anti-PD-1 antibodies at Mayo Clinic in Florida and Rochester. White blood cell count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC (ANC: ALC) ratio, absolute eosinophil count, absolute monocyte count (AMC), platelet counts, and myeloid to lymphoid (M:L) ratio at baseline and throughout treatment were assessed. Kaplan-Meier method and Cox proportional hazards model were performed.RESULTS: We treated 146 patients with nivolumab and 11 with pembrolizumab between January 1, 2015 and April 15, 2017. At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline ANC, AMC, ANC: ALC ratio and M: L ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio.CONCLUSIONS: Increased baseline ANC: ALC ratio and M: L ratio before initiation of anti-PD1 antibodies were associated with poor PFS and OS in advanced NSCLC patients. The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies. These findings warrant further investigation in a larger, prospective study.
CANIT0002147	30470260	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	157	N/A	Retrospective analysis	At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline absolute neutrophil count,absolute monocyte count, absolute neutrophil count: absolute lymphocyte count ratio and absolute monocyte count: absolute lymphocyte count ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio.	N/A	N/A	N/A	Lymphocyte counts (NCIT:C12535); 	Higher baseline of absolute lymphocyte count	Cell percentage/counts in blood	 2018 Nov 23	Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung Cancer patients treated with anti-PD-1 antibodies.	 J Immunother Cancer	BACKGROUND: Anti-programmed cell death 1 (PD-1) antibodies have demonstrated improved overall survival (OS) and progression-free survival (PFS) in a subset of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). To date, no blood biomarkers have been identified in NSCLC to predict clinical outcomes of treatment with anti-PD-1 antibodies.PATIENT AND METHODS: We performed an analysis of retrospectively registered data of 157 patients with advanced NSCLC treated with anti-PD-1 antibodies at Mayo Clinic in Florida and Rochester. White blood cell count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC (ANC: ALC) ratio, absolute eosinophil count, absolute monocyte count (AMC), platelet counts, and myeloid to lymphoid (M:L) ratio at baseline and throughout treatment were assessed. Kaplan-Meier method and Cox proportional hazards model were performed.RESULTS: We treated 146 patients with nivolumab and 11 with pembrolizumab between January 1, 2015 and April 15, 2017. At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline ANC, AMC, ANC: ALC ratio and M: L ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio.CONCLUSIONS: Increased baseline ANC: ALC ratio and M: L ratio before initiation of anti-PD1 antibodies were associated with poor PFS and OS in advanced NSCLC patients. The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies. These findings warrant further investigation in a larger, prospective study.
CANIT0002148	30470260	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	157	N/A	Retrospective analysis	At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline absolute neutrophil count,absolute monocyte count, absolute neutrophil count: absolute lymphocyte count ratio and absolute monocyte count: absolute lymphocyte count ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio.	N/A	N/A	N/A	Monocyte counts (NCIT:C12547); 	Absolute monocyte counts	Cell percentage/counts in blood	 2018 Nov 23	Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung Cancer patients treated with anti-PD-1 antibodies.	 J Immunother Cancer	BACKGROUND: Anti-programmed cell death 1 (PD-1) antibodies have demonstrated improved overall survival (OS) and progression-free survival (PFS) in a subset of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). To date, no blood biomarkers have been identified in NSCLC to predict clinical outcomes of treatment with anti-PD-1 antibodies.PATIENT AND METHODS: We performed an analysis of retrospectively registered data of 157 patients with advanced NSCLC treated with anti-PD-1 antibodies at Mayo Clinic in Florida and Rochester. White blood cell count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC (ANC: ALC) ratio, absolute eosinophil count, absolute monocyte count (AMC), platelet counts, and myeloid to lymphoid (M:L) ratio at baseline and throughout treatment were assessed. Kaplan-Meier method and Cox proportional hazards model were performed.RESULTS: We treated 146 patients with nivolumab and 11 with pembrolizumab between January 1, 2015 and April 15, 2017. At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline ANC, AMC, ANC: ALC ratio and M: L ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio.CONCLUSIONS: Increased baseline ANC: ALC ratio and M: L ratio before initiation of anti-PD1 antibodies were associated with poor PFS and OS in advanced NSCLC patients. The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies. These findings warrant further investigation in a larger, prospective study.
CANIT0002149	30470260	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	157	N/A	Retrospective analysis	At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline absolute neutrophil count,absolute monocyte count, absolute neutrophil count: absolute lymphocyte count ratio and absolute monocyte count: absolute lymphocyte count ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio.	N/A	N/A	N/A	Myeloid to lymphoid ratio ()	Baseline myeloid-to-lymphoid ratios	Cell percentage/counts in blood	 2018 Nov 23	Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung Cancer patients treated with anti-PD-1 antibodies.	 J Immunother Cancer	BACKGROUND: Anti-programmed cell death 1 (PD-1) antibodies have demonstrated improved overall survival (OS) and progression-free survival (PFS) in a subset of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). To date, no blood biomarkers have been identified in NSCLC to predict clinical outcomes of treatment with anti-PD-1 antibodies.PATIENT AND METHODS: We performed an analysis of retrospectively registered data of 157 patients with advanced NSCLC treated with anti-PD-1 antibodies at Mayo Clinic in Florida and Rochester. White blood cell count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC (ANC: ALC) ratio, absolute eosinophil count, absolute monocyte count (AMC), platelet counts, and myeloid to lymphoid (M:L) ratio at baseline and throughout treatment were assessed. Kaplan-Meier method and Cox proportional hazards model were performed.RESULTS: We treated 146 patients with nivolumab and 11 with pembrolizumab between January 1, 2015 and April 15, 2017. At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline ANC, AMC, ANC: ALC ratio and M: L ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio.CONCLUSIONS: Increased baseline ANC: ALC ratio and M: L ratio before initiation of anti-PD1 antibodies were associated with poor PFS and OS in advanced NSCLC patients. The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies. These findings warrant further investigation in a larger, prospective study.
CANIT0002150	30474475	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab or nivolumab	Chemotherapy or targeted therapy	Immune checkpoint therapy	Durvalumab (DB11714); nivolumab (DB09035); 	11719	N/A	Meta-analysis	The incidences were 23.4 and 2.1% for all- and high-grade fatigue, respectively. The highest incidence of high-grade fatigue was reported by the combination of nivolumab and ipilimumab. Overall RR of high-grade fatigue with anti-PD-1/PD-L1 compared with chemotherapy or targeted therapy was 0.48.	Fatigue	N/A	N/A	N/A	N/A	N/A	 2018 Nov	Risk of fatigue in cancer patients treated with anti programmed cell death-1/anti programmed cell death ligand-1 agents: a systematic review and meta-analysis.	 Immunotherapy	AIM: We aimed to assess the incidence and relative risk (RR) of fatigue in cancer patients treated with anti programmed cell death-1 (PD-1) and anti programmed cell death ligand-1 (PD-L1) agents.PATIENTS & METHODS: Eligible studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Incidence, RR and 95% CIs were calculated using random or fixed-effects models.RESULTS: Thirty-eight studies were included in this analysis, with a total of 11,719 patients. The incidences were 23.4 and 2.1% for all- and high-grade fatigue, respectively. The highest incidence of high-grade fatigue was reported by the combination of nivolumab and ipilimumab. Overall RR of high-grade fatigue with anti-PD-1/PD-L1 compared with chemotherapy or targeted therapy was 0.48.CONCLUSION: Treatment with anti-PD-1/PD-L1 agents correlates with lower incidence and RR of fatigue compared with standard therapies.
CANIT0002151	30474476	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	N/A	N/A	Meta-analysis	PD-1 inhibitors significantly improved the progression-free survival, overall survival and overall response rate in patients with advanced melanoma. Progression-free survival, overall survival and overall response rate did not vary significantly according to PD-L1 status, V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations and type of drug, but varied significantly by control therapy. 	PD-1 inhibitors were associated with a decreased risk of adverse events compared with ipilimumab, but an increased risk of immune-related events compared with chemotherapy.	N/A	N/A	N/A	N/A	N/A	 2018 Nov	Efficacy and safety of PD-1 inhibitors for treating advanced melanoma: a systematic review and meta-analysis.	 Immunotherapy	AIM: We conducted a meta-analysis to systematically review the efficacy and safety of programmed cell death 1 (PD-1) inhibitors for advanced melanoma.STUDY DESIGN: The relevant studies of the randomized controlled trials in melanoma patients treated with PD-1 inhibitors were retrieved and the systematic evaluation was conducted. Databases were searched till June 2018.RESULTS: PD-1 inhibitors significantly improved the progression-free survival, overall survival and overall response rate in patients with advanced melanoma. Progression-free survival, overall survival and overall response rate did not vary significantly according to PD-L1 status, V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations and type of drug, but varied significantly by control therapy. PD-1 inhibitors were associated with a decreased risk of adverse events compared with ipilimumab, but an increased risk of immune-related events compared with chemotherapy.CONCLUSION: The PD-1 inhibitors-containing therapy was efficacious in treating advanced melanoma.
CANIT0002152	30475947	Clinical research	Metastatic triple-negative breast cancer	Triple-negative breast cancer	EFO:0005537	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	84	N/A	Cohort B of the phase II KEYNOTE-086 study	Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9-31.4). Of the 13 patients with stable disease, 2 had stable disease lasting >=24 weeks, for a disease control rate of 23.8% (95% CI 15.9-34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0-2.2), and median overall survival was 18.0 months (95% CI 12.9-23.0).	Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs.	N/A	N/A	N/A	N/A	N/A	 2019 Mar 1	Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study.	 Ann Oncol	BACKGROUND: Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC.PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score >=1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for >=24 weeks), duration of response, progression-free survival and overall survival.RESULTS: All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9-31.4). Of the 13 patients with stable disease, 2 had stable disease lasting >=24 weeks, for a disease control rate of 23.8% (95% CI 15.9-34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0-2.2), and median overall survival was 18.0 months (95% CI 12.9-23.0).CONCLUSIONS: Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.
CANIT0002153	30475950	Clinical research	Metastatic triple-negative breast cancer	Triple-negative breast cancer	EFO:0005537	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	170	N/A	Phase II KEYNOTE-086 study	61.8% had PD-L1-positive tumors, and 43.5% had received >=3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. Disease control rate (95% CI) was 7.6% (4.4-12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2+-21.5+) and in the PD-L1-positive (range, 6.3-21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6-11.2), and the 6-month rate was 69.1%.	Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Mar 1	Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study.	 Ann Oncol	BACKGROUND: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC.PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, >=1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1-positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for >=24 weeks), progression-free survival, and overall survival.RESULTS: All enrolled patients (N = 170) were women, 61.8% had PD-L1-positive tumors, and 43.5% had received >=3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. Disease control rate (95% CI) was 7.6% (4.4-12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2+-21.5+) and in the PD-L1-positive (range, 6.3-21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs.CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.
CANIT0002154	30506406	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	195	N/A	Retrospective analysis	Median PFS was 5.7 months in immune-related adverse events group compared to 2.0 months of no-immune-related adverse events group [HR: 0.41 (95% CI 0.3-0.57), P < 0.0001]. Median OS was 17.8 months compared to 4.0 months of no-immune-related adverse events group [HR: 0.33 (95% CI 0.23-0.47), P < 0.0001]. immune-related adverse events were significantly associated with improved clinical outcome in 12- and 6-week landmark analysis. Patients who developed >= 2 immune-related adverse events during treatment (n: 37) had a significantly longer median PFS and OS compared to those with one (n: 48) or none AEs (n: 110) (PFS: 8.5 months vs. 4.6 vs. 2.0, P < 0.0001; OS: 26.8 months vs. 11.9 vs. 4.0, P < 0.0001). Multivariable analysis revealed that immune-related adverse events were positively associated with PFS [HR: 0.48 (95% CI 0.34-0.67), P < 0.0001] and OS [HR: 0.38 (95% CI 0.26-0.56), P < 0.0001].In this study we confirmed that the development of irAEs was a strong predictor of survival outcomes in NSCLC patients treated with nivolumab monotherapy in landmark and multivariable models. Patients who experienced >= 2 irAEs had a more pronounced survival benefit compared to those with 1 irAE further suggesting a mechanistic association between irAEs and immunotherapy efficacy.	Among 195 patients [median (range) age, 63 (30-84) years; 128 men (65.6%), 67 women (34.4%)], irAEs were observed in 85 patients (43.6%), including 15 patients (7.6%) with grade 3 or 4 events.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2019 Feb	Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis.	 J Cancer Res Clin Oncol	PURPOSE: Immune-checkpoint inhibitors (ICIs) represent the standard of care for platinum-pretreated advanced non-small cell lung cancer patients. Patients treated with ICIs may experience immune-related adverse events (irAEs), that might reflect antitumor responses. Here we evaluated nivolumab efficacy according to the development of irAEs.METHODS: We conducted a multicenter retrospective study of patients with advanced NSCLC treated with nivolumab between October 2013 and September 2017. IrAEs were defined as AEs having immunological basis that required intensive monitoring and interventions.RESULTS: Among 195 patients [median (range) age, 63 (30-84) years; 128 men (65.6%), 67 women (34.4%)], irAEs were observed in 85 patients (43.6%), including 15 patients (7.6%) with grade 3 or 4 events. Median PFS was 5.7 months in irAEs group compared to 2.0 months of no-irAEs group [HR: 0.41 (95% CI 0.3-0.57), P < 0.0001]. Median OS was 17.8 months compared to 4.0 months of no-irAEs group [HR: 0.33 (95% CI 0.23-0.47), P < 0.0001]. IrAEs were significantly associated with improved clinical outcome in 12- and 6-week landmark analysis. Patients who developed >= 2 irAEs during treatment (n: 37) had a significantly longer median PFS and OS compared to those with one (n: 48) or none AEs (n: 110) (PFS: 8.5 months vs. 4.6 vs. 2.0, P < 0.0001; OS: 26.8 months vs. 11.9 vs. 4.0, P < 0.0001). Multivariable analysis revealed that irAEs were positively associated with PFS [HR: 0.48 (95% CI 0.34-0.67), P < 0.0001] and OS [HR: 0.38 (95% CI 0.26-0.56), P < 0.0001].CONCLUSION: In this study we confirmed that the development of irAEs was a strong predictor of survival outcomes in NSCLC patients treated with nivolumab monotherapy in landmark and multivariable models. Patients who experienced >= 2 irAEs had a more pronounced survival benefit compared to those with 1 irAE further suggesting a mechanistic association between irAEs and immunotherapy efficacy.
CANIT0002155	30507339	Basic research	Cancer	Cancer	EFO:0000311	Other	IDO1 (P14902); 	IDO1; 	Epacadostat	N/A	Immune checkpoint therapy	Epacadostat (DB11717); 	Cell lines/ animal models	N/A	Basic research	The pharmacokinetic study in rats showed the exposure (AUClast) of S-EPA in plasma and blood cells was 1.7-fold and 3.9-fold higher than that of EPA, respectively. Moreover, the exposure ratio of S-EPA in blood cells to plasma was 3.7, while the ratio of EPA was 1.6.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Nov	Pharmacokinetics of S-EPA, and its inhibition on indoleamine 2,3-dioxgenase: a case of sulfur-substitution affecting distributions in blood cells.	 Xenobiotica	1. S-EPA is a sulfur-substitution analog of epacadostat (EPA), an effective small molecule indoleamine 2,3-dioxgenase1 (IDO) inhibitor. By in vitro and in vivo experiments, pharmacokinetic differences of two closely related analogs, S-EPA and EPA was investigated in this study. 2. Liver microsomes clearance experiments showed S-EPA had comparable metabolic stability with EPA in rat and human liver microsomes. The whole blood distribution experiments showed the distribution ratio of S-EPA in blood cells to plasma in mice, rats, dogs and monkey was 1.2, 4.8, 2.2 and 40.6, respectively. While the distribution ratio of EPA ranged from 0.94 to 1.30 in mice, rats, dogs and was 3.1 in monkeys. 3. The pharmacokinetic study in rats showed the exposure (AUClast) of S-EPA in plasma and blood cells was 1.7-fold and 3.9-fold higher than that of EPA, respectively. Moreover, the exposure ratio of S-EPA in blood cells to plasma was 3.7, while the ratio of EPA was 1.6. 4. In CT26 tumor bearing mice, the IDO inhibition of S-EPA and EPA on plasma or tumor kynurenine was generally consistent. And the inhibition ratio could reach at more than 50% at 3 h after single dose, at least lasting up to 8 h.
CANIT0002156	30508191	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Twenty-six patients with ICI-induced inflammatory arthritis were of European descent, and one was African American. In those 26 patients, 16 (61.5%) had at least one SE allele, significantly different from healthy controls of European descent, in whom 299 (41.2%) had at least one SE allele (odds ratio 2.3, P = 0.04). The allele-positivity rate of DRB1*04: 05 was also higher in the ICI-induced inflammatory arthritis group. The ICI-induced inflammatory arthritis population and RA patients of European descent did not differ in frequency of having at least one SE allele, but ICI-induced inflammatory arthritis patients were more likely to be autoantibody-negative for RF and anti-CCP antibodies.	ICI-induced inflammatory arthritis	N/A	N/A	HLA-DRB1 (P01911); 	HLA-DRB1 shared epitope alleles	Gene expression signature on/in immune cell	 2019 Mar 1	Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis.	 Rheumatology (Oxford)	OBJECTIVE: To evaluate the frequency of HLA class I and II alleles associated with traditional forms of inflammatory arthritis in patients with immune checkpoint inhibitor (ICI)-induced inflammatory arthritis as compared with population controls.METHODS: High-resolution HLA typing was performed on 27 patients with ICI-induced inflammatory arthritis and 726 healthy controls. Genotyping at the shared epitope (SE) locus (HLA DRB1) was performed on 220 RA cases. Allele-positivity rates and frequency of having at least one SE allele were compared using Fisher's exact test between ICI-induced inflammatory arthritis and healthy controls. Frequency of having at least one SE allele was also compared between ICI-induced inflammatory arthritis and RA cases.RESULTS: Twenty-six patients with ICI-induced inflammatory arthritis were of European descent, and one was African American. In those 26 patients, 16 (61.5%) had at least one SE allele, significantly different from healthy controls of European descent, in whom 299 (41.2%) had at least one SE allele (odds ratio 2.3, P = 0.04). The allele-positivity rate of DRB1*04: 05 was also higher in the ICI-induced inflammatory arthritis group. The ICI-induced inflammatory arthritis population and RA patients of European descent did not differ in frequency of having at least one SE allele, but ICI-induced inflammatory arthritis patients were more likely to be autoantibody-negative for RF and anti-CCP antibodies.CONCLUSION: Patients with ICI-induced inflammatory arthritis of European descent were more likely to have at least one SE allele than healthy controls. Further studies are needed to validate these findings and investigate whether a unique immunogenetic framework increases risk for different immune-related adverse events.
CANIT0002157	30527198	Basic research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	Cell lines	N/A	Basic research	The implementation of PD-L1 immunocytochemistry on cytological smears will likely expand the pool of NSCLC patients candidate to first-line immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Dec	Validation of the immunohistochemical expression of programmed death ligand 1 (PD-L1) on cytological smears in advanced non small cell lung cancer.	 Lung Cancer	Introduction The assessment of PD-L1 expression by immunohistochemistry is mandatory for the administration as first-line therapy of the anti PD-1 check-point inhibitor Pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC). Currently, only formalin-fixed paraffin-embedded samples are acceptable for PD-L1 immunostaining with the anti-PD-L1 antibodies 22-C3 and SP263. We investigated retrospectively the accuracy of the anti PD-L1 antibodies 22-C3, 28-28, SP263 in 50 paired histological samples and cytological smears of NSCLC patients. Results The accuracy of the three antibodies for the detection of PD-L1 in histological samples was higher for the antibody SP263 (AUC/ROC = 1) compared to the clones 28-8 (AUC/ROC =,991) and 22-C3 (AUC/ROC =,942). The overall concordance between histological samples and cytological smears using the SP263 clone was moderate (kappa = 0,364). However when the cyto-histological concordance was calculated using just the <50% vs >=50% cut-off the agreement (kappa = 0.626) was good. The accuracy of the antibody SP263 in cytological smears was good (AUC/ROC =,921). A fluorescent in situ hybridization analysis on 10 histological cases positive for PD-L1 at immunohistochemistry showed amplification of the CD274 gene only in one case. Conclusions Immunocytochemical staining for PD-L1 in diagnostic cytological smears of NSCLC is feasible and applicable at least using the >50% cancer cell cut-off. The three antibodies SP263, 22-C3 and 28-8 are all suitable for the diagnostic detection of PD-L1 on tissue sections with a superiority of the SP263 clone. The implementation of PD-L1 immunocytochemistry on cytological smears will likely expand the pool of NSCLC patients candidate to first-line immunotherapy.
CANIT0002158	30535675	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	N/A	N/A	N/A	Nivolumab was associated with both higher costs and benefits in both PS and Markov models. In particular, from the PS model, nivolumab cost an additional A$198,862/QALY and A$181,623/LY gained. The Markov model showed that nivolumab had an incremental cost-effectiveness ratio (ICER) of A$220,029/QALY and A$193,459/LY, respectively. The sensitivity analyses showed base-case results were sensitive to the extrapolation approach, duration of treatment, cost of nivolumab and time horizon modelled.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Modelled Economic Evaluation of Nivolumab for the Treatment of Second-Line Advanced or Metastatic Squamous Non-Small-Cell Lung Cancer in Australia Using Both Partition Survival and Markov Models.	 Appl Health Econ Health Policy	OBJECTIVES: To assess the cost-effectiveness of nivolumab for patients with advanced or metastatic squamous non-small-cell lung cancer (NSCLC) progressed on or after platinum-based chemotherapy using a modelled economic evaluation.METHODS: Both partition survival (PS) and Markov models, comprised of three health states, were adopted to evaluate the cost-effectiveness of nivolumab compared to docetaxel from an Australian healthcare system perspective with a 6-year time horizon. Reconstructed individual patient data (IPD) were derived from published Kaplan-Meier curves from the pivotal trial for overall survival (OS) and progression-free survival (PFS) using a validated algorithm. Best-fitting survival curves were selected to extrapolate the OS, PFS and post-progression survival (PPS) beyond trial duration. Expected costs and health outcomes [i.e. quality-adjusted life year (QALY), and life year (LY)] associated with each of the health states (i.e. PF, PD and dead) were accrued over the time horizon. Both deterministic and probabilistic sensitivity analyses were undertaken.RESULTS: Nivolumab was associated with both higher costs and benefits in both PS and Markov models. In particular, from the PS model, nivolumab cost an additional A$198,862/QALY and A$181,623/LY gained. The Markov model showed that nivolumab had an incremental cost-effectiveness ratio (ICER) of A$220,029/QALY and A$193,459/LY, respectively. The sensitivity analyses showed base-case results were sensitive to the extrapolation approach, duration of treatment, cost of nivolumab and time horizon modelled.CONCLUSIONS: Using an often-quoted willingness-to-pay per QALY threshold in Australia (i.e. A$50,000), the treatment with nivolumab cannot be considered cost-effective. It might be funded publicly by special arrangements given unmet clinical needs for patients.
CANIT0002159	30544423	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus pemetrexed plus cisplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); pemetrexed (DB00642); cisplatin (DB00515); 	1	N/A	Case	The patient received pemetrexed plus cisplatin (Pem-Cis) treatment for 6 cycles and sequential thoracic radiation as a therapeutic schedule. Computed tomography (CT) demonstrated a confirmed partial response after these treatments. Three months later, the tumors continued to grow. The patient received successive pemetrexed-based chemotherapy regimens; however, these regimens failed to stop tumor progression. The patient subsequently underwent 6 cycles of PD-1 mAb pembrolizumab treatment. Sensitivity of chemotherapy was restored, and the patient displayed a reduction in the size of enlarged mediastinal and hilar lymph nodes after 2 cycles of treatment with Pem-Cis, the initially used chemotherapy regimen.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Dec	Reversal of resistance to chemotherapy following anti-programmed cell death-1 immunotherapy in metastatic lung adenocarcinoma: A case report.	 Medicine (Baltimore)	RATIONALE: For metastatic non-small cell lung cancer with no epidermal growth factor receptor mutations or anaplastic lymphoma kinase gene rearrangements, programmed cell death-1 (PD-1) blockade is preferentially recommended post first-line chemotherapy. However, still many patients do not respond to these agents. After development of resistance to PD-1 blockade, further evaluation of chemotherapy regimen will be necessary.PATIENT CONCERNS: A 57-year old man had cough with minimal whitish expectoration. Computed tomography (CT) scans showed that he had an upper lobe mass of his left lung and multiple lymphadenectasis, including mediastinal and hilar lymph nodes, and also to the right intrapulmonary lymph nodes.DIAGNOSES: The patient was diagnosed with adenocarcinoma after a biopsy was conducted on the upper lobe mass of his left lung.INTERVENTIONS: The patient received pemetrexed plus cisplatin (Pem-Cis) treatment for 6 cycles and sequential thoracic radiation as a therapeutic schedule. CT demonstrated a confirmed partial response after these treatments. Three months later, the tumors continued to grow. The patient received successive pemetrexed-based chemotherapy regimens; however, these regimens failed to stop tumor progression. The patient subsequently underwent 6 cycles of PD-1 mAb pembrolizumab treatment.OUTCOMES: Sensitivity of chemotherapy was restored, and the patient displayed a reduction in the size of enlarged mediastinal and hilar lymph nodes after 2 cycles of treatment with Pem-Cis, the initially used chemotherapy regimen.LESSONS: This outcome suggests that PD-1 blockade holds promise as a treatment strategy for reversion of chemotherapy resistance in refractory lung adenocarcinoma and warrants additional studies.
CANIT0002160	30547218	Basic research	Hepatocellular carcinoma	Hepatocellular carcinoma	EFO:0000182	Liver	CTLA-4 (P16410); PD-1 (Q15116); HDAC9 (Q9UKV0); 	CTLA-4 ;  PD-1 ;  HDAC9 	Ipilimumab or nivolumab plus Belinostat	N/A	Immune checkpoint therapy plus Target therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFNG production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	Early upregulation of PD-L1 on tumor antigen-presenting cells	Gene expression signature on/in immune cell	 2019 Mar	Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model.	 Cancer Immunol Immunother	Immune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-line setting in the USA. Epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunotherapy agents. Our aim was to study the therapeutic efficacy of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 antibodies) in combination with the histone deacetylase inhibitor (HDACi) Belinostat. In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFN-¦Ã production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection. These results provide a rationale for testing Belinostat in combination with checkpoint inhibitors to enhance their therapeutic activity in patients with HCC.
CANIT0002161	30547218	Basic research	Hepatocellular carcinoma	Hepatocellular carcinoma	EFO:0000182	Liver	CTLA-4 (P16410); PD-1 (Q15116); HDAC9 (Q9UKV0); 	CTLA-4 ;  PD-1 ;  HDAC9 	Ipilimumab or nivolumab plus Belinostat	N/A	Immune checkpoint therapy plus Target therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFNG production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	Late expression of PD-1 on tumor-infiltrating effector T-cells	Gene expression signature on/in immune cell	 2019 Mar	Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model.	 Cancer Immunol Immunother	Immune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-line setting in the USA. Epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunotherapy agents. Our aim was to study the therapeutic efficacy of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 antibodies) in combination with the histone deacetylase inhibitor (HDACi) Belinostat. In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFN-¦Ã production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection. These results provide a rationale for testing Belinostat in combination with checkpoint inhibitors to enhance their therapeutic activity in patients with HCC.
CANIT0002162	30549256	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	244	N/A	Retrospective analysis	Of 244 episodes of therapy, a non-cutaneous irAE occurred in 72 (29.5%). Rheumatic immune-related adverse events were diagnosed in 19 episodes of therapy (7.8%), with 12 de novo diagnoses (5.1% of episodes without a pre-existing autoimmune rheumatic disease) and 7 exacerbations of existing disease. Review by a rheumatologist occurred in only 11 of these. Rheumatic immune-related adverse events were more common in patients with a good oncological response to therapy (relative risk [RR] 11.16), those being treated for melanoma (RR 2.94) and those who developed another non-cutaneous irAE (RR 2.64).	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Rheumatic Immune-related adverse events	Adverse events	 2019 Feb	Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy.	 Int J Rheum Dis	AIM: To investigate whether any patient or treatment characteristics are associated with the development of rheumatic immune-related adverse events (irAEs) following programmed cell death protein 1 (PD-1) inhibitor therapy for cancer.METHOD: This was a retrospective chart review of all patients who were dispensed nivolumab or pembrolizumab at a single center before 1 January, 2017, with follow-up until 1 July, 2017. Patients with any diagnosis of a non-cutaneous irAE were identified, regardless of severity, and rheumatic irAEs were characterized.RESULTS: Of 244 episodes of therapy, a non-cutaneous irAE occurred in 72 (29.5%). Rheumatic irAEs were diagnosed in 19 episodes of therapy (7.8%), with 12 de novo diagnoses (5.1% of episodes without a pre-existing autoimmune rheumatic disease) and 7 exacerbations of existing disease. Review by a rheumatologist occurred in only 11 of these. Rheumatic irAEs were more common in patients with a good oncological response to therapy (relative risk [RR] 11.16), those being treated for melanoma (RR 2.94) and those who developed another non-cutaneous irAE (RR 2.64).CONCLUSION: Rheumatic irAEs are relatively common with PD-1 inhibitor therapy, and appear to be associated with a good oncological response to therapy. Many rheumatic irAEs were not referred to rheumatological services. Prospective systematic investigation would be of benefit to explore these characteristics.
CANIT0002163	30567561	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	66	N/A	N/A	Its found that baseline levels of Type III collagen formation (PRO-C3) (p = 0.011), MMP-degraded type I collagens (C1M) (p = 0.003), MMP-degraded type III collagens (C3M) (p = 0.013) and MMP-degraded type IV collagens (C4M) (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified citrullinated and MMP-degraded vimentin (VICM)  as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.	N/A	N/A	N/A	MMP-degraded type I collagens ()	Baseline MMP-degraded type I collagens levels	Gene expression signature in serum	 2018 Dec 19	Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients.	 J Immunother Cancer	BACKGROUND: Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated the association between serum biomarkers of collagen and vimentin turnover and outcomes in metastatic melanoma patients treated with the anti-CTLA-4 antibody ipilimumab (IPI).METHODS: Type III collagen formation (PRO-C3), MMP-degraded type I, type III and type IV collagens (C1M, C3M and C4M), and citrullinated and MMP-degraded vimentin (VICM) were measured with ELISAs in serum from metastatic melanoma patients before (n = 66) and 3 weeks after (n = 52) initiation of IPI treatment. Biomarker levels were associated with Disease Control Rate (DCR) and survival outcomes.RESULTS: We found that baseline levels of PRO-C3 (p = 0.011), C1M (p = 0.003), C3M (p = 0.013) and C4M (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified VICM as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.CONCLUSIONS: ECM and tissue remodeling quantified in pre-treatment serum were associated with response and survival outcomes in metastatic melanoma patients treated with IPI. This highlights the importance of addressing the ECM and stromal component non-invasively in future ICI studies.
CANIT0002164	30567561	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	66	N/A	N/A	Its found that baseline levels of Type III collagen formation (PRO-C3) (p = 0.011), MMP-degraded type I collagens (C1M) (p = 0.003), MMP-degraded type III collagens (C3M) (p = 0.013) and MMP-degraded type IV collagens (C4M) (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified citrullinated and MMP-degraded vimentin (VICM)  as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.	N/A	N/A	N/A	MMP-degraded type III collagens ()	Baseline MMP-degraded type III collagens levels	Gene expression signature in serum	 2018 Dec 19	Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients.	 J Immunother Cancer	BACKGROUND: Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated the association between serum biomarkers of collagen and vimentin turnover and outcomes in metastatic melanoma patients treated with the anti-CTLA-4 antibody ipilimumab (IPI).METHODS: Type III collagen formation (PRO-C3), MMP-degraded type I, type III and type IV collagens (C1M, C3M and C4M), and citrullinated and MMP-degraded vimentin (VICM) were measured with ELISAs in serum from metastatic melanoma patients before (n = 66) and 3 weeks after (n = 52) initiation of IPI treatment. Biomarker levels were associated with Disease Control Rate (DCR) and survival outcomes.RESULTS: We found that baseline levels of PRO-C3 (p = 0.011), C1M (p = 0.003), C3M (p = 0.013) and C4M (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified VICM as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.CONCLUSIONS: ECM and tissue remodeling quantified in pre-treatment serum were associated with response and survival outcomes in metastatic melanoma patients treated with IPI. This highlights the importance of addressing the ECM and stromal component non-invasively in future ICI studies.
CANIT0002165	30567561	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	66	N/A	N/A	Its found that baseline levels of Type III collagen formation (PRO-C3) (p = 0.011), MMP-degraded type I collagens (C1M) (p = 0.003), MMP-degraded type III collagens (C3M) (p = 0.013) and MMP-degraded type IV collagens (C4M) (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified citrullinated and MMP-degraded vimentin (VICM)  as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.	N/A	N/A	N/A	MMP-degraded type IV collagens ()	Baseline MMP-degraded type IV levels	Gene expression signature in serum	 2018 Dec 19	Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients.	 J Immunother Cancer	BACKGROUND: Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated the association between serum biomarkers of collagen and vimentin turnover and outcomes in metastatic melanoma patients treated with the anti-CTLA-4 antibody ipilimumab (IPI).METHODS: Type III collagen formation (PRO-C3), MMP-degraded type I, type III and type IV collagens (C1M, C3M and C4M), and citrullinated and MMP-degraded vimentin (VICM) were measured with ELISAs in serum from metastatic melanoma patients before (n = 66) and 3 weeks after (n = 52) initiation of IPI treatment. Biomarker levels were associated with Disease Control Rate (DCR) and survival outcomes.RESULTS: We found that baseline levels of PRO-C3 (p = 0.011), C1M (p = 0.003), C3M (p = 0.013) and C4M (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified VICM as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.CONCLUSIONS: ECM and tissue remodeling quantified in pre-treatment serum were associated with response and survival outcomes in metastatic melanoma patients treated with IPI. This highlights the importance of addressing the ECM and stromal component non-invasively in future ICI studies.
CANIT0002166	30567561	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	66	N/A	N/A	Its found that baseline levels of Type III collagen formation (PRO-C3) (p = 0.011), MMP-degraded type I collagens (C1M) (p = 0.003), MMP-degraded type III collagens (C3M) (p = 0.013) and MMP-degraded type IV collagens (C4M) (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified citrullinated and MMP-degraded vimentin (VICM)  as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.	N/A	N/A	N/A	MMP-degraded type III collagens (); PRO-C3 (P01024); 	High MMP-degraded type III collagens/PRO-C3 ratio	Gene expression signature in serum	 2018 Dec 19	Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients.	 J Immunother Cancer	BACKGROUND: Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated the association between serum biomarkers of collagen and vimentin turnover and outcomes in metastatic melanoma patients treated with the anti-CTLA-4 antibody ipilimumab (IPI).METHODS: Type III collagen formation (PRO-C3), MMP-degraded type I, type III and type IV collagens (C1M, C3M and C4M), and citrullinated and MMP-degraded vimentin (VICM) were measured with ELISAs in serum from metastatic melanoma patients before (n = 66) and 3 weeks after (n = 52) initiation of IPI treatment. Biomarker levels were associated with Disease Control Rate (DCR) and survival outcomes.RESULTS: We found that baseline levels of PRO-C3 (p = 0.011), C1M (p = 0.003), C3M (p = 0.013) and C4M (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified VICM as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.CONCLUSIONS: ECM and tissue remodeling quantified in pre-treatment serum were associated with response and survival outcomes in metastatic melanoma patients treated with IPI. This highlights the importance of addressing the ECM and stromal component non-invasively in future ICI studies.
CANIT0002167	30567561	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	66	N/A	N/A	Its found that baseline levels of Type III collagen formation (PRO-C3) (p = 0.011), MMP-degraded type I collagens (C1M) (p = 0.003), MMP-degraded type III collagens (C3M) (p = 0.013) and MMP-degraded type IV collagens (C4M) (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified citrullinated and MMP-degraded vimentin (VICM)  as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.	N/A	N/A	N/A	PRO-C3 (P01024); 	Baseline PRO-C3 levels	Gene expression signature in serum	 2018 Dec 19	Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients.	 J Immunother Cancer	BACKGROUND: Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated the association between serum biomarkers of collagen and vimentin turnover and outcomes in metastatic melanoma patients treated with the anti-CTLA-4 antibody ipilimumab (IPI).METHODS: Type III collagen formation (PRO-C3), MMP-degraded type I, type III and type IV collagens (C1M, C3M and C4M), and citrullinated and MMP-degraded vimentin (VICM) were measured with ELISAs in serum from metastatic melanoma patients before (n = 66) and 3 weeks after (n = 52) initiation of IPI treatment. Biomarker levels were associated with Disease Control Rate (DCR) and survival outcomes.RESULTS: We found that baseline levels of PRO-C3 (p = 0.011), C1M (p = 0.003), C3M (p = 0.013) and C4M (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified VICM as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.CONCLUSIONS: ECM and tissue remodeling quantified in pre-treatment serum were associated with response and survival outcomes in metastatic melanoma patients treated with IPI. This highlights the importance of addressing the ECM and stromal component non-invasively in future ICI studies.
CANIT0002168	30567561	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	66	N/A	N/A	Its found that baseline levels of Type III collagen formation (PRO-C3) (p = 0.011), MMP-degraded type I collagens (C1M) (p = 0.003), MMP-degraded type III collagens (C3M) (p = 0.013) and MMP-degraded type IV collagens (C4M) (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified citrullinated and MMP-degraded vimentin (VICM)  as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.	N/A	N/A	N/A	VICM (P08670); 	VICM expression levels	Gene expression signature on/in tumor cell	 2018 Dec 19	Non-invasive biomarkers derived from the extracellular matrix associate with response to immune checkpoint blockade (anti-CTLA-4) in metastatic melanoma patients.	 J Immunother Cancer	BACKGROUND: Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated the association between serum biomarkers of collagen and vimentin turnover and outcomes in metastatic melanoma patients treated with the anti-CTLA-4 antibody ipilimumab (IPI).METHODS: Type III collagen formation (PRO-C3), MMP-degraded type I, type III and type IV collagens (C1M, C3M and C4M), and citrullinated and MMP-degraded vimentin (VICM) were measured with ELISAs in serum from metastatic melanoma patients before (n = 66) and 3 weeks after (n = 52) initiation of IPI treatment. Biomarker levels were associated with Disease Control Rate (DCR) and survival outcomes.RESULTS: We found that baseline levels of PRO-C3 (p = 0.011), C1M (p = 0.003), C3M (p = 0.013) and C4M (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified VICM as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.CONCLUSIONS: ECM and tissue remodeling quantified in pre-treatment serum were associated with response and survival outcomes in metastatic melanoma patients treated with IPI. This highlights the importance of addressing the ECM and stromal component non-invasively in future ICI studies.
CANIT0002169	30568021	Clinical research	Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	53	N/A	Retrospective analysis	The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Outcomes and Toxicities of Programmed Death-1 (PD-1) Inhibitors in Hodgkin Lymphoma Patients in the United States: A Real-World, Multicenter Retrospective Analysis.	 Oncologist	BACKGROUND: Although classical Hodgkin lymphoma (cHL) is highly curable, 20%-30% of patients will not be cured with conventional treatments. The programmed death-1 (PD-1) inhibitors (PD-1i) nivolumab and pembrolizumab have been Food and Drug Administration-approved for relapsed/refractory (R/R) cHL. There is limited data on the real-world experience with PD-1i in cHL and it is unknown whether fewer selected patients treated with PD-1i derive benefits similar to those observed in published trials.MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of R/R cHL patients treated with PD-1i in the nontrial setting. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) in this population. Secondary objectives were to characterize response rates, toxicities, discontinuation patterns, and post-PD-1i therapies.RESULTS: The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses.CONCLUSION: To our knowledge, this analysis is the first describing real-world experience with PD-1i in cHL patients in the U.S. Here, we demonstrate similar response rates compared to prior studies. The toxicity profile of PD-1i was similar to that seen in previous studies; we further describe toxicity patterns in those with prior autoimmune disease or allogeneic transplant. Post-PD-1i systemic therapies appear active. These results support the effectiveness and tolerability of PD-1i therapy in R/R cHL in a real-world setting.IMPLICATIONS FOR PRACTICE: Two PD-1 inhibitors have recently been approved for patients with relapsed/refractory classical Hodgkin lymphoma based on results from nonrandomized clinical trials. However, to date, there have been no studies evaluating the effectiveness and toxicity profile of these drugs in the real-world setting in the U.S. The present study demonstrates that patients treated in a real-world context experience similar rates of overall effectiveness compared with published clinical trials. Patients who discontinue PD-1 inhibitors may experience clinical responses to subsequent treatment with systemic chemotherapy or targeted therapy. This study provides clinicians with further insight into the effectiveness and tolerability of PD-1 inhibitors and suggests that when patients progress while on these drugs, conventional systemic chemotherapy may be an effective treatment option.
CANIT0002170	30568305	Clinical research	Glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	Neoantigen (NCIT:C120475); 	Neoantigen; 	Personalized neoantigen-targeting vaccines	N/A	Tumor vaccine	N/A	10	N/A	Phase I/Ib	Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jan	Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial.	 Nature	Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically 'cold' tumour microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.
CANIT0002171	30576970	Clinical research	Recurrent/metastatic head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	111	N/A	International, multi-institutional, single-arm, phase II HAWK study (NCT02207530)	Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7).	Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade >=3); none led to death.	N/A	N/A	HPV (NCIT:C14226); 	HPV-positive	Microbiota	 2019 Jan	Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ¡Ý25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy.	 Eur J Cancer	BACKGROUND: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC.PATIENTS AND METHODS: Immunotherapy-na ve patients with confirmed PD-L1-high tumour cell expression (defined as patients with >=25% of tumour cells expressing PD-L1 [TC >= 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS).RESULTS: Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade >=3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up.CONCLUSION: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.
CANIT0002172	30577837	Clinical research	Non-small-cell lung carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab or nivolumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Durvalumab (DB11714); nivolumab (DB09035); 	1668	1476	Meta-analysis	Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS.	In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2018 Dec 22	Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis.	 J Immunother Cancer	BACKGROUND: Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors.METHODS: We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.RESULTS: Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).CONCLUSIONS: PD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.
CANIT0002173	30577837	Clinical research	Non-small-cell lung carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab or nivolumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Durvalumab (DB11714); nivolumab (DB09035); 	1668	1476	Meta-analysis	Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS.	In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Dec 22	Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis.	 J Immunother Cancer	BACKGROUND: Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors.METHODS: We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.RESULTS: Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).CONCLUSIONS: PD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.
CANIT0002174	30577837	Clinical research	Non-small-cell lung carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab or nivolumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Durvalumab (DB11714); nivolumab (DB09035); 	1668	1476	Meta-analysis	Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS.	In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2018 Dec 22	Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis.	 J Immunother Cancer	BACKGROUND: Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors.METHODS: We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.RESULTS: Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).CONCLUSIONS: PD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.
CANIT0002175	30577837	Clinical research	Non-small-cell lung carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab or nivolumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Durvalumab (DB11714); nivolumab (DB09035); 	1668	1476	Meta-analysis	Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS.	In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	 2018 Dec 22	Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis.	 J Immunother Cancer	BACKGROUND: Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors.METHODS: We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.RESULTS: Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).CONCLUSIONS: PD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.
CANIT0002176	30577837	Clinical research	Non-small-cell lung carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab or nivolumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Durvalumab (DB11714); nivolumab (DB09035); 	1668	1476	Meta-analysis	Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS.	In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).	N/A	N/A	Treatment history (NCIT:C160179); 	Types of checkpoint inhibitor	Exposure factors/status	 2018 Dec 22	Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis.	 J Immunother Cancer	BACKGROUND: Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors.METHODS: We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.RESULTS: Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).CONCLUSIONS: PD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.
CANIT0002177	30578473	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	221	N/A	Retrospective, multicentre and observational study	Squamous tumours accounted for 59.7% of the total, and 78.7% of the patients presented a time since platinum therapy (TPT) > 6 months. The mean nivolumab dose was 216 mg (SD 211), and the treatment duration was 7.0 months (95% CI 5.8-8.1). The median PFS was 5.3 months (95% CI 3.2-7.3), and OS was 9.7 months (95% CI 7.6-11.8). The median PFS and OS values were statistically significantly superior for patients with an ECOG score of 0-1 and for patients with a TPT > 6 months. The median OS was also statistically significantly superior for patients with non-squamous histology. The cost of nivolumab per patient was €19,910.00 (SD 19,369), and the cost per LYG was €110,026.00 (€77,557.00-€231,171.00).	Regarding safety, 71% of the patients presented AEs of any grade, and in 18.6%, the nivolumab treatment had to be delayed or discontinued.	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Feb	A multicentre observational study of the effectiveness, safety and economic impact of nivolumab on non-small-cell lung cancer in real clinical practice.	 Int J Clin Pharm	Background Immunotherapy has become a standard treatment for lung cancer; however, the high cost makes it necessary to assess health outcomes. Objective The aim of this study was to evaluate the effectiveness, safety and economic cost of nivolumab in real-world clinical practice. Setting Fifteen regional and academic hospitals from Spain participated in this study. Methods This study was a retrospective, multicentre and observational study involving patients who experienced progression after first-line therapy for non-small-cell lung cancer and were treated with nivolumab between January 2016 and July 2017. Effectiveness and safety were evaluated by the oncologist, and the data from the electronic clinical records of the patients were collected by the research team. Economic cost was calculated using the cost of acquiring nivolumab for the public health system. Main outcome measures Effectiveness variables were overall survival (OS) and progression-free survival (PFS). The safety variable was the incidence of adverse events (AEs), and the cost per life-year gained (LYG) was the economic variable. Results A total of 221 patients were enrolled (83.7% men). The mean age was 64.5 years, and 84.6% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0-1. Squamous tumours accounted for 59.7% of the total, and 78.7% of the patients presented a time since platinum therapy (TPT) > 6 months. The mean nivolumab dose was 216 mg (SD 211), and the treatment duration was 7.0 months (95% CI 5.8-8.1). The median PFS was 5.3 months (95% CI 3.2-7.3), and OS was 9.7 months (95% CI 7.6-11.8). The median PFS and OS values were statistically significantly superior for patients with an ECOG score of 0-1 and for patients with a TPT > 6 months. The median OS was also statistically significantly superior for patients with non-squamous histology. Regarding safety, 71% of the patients presented AEs of any grade, and in 18.6%, the nivolumab treatment had to be delayed or discontinued. The cost of nivolumab per patient was €19,910.00 (SD 19,369), and the cost per LYG was €110,026.00 (€77,557.00-€231,171.00). Conclusions This study confirms that the efficacy and safety of nivolumab treatment in a real population are comparable to the results obtained in clinical trials. A greater clinical benefit of nivolumab therapy was observed in patients with an ECOG score of 0-1, a TPT > 6 months or non-squamous histology. Despite the benefit observed, the cost per LYG is above the threshold of efficiency established by public health institutes.
CANIT0002178	30578473	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	221	N/A	Retrospective, multicentre and observational study	Squamous tumours accounted for 59.7% of the total, and 78.7% of the patients presented a time since platinum therapy (TPT) > 6 months. The mean nivolumab dose was 216 mg (SD 211), and the treatment duration was 7.0 months (95% CI 5.8-8.1). The median PFS was 5.3 months (95% CI 3.2-7.3), and OS was 9.7 months (95% CI 7.6-11.8). The median PFS and OS values were statistically significantly superior for patients with an ECOG score of 0-1 and for patients with a TPT > 6 months. The median OS was also statistically significantly superior for patients with non-squamous histology. The cost of nivolumab per patient was €19,910.00 (SD 19,369), and the cost per LYG was €110,026.00 (€77,557.00-€231,171.00).	Regarding safety, 71% of the patients presented AEs of any grade, and in 18.6%, the nivolumab treatment had to be delayed or discontinued.	N/A	N/A	Treatment history (NCIT:C160179); 	Time since platinum therapy (TPT) > 6 months	Disease status	 2019 Feb	A multicentre observational study of the effectiveness, safety and economic impact of nivolumab on non-small-cell lung cancer in real clinical practice.	 Int J Clin Pharm	Background Immunotherapy has become a standard treatment for lung cancer; however, the high cost makes it necessary to assess health outcomes. Objective The aim of this study was to evaluate the effectiveness, safety and economic cost of nivolumab in real-world clinical practice. Setting Fifteen regional and academic hospitals from Spain participated in this study. Methods This study was a retrospective, multicentre and observational study involving patients who experienced progression after first-line therapy for non-small-cell lung cancer and were treated with nivolumab between January 2016 and July 2017. Effectiveness and safety were evaluated by the oncologist, and the data from the electronic clinical records of the patients were collected by the research team. Economic cost was calculated using the cost of acquiring nivolumab for the public health system. Main outcome measures Effectiveness variables were overall survival (OS) and progression-free survival (PFS). The safety variable was the incidence of adverse events (AEs), and the cost per life-year gained (LYG) was the economic variable. Results A total of 221 patients were enrolled (83.7% men). The mean age was 64.5 years, and 84.6% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0-1. Squamous tumours accounted for 59.7% of the total, and 78.7% of the patients presented a time since platinum therapy (TPT) > 6 months. The mean nivolumab dose was 216 mg (SD 211), and the treatment duration was 7.0 months (95% CI 5.8-8.1). The median PFS was 5.3 months (95% CI 3.2-7.3), and OS was 9.7 months (95% CI 7.6-11.8). The median PFS and OS values were statistically significantly superior for patients with an ECOG score of 0-1 and for patients with a TPT > 6 months. The median OS was also statistically significantly superior for patients with non-squamous histology. Regarding safety, 71% of the patients presented AEs of any grade, and in 18.6%, the nivolumab treatment had to be delayed or discontinued. The cost of nivolumab per patient was €19,910.00 (SD 19,369), and the cost per LYG was €110,026.00 (€77,557.00-€231,171.00). Conclusions This study confirms that the efficacy and safety of nivolumab treatment in a real population are comparable to the results obtained in clinical trials. A greater clinical benefit of nivolumab therapy was observed in patients with an ECOG score of 0-1, a TPT > 6 months or non-squamous histology. Despite the benefit observed, the cost per LYG is above the threshold of efficiency established by public health institutes.
CANIT0002179	30578473	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	221	N/A	Retrospective, multicentre and observational study	Squamous tumours accounted for 59.7% of the total, and 78.7% of the patients presented a time since platinum therapy (TPT) > 6 months. The mean nivolumab dose was 216 mg (SD 211), and the treatment duration was 7.0 months (95% CI 5.8-8.1). The median PFS was 5.3 months (95% CI 3.2-7.3), and OS was 9.7 months (95% CI 7.6-11.8). The median PFS and OS values were statistically significantly superior for patients with an ECOG score of 0-1 and for patients with a TPT > 6 months. The median OS was also statistically significantly superior for patients with non-squamous histology. The cost of nivolumab per patient was €19,910.00 (SD 19,369), and the cost per LYG was €110,026.00 (€77,557.00-€231,171.00).	Regarding safety, 71% of the patients presented AEs of any grade, and in 18.6%, the nivolumab treatment had to be delayed or discontinued.	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	 2019 Feb	A multicentre observational study of the effectiveness, safety and economic impact of nivolumab on non-small-cell lung cancer in real clinical practice.	 Int J Clin Pharm	Background Immunotherapy has become a standard treatment for lung cancer; however, the high cost makes it necessary to assess health outcomes. Objective The aim of this study was to evaluate the effectiveness, safety and economic cost of nivolumab in real-world clinical practice. Setting Fifteen regional and academic hospitals from Spain participated in this study. Methods This study was a retrospective, multicentre and observational study involving patients who experienced progression after first-line therapy for non-small-cell lung cancer and were treated with nivolumab between January 2016 and July 2017. Effectiveness and safety were evaluated by the oncologist, and the data from the electronic clinical records of the patients were collected by the research team. Economic cost was calculated using the cost of acquiring nivolumab for the public health system. Main outcome measures Effectiveness variables were overall survival (OS) and progression-free survival (PFS). The safety variable was the incidence of adverse events (AEs), and the cost per life-year gained (LYG) was the economic variable. Results A total of 221 patients were enrolled (83.7% men). The mean age was 64.5 years, and 84.6% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0-1. Squamous tumours accounted for 59.7% of the total, and 78.7% of the patients presented a time since platinum therapy (TPT) > 6 months. The mean nivolumab dose was 216 mg (SD 211), and the treatment duration was 7.0 months (95% CI 5.8-8.1). The median PFS was 5.3 months (95% CI 3.2-7.3), and OS was 9.7 months (95% CI 7.6-11.8). The median PFS and OS values were statistically significantly superior for patients with an ECOG score of 0-1 and for patients with a TPT > 6 months. The median OS was also statistically significantly superior for patients with non-squamous histology. Regarding safety, 71% of the patients presented AEs of any grade, and in 18.6%, the nivolumab treatment had to be delayed or discontinued. The cost of nivolumab per patient was €19,910.00 (SD 19,369), and the cost per LYG was €110,026.00 (€77,557.00-€231,171.00). Conclusions This study confirms that the efficacy and safety of nivolumab treatment in a real population are comparable to the results obtained in clinical trials. A greater clinical benefit of nivolumab therapy was observed in patients with an ECOG score of 0-1, a TPT > 6 months or non-squamous histology. Despite the benefit observed, the cost per LYG is above the threshold of efficiency established by public health institutes.
CANIT0002180	30587403	Case report	Metastatic Castration-Resistant Prostate Cancer	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus enzalutamide	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); enzalutamide (DB08899); 	1	N/A	Case	We describe a patient with metastatic castration-resistant prostate cancer with disease that progressed while receiving enzalutamide therapy. Disease had a favorable response to pembrolizumab and enzalutamide despite the lack of mismatch-repair deficiency, homologous recombination deficiency, or CDK12 inactivation.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Favorable Response to Pembrolizumab in a Patient With Metastatic Castration-Resistant Prostate Cancer Progressing While Receiving Enzalutamide.	 Clin Genitourin Cancer	Unable to provide
CANIT0002181	30591082	Clinical research	Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab or ipilimumab or pembrolizumab or nivolumab or tremelimumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); tremelimumab (DB11771); 	24	N/A	Retrospective analysis	Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1-22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1-40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 ¡Á 10- 6).	N/A	N/A	N/A	BRD8 (Q9H0E9); PBRM1 (Q86U86); 	PBRM1 and BRD8 mutational status	Mutational status	 2018 Dec 27	Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders.	 J Immunother Cancer	BACKGROUND: Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population.PATIENTS AND METHODS: This multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients.RESULTS: Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1-22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1-40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 ¡Á 10- 6).CONCLUSIONS: MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.
CANIT0002182	30600905	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	23	N/A	N/A	Baseline skeletal muscle mass (SMM) was evaluated using gender-specific cutoffs for skeletal muscle index in NSCLC patients administered immunotherapy with nivolumab to evaluate its possible correlations with clinical outcomes.  Nine patients (39.1%) had low SMM. Among patients with baseline low and non-low SMM, median progression free survival was 3.1 and 3.8 months, respectively (P = 0.0560), while median overall survival was 4.1 and 13 months, respectively (P = 0.2866). This hypothesis-generating preliminary report offers the opportunity to speculate about the negative influence of sarcopenia on immune response. In our opinion, nutritional status could affect the clinical outcomes of immunotherapy, even if we cannot make definitive conclusions here.	N/A	N/A	N/A	Skeletal muscle mass (MP:0004818); 	Skeletal muscle mass	Personal feature	 2019 Feb	Predictive value of skeletal muscle mass for immunotherapy with nivolumab in non-small cell lung cancer patients: A hypothesis-generator preliminary report.	 Thorac Cancer	Sarcopenia represents one of the hallmarks of all chronic disease, including non-small cell lung cancer (NSCLC). A computed tomography scan is an easy modality to estimate the skeletal muscle mass through cross-sectional image analysis at the level of the third lumbar vertebra (L3). Baseline skeletal muscle mass (SMM) was evaluated using gender-specific cutoffs for skeletal muscle index in NSCLC patients administered immunotherapy with nivolumab to evaluate its possible correlations with clinical outcomes. From April 2015 to August 2018, 23 stage IV NSCLC patients were eligible for image analysis. Nine patients (39.1%) had low SMM. Among patients with baseline low and non-low SMM, median progression free survival was 3.1 and 3.8 months, respectively (P = 0.0560), while median overall survival was 4.1 and 13 months, respectively (P = 0.2866). This hypothesis-generating preliminary report offers the opportunity to speculate about the negative influence of sarcopenia on immune response. In our opinion, nutritional status could affect the clinical outcomes of immunotherapy, even if we cannot make definitive conclusions here. Further studies on the topic are required.
CANIT0002183	30614126	Case report	Recurrent or metastatic head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Case	Our case reports achieved an unforeseen response to conventional therapies supporting the hypothesis of restored responses to conventional therapies after immunotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Unexpected response with palliative conventional therapy in head and neck squamous cell carcinoma after anti-programmed death-1 progression.	 Head Neck	BACKGROUND: The application of anti-programmed death-1 (PD-1) therapies for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has found promising results. It is the first second-line therapy in this setting to impact on prognosis. The studies demonstrated overall response rates in the range of 20%. Therefore, HNSCC showed 60%-80% progression at first evaluation with better overall survival, suggesting regained efficacy of treatments given thereafter.METHODS: We report three clinical cases treated with anti-PD-1 after platinum-based chemotherapy.RESULTS: Our case reports achieved an unforeseen response to conventional therapies supporting the hypothesis of restored responses to conventional therapies after immunotherapy.CONCLUSIONS: We believe that the inhibition of the PD-1/PD-ligand 1 checkpoint may synergize with both chemotherapy or radiotherapy through immunologic interplay, reversing the HNSCC-induced immune suppression.
CANIT0002184	30616146	Clinical research	Metastatic renal cell carcinomas	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Nivolumab-ipilimumab failure followed by axitinib	N/A	Immune checkpoint therapy followed by Target therapy	Nivolumab (DB09035); axitinib (DB06626); 	33	N/A	As part of Checkmate 214 study	This is the first report of outcomes with tyrosine kinase inhibitor (TKI), after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>=6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months.	Toxicity was as expected: 42% developed at least one toxicity grade >=3.	N/A	N/A	Performance status (NCIT:C20641); 	Nivolumab-ipilimumab failure	Disease status	 2019 Feb	Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma.	 Eur J Cancer	BACKGROUND: Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for na ve patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear.METHODS: Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected.RESULTS: Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>=6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade >=3.CONCLUSION: This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.
CANIT0002185	30616146	Clinical research	Metastatic renal cell carcinomas	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Nivolumab-ipilimumab failure followed by cabozantinib	N/A	Immune checkpoint therapy followed by Target therapy	Nivolumab (DB09035); cabozantinib (DB08875); 	33	N/A	As part of Checkmate 214 study	This is the first report of outcomes with tyrosine kinase inhibitor (TKI), after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>=6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months.	Toxicity was as expected: 42% developed at least one toxicity grade >=3.	N/A	N/A	Performance status (NCIT:C20641); 	Nivolumab-ipilimumab failure	Disease status	 2019 Feb	Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma.	 Eur J Cancer	BACKGROUND: Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for na ve patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear.METHODS: Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected.RESULTS: Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>=6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade >=3.CONCLUSION: This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.
CANIT0002186	30616146	Clinical research	Metastatic renal cell carcinomas	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Nivolumab-ipilimumab failure followed by pazopanib	N/A	Immune checkpoint therapy followed by Target therapy	Nivolumab (DB09035); pazopanib (DB06589); 	33	N/A	As part of Checkmate 214 study	This is the first report of outcomes with tyrosine kinase inhibitor (TKI), after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>=6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months.	Toxicity was as expected: 42% developed at least one toxicity grade >=3.	N/A	N/A	Performance status (NCIT:C20641); 	Nivolumab-ipilimumab failure	Disease status	 2019 Feb	Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma.	 Eur J Cancer	BACKGROUND: Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for na ve patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear.METHODS: Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected.RESULTS: Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>=6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade >=3.CONCLUSION: This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.
CANIT0002187	30616146	Clinical research	Metastatic renal cell carcinomas	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Nivolumab-ipilimumab failure followed by sunitinib	N/A	Immune checkpoint therapy followed by Target therapy	Nivolumab (DB09035); sunitinib (DB01268); 	33	N/A	As part of Checkmate 214 study	This is the first report of outcomes with tyrosine kinase inhibitor (TKI), after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>=6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months.	Toxicity was as expected: 42% developed at least one toxicity grade >=3.	N/A	N/A	Performance status (NCIT:C20641); 	Nivolumab-ipilimumab failure	Disease status	 2019 Feb	Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma.	 Eur J Cancer	BACKGROUND: Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for na ve patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear.METHODS: Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected.RESULTS: Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>=6 months) with 8 versus 5 months for short responder (<6 months) (p = 0.03). OS rate was 54% at 12 months. Toxicity was as expected: 42% developed at least one toxicity grade >=3.CONCLUSION: This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence.
CANIT0002188	30622030	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab or chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Ipilimumab (DB06186); nivolumab (DB09035); 	3308	N/A	Meta-analysis	For combination regimens compared to monotherapy, the pooled HR for overall survival (OS) was 0.67 (95%CI 0.53-0.81) and for progression-free survival (PFS) was 0.56 (95%CI 0.41-0.71). For CTLA-4 inhibitors plus PD-1 inhibitors, the combined one-year OS rate (OSR1y), six-month PFS rate (PFSR6m) and disease control rate (DCR) were 64.0% (95%CI: 49.6%-78.4%), 56.4% (95%CI: 50.1%-62.7%) and 69.9% (95%CI: 65.1%-74.7%), respectively. For CTLA-4 inhibitors plus chemotherapy, the combined OSR1y, PFSR6m and DCR were 35.2% (95%CI: 25.4%-45.0%), 54.6% (95%CI: 42.7%-66.60%) and 33.5% (95%CI: 28.0%-38.9%), respectively.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Efficacy and safety of CTLA-4 inhibitors combined with PD-1 inhibitors or chemotherapy in patients with advanced melanoma.	 Int Immunopharmacol	BACKGROUND: Although immune checkpoint inhibitor monotherapy has demonstrated significant efficacy in advanced melanoma, no study has systematically evaluated the efficacy and safety of the combination regimens. In this study, we conduct a comprehensive meta-analysis to explore the efficacy and safety of CTLA-4 inhibitors combined with PD-1 inhibitors or chemotherapy in advanced melanoma.METHODS: We performed a systematic search of Medline, PubMed, Embase and Web of Science for relevant clinical trials. The primary objective was to explore the efficacy and safety of combination regimens compared to monotherapy. The secondary objective was to compare the difference in efficacy between CTLA-4 inhibitors plus PD-1 inhibitors and CTLA-4 inhibitors plus chemotherapy.RESULTS: A total of 12 trials involving 3308 patients were included for our meta-analysis. For combination regimens compared to monotherapy, the pooled HR for overall survival (OS) was 0.67 (95%CI 0.53-0.81) and for progression-free survival (PFS) was 0.56 (95%CI 0.41-0.71). For CTLA-4 inhibitors plus PD-1 inhibitors, the combined one-year OS rate (OSR1y), six-month PFS rate (PFSR6m) and disease control rate (DCR) were 64.0% (95%CI: 49.6%-78.4%), 56.4% (95%CI: 50.1%-62.7%) and 69.9% (95%CI: 65.1%-74.7%), respectively. For CTLA-4 inhibitors plus chemotherapy, the combined OSR1y, PFSR6m and DCR were 35.2% (95%CI: 25.4%-45.0%), 54.6% (95%CI: 42.7%-66.60%) and 33.5% (95%CI: 28.0%-38.9%), respectively.CONCLUSIONS: Combination regimens significantly improved OS and PFS of advanced melanoma patients compared to monotherapy. An acceptable safety profile was observed in both CTLA-4 inhibitors plus PD-1 inhibitors and CTLA-4 inhibitors plus chemotherapy. A comparison of these two combination regimens showed that patients who received CTLA-4 inhibitors plus PD-1 inhibitors had a better therapeutic effect compared to those receiving CTLA-4 inhibitors plus chemotherapy. Further randomized clinical trials are urgently required to validate our results.
CANIT0002189	30637917	Clinical research	Recurrent or refractory childhood Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	42	N/A	N/A	At the time of diagnosis, PD-1 expression was low (1-3% of intratumoral lymphocytes labeled) in <20% of cases, whereas PD-L1 was expressed by tumor cells in all cases, and strongly (>=50%) in most cases. There were no significant differences in the expression levels of the two checkpoint molecules between the groups. Initial biopsies showed strong expression of PD-L1, whereas expression of PD-1 was rare.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 May	Expression of PD-1/PD-L1 in children's classical Hodgkin lymphomas.	 Pediatr Blood Cancer	BACKGROUND: Although a prognosis of recurrent or refractory childhood Hodgkin lymphoma (HL) is associated with poor outcomes despite intensive therapy, the immune checkpoint inhibitors PD-1/PD-L1 appear to be therapeutic alternatives for advanced adult cases. However, these pharmacotherapies are yet to be studied in a pediatric population.PROCEDURE: The present study measured the expression of PD-1/PD-L1 in diagnostic samples of children with classical HL, according to the disease course. This study included two groups of patients treated at the Department of Pediatric Oncology, Bordeaux University Hospital-a group of cured or in-remission cases and a group of relapsed or refractory cases. Immunohistochemical analyses of anti-PD-1 and anti-PD-L1 (clone 28-8, companion test for nivolumab) were performed on baseline and follow-up biopsies.RESULTS: Of the 42 included patients, 31 were cured or in remission and 11 were categorized as relapsed or refractory. At the time of diagnosis, PD-1 expression was low (1-3% of intratumoral lymphocytes labeled) in <20% of cases, whereas PD-L1 was expressed by tumor cells in all cases, and strongly (>=50%) in most cases. There were no significant differences in the expression levels of the two checkpoint molecules between the groups. Initial biopsies showed strong expression of PD-L1, whereas expression of PD-1 was rare.CONCLUSIONS: The identical labeling profiles of the cured and relapsed/refractory patients suggest that comparable responses to inhibitors of the PD1/PDL1 immunological checkpoints could be expected in patients undergoing first-, second-, or third-line therapy.
CANIT0002190	30638772	Case report	Metastatic giant bone cell tumor	Giant bone cell tumor	EFO:0007176	Bone	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We present the first reported case showing metastatic giant bone cell tumor being treated successfully with pembrolizumab after failing prior tyrosine kinase inhibitor therapy. Of note, the patient developed multiple systemic effects associated with checkpoint inhibitor use. One year after starting the checkpoint inhibitor (ICI), the patient also developed hepatitis that was confirmed by liver biopsy and pathology to be, in part, due to drug-mediated toxicity similar to prior ICI toxicity cases that have been reported. Additionally, although the patient had vascular risk factors (hypertension, diabetes and smoking), it was notable from a cardiology perspective that the patient developed 2 subsequent non-ST-elevation myocardial infarctions, with rapid progression of stenosis of the left circumflex artery 2 months apart. The first left heart catheterization showing minimal disease of the left circumflex, but 2 months later, presenting with chest pain, a repeat left heart catheterization showed significant stenosis of the left proximal circumflex, raising the possibilities that either ICI can promote plaque rupture and/or accelerated atherosclerosis; both phenomena have been shown to occur in animal models. The patient also developed thyroiditis with subsequent hypothyroidism, now on thyroid replacement from checkpoint inhibitor use.	Hepatotoxicity and Recurrent NSTEMI	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Hepatotoxicity and Recurrent NSTEMI While on Pembrolizumab for Metastatic Giant Cell Bone Tumor.	 Am J Med Sci	We present the first reported case showing metastatic giant bone cell tumor being treated successfully with pembrolizumab after failing prior tyrosine kinase inhibitor therapy. Of note, the patient developed multiple systemic effects associated with checkpoint inhibitor use. One year after starting the checkpoint inhibitor (ICI), the patient also developed hepatitis that was confirmed by liver biopsy and pathology to be, in part, due to drug-mediated toxicity similar to prior ICI toxicity cases that have been reported. Additionally, although the patient had vascular risk factors (hypertension, diabetes and smoking), it was notable from a cardiology perspective that the patient developed 2 subsequent non-ST-elevation myocardial infarctions, with rapid progression of stenosis of the left circumflex artery 2 months apart. The first left heart catheterization showing minimal disease of the left circumflex, but 2 months later, presenting with chest pain, a repeat left heart catheterization showed significant stenosis of the left proximal circumflex, raising the possibilities that either ICI can promote plaque rupture and/or accelerated atherosclerosis; both phenomena have been shown to occur in animal models. The patient also developed thyroiditis with subsequent hypothyroidism, now on thyroid replacement from checkpoint inhibitor use. This case demonstrates the multiorgan adverse effects this new antioncologic agent can have and yet also its promising antitumor effects. Awareness of the side effects among primary care doctors and all specialists will be helpful in managing these potential side effects and research will help elucidate ways to prevent the adverse effects.
CANIT0002191	30642544	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	31	N/A	Retrospective analysis	KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	High baseline circulating NK and PD-1(+)CD8(+) cells	Gene expression signature on/in immune cell	 2019 Jan	The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC.	 Lung Cancer	INTRODUCTION: A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters.METHODS: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3¦Æ, Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes.RESULTS: KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg.CONCLUSION: The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy.
CANIT0002192	30642544	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	31	N/A	Retrospective analysis	KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	High circulating NK and PD-1(+)CD8(+) cells combined with low PD-1/CD8(+) ratio in tumor-infiltrating effector T-cells	Tumor-infiltrating immune cell	 2019 Jan	The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC.	 Lung Cancer	INTRODUCTION: A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters.METHODS: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3¦Æ, Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes.RESULTS: KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg.CONCLUSION: The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy.
CANIT0002193	30642544	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	31	N/A	Retrospective analysis	KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Higher number of phenotypically active NK and PD-1(+)CD8(+) cells	Gene expression signature on/in immune cell	 2019 Jan	The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC.	 Lung Cancer	INTRODUCTION: A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters.METHODS: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3¦Æ, Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes.RESULTS: KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg.CONCLUSION: The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy.
CANIT0002194	30642544	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	31	N/A	Retrospective analysis	KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Low PD-1 expression in CD8 (+) tumor-infiltrating effector T-cells	Gene expression signature on/in immune cell	 2019 Jan	The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC.	 Lung Cancer	INTRODUCTION: A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters.METHODS: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3¦Æ, Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes.RESULTS: KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg.CONCLUSION: The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy.
CANIT0002195	30642550	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Standard-of-care chemotherapy	Immune checkpoint therapy	Pembrolizumab (DB09037); 	N/A	N/A	A randomized, open-label, phase III trial	Pembrolizumab appears cost-effective versus SoC chemotherapy for first-line treatment of PD-L1-positive (50%) metastatic NSCLC patients in France, assuming willingness-to-pay under 100,000€/QALY (OECD threshold in the discussion section).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Cost-effectiveness analysis of pembrolizumab versus standard-of-care chemotherapy for first-line treatment of PD-L1 positive (>50%) metastatic squamous and non-squamous non-small cell lung cancer in France.	 Lung Cancer	INTRODUCTION: In the KEYNOTE-024 trial, pembrolizumab demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) versus Standard-of-Care (SoC) platinum-based doublets for first-line treatment of PD-L1 -positive (>=50%) metastatic Non-Small-Cell Lung Cancer (NSCLC) patients with no EGFR mutations or ALK translocations. This study aims to assess the cost-effectiveness of pembrolizumab versus SoC platinum-based chemotherapy from the French healthcare system perspective.METHODS: A three-state partitioned-survival model was adapted to project outcomes and costs of squamous and non-squamous NSCLC patients respectively, over a 10-year time horizon. Clinical and utility data were collected from the trial. A network meta-analysis was performed to consider platinum-based triplets also used for non-squamous NSCLC. Direct medical costs were considered based on ressources identified from the trial and literature. Costs and outcomes were discounted at 4% per year. Incremental cost-effectiveness ratios (ICERs) were calculated as cost per Life Year (LY) and cost per Quality-Adjusted Life Year (QALY). Sensitivity and scenario analyses were performed to assess the robustness of results.RESULTS: For squamous NSCLC, pembrolizumab was projected to increase life expectancy of patients by 0.93 LY (11 months), and 0.74 QALY (9 months) for an incremental cost of €62,032 compared with platinum-based doublets. The ICER of pembrolizumab versus platinum-based doublets was €66,825/LY and €84,097/QALY. For non-squamous NSCLC, pembrolizumab was projected to increase life expectancy of patients by 0.85-1.32 LYs (10.2-15.8 months) and 0.64-1.02 QALYs (7.7-12.2 months) for an incremental cost varying from €-14,947-+47,064 depending on the specific comparator. The ICER of pembrolizumab versus platinum-based chemotherapy with paclitaxel plus bevacizumab was €62,846/LY and €78,729/QALY; regimens including pemetrexed were dominated. Results were most sensitive to extrapolations of survival outcomes and assumptions for continued effectiveness and treatment duration of pembrolizumab.CONCLUSIONS: Pembrolizumab appears cost-effective versus SoC chemotherapy for first-line treatment of PD-L1-positive (50%) metastatic NSCLC patients in France, assuming willingness-to-pay under 100,000€/QALY (OECD threshold in the discussion section).
CANIT0002196	30654225	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	76	N/A	N/A	Responders (n = 15) had higher mean trough concentrations than patients with progression (n = 33): 47% higher after 2 weeks (p = 0.001), 53% higher after 4 weeks (p = 0.008) and 73% higher after 10 weeks (p = 0.002). Higher trough concentrations were associated with longer OS (p = 0.001).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer.	 Eur J Cancer	INTRODUCTION: Nivolumab treatment is subject to large interpatient variability in both efficacy and toxicity, which may partly be explained by differences in nivolumab exposure. Exposure-response relationships in regular healthcare have not been extensively investigated for nivolumab. Therefore, we aimed to identify possible exposure-response relationships in nivolumab-treated patients with non-small-cell lung cancer (NSCLC).METHODS: Patients with NSCLC who started second-line nivolumab therapy (3 mg/kg Q2W) between May 5th 2016 and August 1st 2017, and from whom serial blood samples, toxicity data and outcome data were prospectively collected, were included. Follow-up was carried out until November 1st 2017. Patients were classified according to the best overall response (BOR) based on the Response Evaluation Criteria in Solid Tumours, v1.1, and toxicities according to the Common Terminology Criteria for Adverse Events. Nivolumab trough concentrations were measured after 2, 4 and 10 weeks of treatment, excluding dose delays, and calculated geometric means were tested versus BOR or toxicity using analysis of variance and an independent samples t-test, respectively. Overall survival (OS) and progression-free survival were compared between high and low trough concentration groups.RESULTS: Seventy-six patients were evaluable for analyses. Responders (n = 15) had higher mean trough concentrations than patients with progression (n = 33): 47% higher after 2 weeks (p = 0.001), 53% higher after 4 weeks (p = 0.008) and 73% higher after 10 weeks (p = 0.002). Higher trough concentrations were associated with longer OS (p = 0.001).CONCLUSIONS: This study shows that patients with NSCLC with a response to nivolumab had a higher nivolumab exposure than patients with progression, indicating a potential exposure-response relationship. Further clinical research should focus on clarifying these exposure-response relationships.
CANIT0002197	30657853	Clinical research	Non-metastatic bladder cancer	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Docetaxel	Immune checkpoint therapy	Pembrolizumab (DB09037); 	690	343	An international, open-label, phase II/III study	Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS >=50%. For TPS >=50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS >=1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS >=50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS >=1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)].	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial.	 Ann Oncol	BACKGROUND: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data.PATIENTS AND METHODS: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) >=50% and >=1%; pembrolizumab doses were pooled in this analysis.RESULTS: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS >=50%. For TPS >=50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS >=1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS >=50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS >=1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)].CONCLUSION: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples.TRIAL REGISTRATION: ClinicalTrials.gov: NCT01905657.
CANIT0002198	30658932	Clinical research	Intermediate or poor risk, previously untreated, advanced renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	425	422	Phase 3, CheckMate 214 trial	Nivolumab plus ipilimumab leads to fewer symptoms and better health-related quality of life (HRQoL) than sunitinib in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved HRQoL.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial.	 Lancet Oncol	BACKGROUND: In the ongoing phase 3, CheckMate 214 trial, nivolumab plus ipilimumab improved overall survival compared with sunitinib in patients with intermediate or poor risk, previously untreated, advanced renal cell carcinoma. We aimed to assess whether health-related quality of life (HRQoL) could be used to further describe the benefit-risk profile of nivolumab plus ipilimumab versus sunitinib.METHODS: In the phase 3, randomised, controlled, CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by risk status into favourable, intermediate, and poor risk subgroups and randomly assigned (1:1) to open-label nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg/day for 4 weeks of each 6-week cycle. Randomisation was done with a block size of four and stratified by risk status and geographical region. Patient-reported outcomes (PROs) were assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five dimensional three level (EQ-5D-3L) instruments. The coprimary endpoints of the trial, reported previously, were overall survival, progression-free survival, and the proportion of patients who had an objective response in those categorised as at intermediate or poor risk. PROs in all randomised participants were assessed as an exploratory endpoint; here we report this exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but is now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) were randomly assigned to treatment, of whom 847 (77%) were at intermediate or poor risk and randomly assigned to nivolumab plus ipilimumab (n=425) or sunitinib (n=422). Median follow-up was 25.2 months (IQR 23.0-27.4). PROs were more favourable with nivolumab plus ipilimumab than sunitinib throughout the first 103 weeks after baseline, with mean change from baseline at week 103 for FKSI-19 total score being 4.00 (95% CI 1.91 to 6.09) for nivolumab plus ipilimumab versus -3.14 (-6.03 to -0.25) for sunitinib (p<0.0001), and for FACT-G total score being 4.77 (1.73 to 7.82) for nivolumab plus ipilimumab versus -4.32 (-8.54 to -0.11) for sunitinib (p=0.0005). Significant differences were also seen for four of five FKSI-19 domains (disease-related symptoms, physical disease-related symptoms, treatment side-effects, and functional wellbeing) and FACT-G physical and functional wellbeing domains. However, there was no significant difference between the treatment groups at week 103 in EQ-5D-3L visual analogue rating scale (VAS) scores, with mean change from baseline to week 103 of 10.07 (95% CI 4.35 to 15.80) for nivolumab plus ipilimumab and 6.40 (-1.36 to 14.16) for sunitinib (p=0.45). Compared with sunitinib, nivolumab plus ipilimumab reduced risk of deterioration in FKSI-19 total score (hazard ratio [HR] 0.54; 95% CI 0.46-0.63), FACT-G total score (0.63, 0.52-0.75), and EQ-5D-3L VAS score (HR 0.75, 95% CI 0.63-0.89) and UK utility scores (0.67, 0.57-0.80).INTERPRETATION: Nivolumab plus ipilimumab leads to fewer symptoms and better HRQoL than sunitinib in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved HRQoL.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
CANIT0002199	30659023	Clinical research	Glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	98	N/A	N/A	CD8+ tumor-infiltrating lymphocytes (TILs) had significantly increased expression of immune checkpoint receptors, including PD-1 and CTLA-4, compared with peripheral blood CD8+ T cells. Among CD8+ TILs, PD-1+ cells exhibited more terminally differentiated phenotypes (i.e., EomeshiT-betlo) than PD-1- cells. These data were confirmed by analyzing NY-ESO-1157-specific CD8+ TILs. Evaluating the proliferation of CD8+ TILs after ex vivo stimulation with anti-CD3 and anti-PD-1, we found that proliferation inversely correlated with the percentage of EomeshiT-betlo cells among PD-1+CD8+ TILs. When anti-CTLA-4 was used in combination with anti-PD-1, an additional increase in CD8+ TIL proliferation was observed in patients with low percentages of EomeshiT-betlo CD8+ TILs, who responded well to anti-PD-1 in ex vivo assays, but not in patients with high percentages of EomeshiT-betlo CD8+ TILs, who did not respond to anti-PD-1.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Low percentages of EomeshiT-betlo CD8(+) tumor-infiltrating effector T-cells	Tumor-infiltrating immune cell	 2019 Apr 15	Immune Checkpoint Inhibitor-induced Reinvigoration of Tumor-infiltrating CD8(+) T Cells is Determined by Their Differentiation Status in Glioblastoma.	 Clin Cancer Res	PURPOSE: Immune checkpoint inhibitors (ICI) are used for the treatment of various cancers, but clinical trials of anti-programmed cell death protein 1 (PD-1) with patients with recurrent glioblastoma (GBM) have failed to show clinical benefits. In this study, we examined the differentiation status of CD8+ tumor-infiltrating lymphocytes (TIL) from patients with primary GBM and their reinvigoration by ICIs to understand the nature of T-cell exhaustion in GBM.EXPERIMENTAL DESIGN: We isolated TILs from 98 patients with newly diagnosed GBM and examined the expression of immune checkpoint receptors and T-cell transcription factors using flow cytometry. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and their proliferation assessed.RESULTS: CD8+ TILs had significantly increased expression of immune checkpoint receptors, including PD-1 and CTLA-4, compared with peripheral blood CD8+ T cells. Among CD8+ TILs, PD-1+ cells exhibited more terminally differentiated phenotypes (i.e., EomeshiT-betlo) than PD-1- cells. These data were confirmed by analyzing NY-ESO-1157-specific CD8+ TILs. Evaluating the proliferation of CD8+ TILs after ex vivo stimulation with anti-CD3 and anti-PD-1, we found that proliferation inversely correlated with the percentage of EomeshiT-betlo cells among PD-1+CD8+ TILs. When anti-CTLA-4 was used in combination with anti-PD-1, an additional increase in CD8+ TIL proliferation was observed in patients with low percentages of EomeshiT-betlo CD8+ TILs, who responded well to anti-PD-1 in ex vivo assays, but not in patients with high percentages of EomeshiT-betlo CD8+ TILs, who did not respond to anti-PD-1.CONCLUSIONS: In primary GBM, the differentiation status of CD8+ TILs determines their reinvigoration ability upon ICI treatment.
CANIT0002200	30659987	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Docetaxel	Immune checkpoint therapy	Nivolumab (DB09035); 	338	166	Randomized, open-label, phase III clinical trial	OS was significantly improved with nivolumab (n = 338) versus docetaxel (n = 166); median OS (95% confidence interval): 12.0 (10.4-14.0) versus 9.6 (7.6-11.2) months, respectively; hazard ratio (97.7% confidence interval): 0.68 (0.52-0.90); p = 0.0006. Objective response rate was 17% with nivolumab versus 4% with docetaxel; median duration of response was not reached versus 5.3 months. Minimum follow-up was 8.8 months.	The frequency of grade 3 or greater treatment-related adverse events was 10% with nivolumab and 48% with docetaxel.	N/A	N/A	N/A	N/A	N/A	 2019 May	Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial.	 J Thorac Oncol	INTRODUCTION: Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly Chinese patient population with previously treated NSCLC.METHODS: CheckMate 078 was a randomized, open-label, phase III clinical trial in patients from China, Russia, and Singapore with squamous or nonsquamous NSCLC that had progressed during/after platinum-based doublet chemotherapy (ClinicalTrials.gov: NCT02613507). Patients with EGFR/ALK alterations were excluded. Patients (N = 504) were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), stratified by performance status, tumor histology, and tumor programmed death ligand 1 expression. The primary endpoint was overall survival (OS); secondary endpoints included objective response rate, progression-free survival, and safety.RESULTS: OS was significantly improved with nivolumab (n = 338) versus docetaxel (n = 166); median OS (95% confidence interval): 12.0 (10.4-14.0) versus 9.6 (7.6-11.2) months, respectively; hazard ratio (97.7% confidence interval): 0.68 (0.52-0.90); p = 0.0006. Objective response rate was 17% with nivolumab versus 4% with docetaxel; median duration of response was not reached versus 5.3 months. Minimum follow-up was 8.8 months. The frequency of grade 3 or greater treatment-related adverse events was 10% with nivolumab and 48% with docetaxel.CONCLUSIONS: This is the first phase III study in a predominantly Chinese population reporting results with a programmed death 1 inhibitor. In this population with previously treated advanced NSCLC, nivolumab improved OS versus docetaxel. Results were consistent with global CheckMate 017 and 057 studies.
CANIT0002201	30666357	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	346	N/A	Retrospective analysis	Any grade GI-immune-related adverse events (HR 0.53, 95% CI 0.36-0.78; P < 0.01) was associated with improved OS rates. Patients who developed GI-immune-related adverse events had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41-0.76; P < 0.01).	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune checkpoint inhibitor-induced colitis	Adverse events	 2019 Apr	Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.	 Cancer Immunol Immunother	BACKGROUND: Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors' (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients' survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.METHODS: This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan-Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.RESULTS: A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2-3 (HR 2.57, 95%CI 1.44-4.57; P < 0.01), LDH >= 618 IU/L (HR 2.20, 95% CI 1.47-3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35-3.60; P < 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36-0.78; P < 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (P = 0.15). High-grade diarrhea was associated with improved OS (P = 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41-0.76; P < 0.01).CONCLUSION: GI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients' OS rates.
CANIT0002202	30666357	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	346	N/A	Retrospective analysis	High-grade diarrhea was associated with improved OS (P = 0.04).	N/A	N/A	N/A	Diarrhea (NCIT:C2987)	High-grade diarrhea	Adverse events	 2019 Apr	Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.	 Cancer Immunol Immunother	BACKGROUND: Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors' (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients' survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.METHODS: This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan-Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.RESULTS: A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2-3 (HR 2.57, 95%CI 1.44-4.57; P < 0.01), LDH >= 618 IU/L (HR 2.20, 95% CI 1.47-3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35-3.60; P < 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36-0.78; P < 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (P = 0.15). High-grade diarrhea was associated with improved OS (P = 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41-0.76; P < 0.01).CONCLUSION: GI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients' OS rates.
CANIT0002203	30666357	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	346	N/A	Retrospective analysis	Immunosuppressive treatment did not affect OS (P = 0.15).	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Immunosuppressive treatment	Exposure factors/status	 2019 Apr	Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.	 Cancer Immunol Immunother	BACKGROUND: Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors' (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients' survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.METHODS: This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan-Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.RESULTS: A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2-3 (HR 2.57, 95%CI 1.44-4.57; P < 0.01), LDH >= 618 IU/L (HR 2.20, 95% CI 1.47-3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35-3.60; P < 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36-0.78; P < 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (P = 0.15). High-grade diarrhea was associated with improved OS (P = 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41-0.76; P < 0.01).CONCLUSION: GI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients' OS rates.
CANIT0002204	30666357	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	346	N/A	Retrospective analysis	In multivariate Cox regression, ECOG 2-3 (HR 2.57, 95%CI 1.44-4.57; P < 0.01), LDH >= 618 IU/L (HR 2.20, 95% CI 1.47-3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35-3.60; P < 0.01) were associated with worse OS rates.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Apr	Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.	 Cancer Immunol Immunother	BACKGROUND: Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors' (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients' survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.METHODS: This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan-Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.RESULTS: A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2-3 (HR 2.57, 95%CI 1.44-4.57; P < 0.01), LDH >= 618 IU/L (HR 2.20, 95% CI 1.47-3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35-3.60; P < 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36-0.78; P < 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (P = 0.15). High-grade diarrhea was associated with improved OS (P = 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41-0.76; P < 0.01).CONCLUSION: GI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients' OS rates.
CANIT0002205	30666357	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	346	N/A	Retrospective analysis	In multivariate Cox regression, ECOG 2-3 (HR 2.57, 95%CI 1.44-4.57; P < 0.01), LDH >= 618 IU/L (HR 2.20, 95% CI 1.47-3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35-3.60; P < 0.01) were associated with worse OS rates.	N/A	N/A	N/A	M1c-stage disease (NCIT:C48703); 	M1c-stage disease	Disease status	 2019 Apr	Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.	 Cancer Immunol Immunother	BACKGROUND: Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors' (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients' survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.METHODS: This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan-Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.RESULTS: A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2-3 (HR 2.57, 95%CI 1.44-4.57; P < 0.01), LDH >= 618 IU/L (HR 2.20, 95% CI 1.47-3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35-3.60; P < 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36-0.78; P < 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (P = 0.15). High-grade diarrhea was associated with improved OS (P = 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41-0.76; P < 0.01).CONCLUSION: GI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients' OS rates.
CANIT0002206	30666357	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	346	N/A	Retrospective analysis	In multivariate Cox regression, ECOG 2-3 (HR 2.57, 95%CI 1.44-4.57; P < 0.01), LDH >= 618 IU/L (HR 2.20, 95% CI 1.47-3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35-3.60; P < 0.01) were associated with worse OS rates.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Apr	Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma.	 Cancer Immunol Immunother	BACKGROUND: Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors' (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients' survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.METHODS: This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan-Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.RESULTS: A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2-3 (HR 2.57, 95%CI 1.44-4.57; P < 0.01), LDH >= 618 IU/L (HR 2.20, 95% CI 1.47-3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35-3.60; P < 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36-0.78; P < 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (P = 0.15). High-grade diarrhea was associated with improved OS (P = 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41-0.76; P < 0.01).CONCLUSION: GI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients' OS rates.
CANIT0002207	30666409	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	37	N/A	Retrospective analysis	The IO module was used to follow 37 patients who had filled in total 559 symptom questionnaires. There was good adherence to ePRO follow-up with a median of 11 questionnaires filled per patient. The reported symptoms and their severity follow closely what has been seen in clinical trials investigating ICIs. Correlation analysis of the symptoms showed the strongest positive correlations between itching and rash; nausea and vomiting, decreased appetite, or stomach pain; cough and shortness of breath.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar	EPROs in the follow-up of cancer patients treated with immune checkpoint inhibitors: a retrospective study.	 J Cancer Res Clin Oncol	PURPOSE: Patient-reported outcome (PRO) follow-up has been shown to improve quality of life (QoL) and survival of cancer patients receiving chemotherapy. Kaiku Health application is a web-based electronic PRO (ePRO) tool which is designed for follow-up of cancer patients receiving immune checkpoint inhibitors (ICI). Purpose of the current study is to investigate whether symptoms collected by Kaiku Health ePRO tool on cancer patients receiving immune checkpoint inhibitors (ICI) follows to symptoms reported in clinical trials and whether coupling of specific symptoms does occur.METHODS: We retrospectively collected data on symptom timing and severity, and QoL of patients followed with Kaiku Health IO module in two Finnish cancer centers between 2017 and 2018. Kaiku Health IO module consists of 18 adaptive questions, which assess the presence and severity of symptoms. Patients were requested (via e-mail) to fill online symptom questionnaires with 3-7 day interval and QoL questionnaires (QLQ-C30) with 1-2 month interval.RESULTS: The IO module was used to follow 37 patients who had filled in total 559 symptom questionnaires. There was good adherence to ePRO follow-up with a median of 11 questionnaires filled per patient. The reported symptoms and their severity follow closely what has been seen in clinical trials investigating ICIs. Correlation analysis of the symptoms showed the strongest positive correlations between itching and rash; nausea and vomiting, decreased appetite, or stomach pain; cough and shortness of breath.CONCLUSIONS: The results of the current study suggest that real-world symptom data collected through the ePRO application on cancer patients receiving ICI therapy aligns with the data from clinical trials. Correlations between different symptoms occur, which might reflect therapeutic efficiency, side effects, or tumor progression. These correlations should be further investigated with data coupled to clinical outcomes.
CANIT0002208	30666802	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	40	N/A	Retrospective analysis	The disease control rates were lower in NSCLC patients with stool abnormalities than in those without stool abnormalities (20% vs. 77.8%, respectively; P = 0.0016). The time to treatment failure with ICI treatment was shorter in NSCLC patients with stool abnormalities compared with those without stool abnormalities (P = 0.003; odds ratio, 3.09; 95% confidence interval 1.41-6.78).	N/A	N/A	N/A	Stool abnormalities ()	Stool abnormalities	Disease status	 2019 Mar	Impact of bowel movement condition on immune checkpoint inhibitor efficacy in patients with advanced non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: Cancer immunotherapy is under development as a promising alternative strategy for treating advanced non-small cell lung cancer (NSCLC). However, the development of novel biomarkers to optimize the use of immune checkpoint inhibitors (ICIs) is still ongoing. Gut microbiota are known to regulate a host's immunity and are associated with the response to ICIs in melanoma. Therefore, we analyzed the association between ICI treatment efficacy and bowel movement condition in patients with NSCLC.METHODS: This retrospective study analyzed patients with advanced NSCLC who were treated with ICIs between December 2015 and March 2018 at University Hospital Kyoto Prefectural University of Medicine in Kyoto, Japan. The association between stool abnormalities and ICI efficacy was investigated. We defined patients with constipation or those who used a laxative as the stool abnormality group.RESULTS: We retrospectively enrolled 40 patients with advanced NSCLC who were treated with ICIs. The median age was 69.5 years; 20 patients had a stool abnormality and 20 patients did not. The disease control rates were lower in NSCLC patients with stool abnormalities than in those without stool abnormalities (20% vs. 77.8%, respectively; P = 0.0016). The time to treatment failure with ICI treatment was shorter in NSCLC patients with stool abnormalities compared with those without stool abnormalities (P = 0.003; odds ratio, 3.09; 95% confidence interval 1.41-6.78).CONCLUSION: Stool abnormality might be a predictive biomarker for the clinical benefit of ICI treatment in patients with NSCLC. Further investigations are warranted to validate our findings.
CANIT0002209	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Cannabis (NCIT:C26659); Treatment history (NCIT:C160179); 	Cannabidiol percentage	Exposure factors/status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002210	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Cannabis (NCIT:C26659); Treatment history (NCIT:C160179); 	Tetrahydrocannabinol percentage	Exposure factors/status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002211	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002212	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002213	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002214	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Cannabis (NCIT:C26659); Treatment history (NCIT:C160179); 	Cannabidiol percentage	Exposure factors/status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002215	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Cannabis (NCIT:C26659); Treatment history (NCIT:C160179); 	Tetrahydrocannabinol percentage	Exposure factors/status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002216	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002217	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002218	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002219	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Cannabis (NCIT:C26659); Treatment history (NCIT:C160179); 	Cannabidiol percentage	Exposure factors/status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002220	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Cannabis (NCIT:C26659); Treatment history (NCIT:C160179); 	Tetrahydrocannabinol percentage	Exposure factors/status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002221	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002222	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002223	30670598	Clinical research	140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus cannabis	Nivolumab	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); cannabis (DB14009); 	51	89	Retrospective analysis	In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2019 Apr	Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies.	 Oncologist	BACKGROUND: There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression-free survival (PFS), and overall survival (OS).SUBJECTS, MATERIALS, AND METHODS: In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015-2016 at our hospital, and cannabis from six cannabis-supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.RESULTS: In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab-cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24-8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).CONCLUSION: In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.IMPLICATIONS FOR PRACTICE: Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
CANIT0002224	30674531	Basic research	Lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-L1 (Q9NZQ7); LEG3 (P17931); 	PD-L1; LEG3	Atezolizumab plus GB1107	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	Cell lines/ animal models	N/A	Basic research	Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8+ T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNG, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Apr 1	An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade.	 Cancer Res	A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a ¦Â-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8+ T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFN¦Ã, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. SIGNIFICANCE: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1480/F1.large.jpg.
CANIT0002225	30678553	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); PD-1 (Q15116); 	PD-L1; PD-1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); pembrolizumab (DB09037); nivolumab (DB09035); 	5504	N/A	Meta-analysis	Pembrolizumab plus chemotherapy had the highest p-score of 0.95 among all the treatments, and was superior to pembrolizumab alone (hazard ratio: 0.87; 95% CI: 0.79-0.95).	Combination therapy had more grade 3-5 adverse events; but toxicity-related discontinuation and treatment-related death did not increase.	N/A	N/A	N/A	N/A	N/A	 2019 Mar	First-line checkpoint inhibitors for wild-type advanced non-small-cell cancer: a pair-wise and network meta-analysis.	 Immunotherapy	AIM: To estimate efficacy of checkpoint inhibitors and rank treatment effects in non-small-cell lung cancer.MATERIALS & METHODS: Prospective randomized trials were included. p-score was used to rank treatment effects.RESULTS: A total of nine trials were identified, involving 5504 patients and three checkpoint inhibitors. Pembrolizumab plus chemotherapy had the highest p-score of 0.95 among all the treatments, and was superior to pembrolizumab alone (hazard ratio: 0.87; 95% CI: 0.79-0.95). Combination therapy had more grade 3-5 adverse events; but toxicity-related discontinuation and treatment-related death did not increase.CONCLUSION: Pembrolizumab plus chemotherapy was likely to be the most effective treatment for patients with wild-type advanced NSCLC.
CANIT0002226	30689736	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	16	N/A	N/A	Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) compared to nonresponders, (P <= 0.021, for each feature).Neither tumoral necrosis nor pretreatment histologic features were associated with response. Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Tumor infiltrate (NCIT:C12546); 	Plasm moderate-high tumor infiltrating lymphocyte densities	Tumor-infiltrating immune cell	 2019 Apr 1	Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response.	 Ann Oncol	BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor.MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, <=10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490).RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P <= 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients.CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.
CANIT0002227	30689736	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	16	N/A	N/A	Specimens from responders in the discovery cohort had features of wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P <= 0.021, for each feature). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Wound-healing/tissue repair (neovascularization, proliferative fibrosis) (); 	Wound-healing/tissue repair (neovascularization, proliferative fibrosis)	Disease status	 2019 Apr 1	Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response.	 Ann Oncol	BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor.MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, <=10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490).RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P <= 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients.CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.
CANIT0002228	30689736	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	N/A	Increasing immune-related pathologic response (irPR) score associated with objective response (P = 0.009). Eight of 16 (50%) of patients with stable disease showed irPR features. Neither tumoral necrosis nor pretreatment histologic features were associated with response. Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related pathologic response	Adverse events	 2019 Apr 1	Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response.	 Ann Oncol	BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor.MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, <=10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490).RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P <= 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients.CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.
CANIT0002229	30689736	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	N/A	Major pathologic response on biopsy (MPRbx) associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Eight of 16 (50%) of patients with stable disease showed irPR features.Neither tumoral necrosis nor pretreatment histologic features were associated with response. Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Major pathologic response on biopsy (); 	Major pathologic response on biopsy	Disease status	 2019 Apr 1	Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response.	 Ann Oncol	BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor.MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, <=10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490).RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate-high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P <= 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPRbx associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054-0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients.CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.
CANIT0002230	30694757	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab followed by surgery	N/A	Immune checkpoint therapy followed by surgery	Ipilimumab (DB06186); nivolumab (DB09035); 	25	N/A	Retrospective analysis	Surgery was well tolerated in this cohort of patients receiving ICI therapy for melanoma. Surgery may benefit select patients with an oligoprogressive disease after ICI therapy. After a mixed response, surgery remains the only definitive method to render some patients free of disease.	Five patients were treated in the adjuvant setting and developed new lesions, whereas 20 patients were treated for metastatic disease and underwent surgery for persistent disease on imaging after ICI therapy. Twenty-five patients underwent 30 operations without complications. Twenty-seven of 30 masses were confirmed to be melanoma on pathology, one was a desmoid tumor and two were necrosis. 	N/A	N/A	Treatment history (NCIT:C160179); 	An oligoprogressive disease after ICI therapy	Adverse events	 2019 Apr	The Emerging Role of Surgery for Patients With Advanced Melanoma Treated With Immunotherapy.	 J Surg Res	BACKGROUND: The emergence of immune checkpoint inhibitors (ICIs) has improved survival for patients with metastatic melanoma. The types of disease-response patterns to ICI therapy can be more complex relative to traditional chemotherapy and include mixed responses, pseudoprogression, and oligoprogression. The potential benefit of surgery after incomplete response to ICI therapy has not been explored. The purpose of this study was to explore outcomes of surgery after ICI therapy in patients with metastatic melanoma.METHODS: A retrospective study was conducted at two centers and included patients with melanoma who underwent surgery after treatment with monotherapy or combination therapy with anti-programmed cell death protein (PD) 1 and/or anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 checkpoint blockade.RESULTS: Of 25 patients, nine received anti-CTLA-4 therapy, eight received anti-PD-1 therapy, and eight received both anti-CTLA-4 and anti-PD-1 therapies before surgery. Five patients were treated in the adjuvant setting and developed new lesions, whereas 20 patients were treated for metastatic disease and underwent surgery for persistent disease on imaging after ICI therapy. Twenty-five patients underwent 30 operations without complications. Twenty-seven of 30 masses were confirmed to be melanoma on pathology, one was a desmoid tumor and two were necrosis. At a median follow-up of 14.2 months, 2 patients died, 8 were alive with a known disease, and 15 continued to have no further evidence of disease.CONCLUSIONS: Surgery was well tolerated in this cohort of patients receiving ICI therapy for melanoma. Surgery may benefit select patients with an oligoprogressive disease after ICI therapy. After a mixed response, surgery remains the only definitive method to render some patients free of disease.
CANIT0002231	30701346	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	11	N/A	Retrospective analysis	We identified 11 patients, without pre-existing autoimmune disease, who developed inflammatory arthritis (IA) following immune checkpoint inhibitor (ICI). Most patients presented with a symmetrical polyarthritis with both large and small joint involvement. All patients were treated according to the outlined treatment protocol with hydroxychloroquine as a first-line steroid-sparing agent: either as monotherapy or in combination with tapering doses of systemic corticosteroids (3) or intra-articular steroid injections (6). One patient required the addition of methotrexate to control symptoms and none required biologic therapy. There were no reported adverse effects from hydroxychloroquine. Inflammatory arthritis is an important complication of ICIs leading to significant impact on patient quality of life. In our experience, in patients without pre-existing autoimmune disease, hydroxychloroquine is an effective first-line therapy for IA secondary to ICI therapy.	Arthritis	N/A	N/A	N/A	N/A	N/A	 2019 May	Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inhibitor-induced inflammatory arthritis.	 Clin Rheumatol	Immunotherapy for cancer treatment continues to evolve, and immune checkpoints have proven successful therapeutic targets. With success has come the challenge of managing the commonly associated immune-related toxicities. Arthralgias and arthritis are a common immune-related adverse event (IrAE), well described in the literature (Pardoll Nat Rev Cancer 12:252-264, 2012; Diesendruck and Benhar Drug Resist Updat 30:39-47, 2017; Cappelli et al. Arthritis Care Res 69:1751-1763, 2017; Brahmer et al. J Clin Oncol 36:1714-1768, 2018; Smith and Bass (2017). The optimal management of immune checkpoint inhibitor (ICI)-induced arthritis remains unclear. We describe the first series using hydroxychloroquine as a first-line disease-modifying antirheumatic drug (DMARD) for patients without pre-existing autoimmune disease, who developed arthritis secondary to ICI's. This was a single-center retrospective observational study reporting all patients evaluated by rheumatologists affiliated with the University of Alberta, a large tertiary health care center in Northern Alberta, Canada, deemed to have inflammatory arthritis (IA) following ICIs. We identified 11 patients, without pre-existing autoimmune disease, who developed IA following ICIs. Most patients presented with a symmetrical polyarthritis with both large and small joint involvement. All patients were treated according to the outlined treatment protocol with hydroxychloroquine as a first-line steroid-sparing agent: either as monotherapy or in combination with tapering doses of systemic corticosteroids (3) or intra-articular steroid injections (6). One patient required the addition of methotrexate to control symptoms and none required biologic therapy. There were no reported adverse effects from hydroxychloroquine. Inflammatory arthritis is an important complication of ICIs leading to significant impact on patient quality of life. In our experience, in patients without pre-existing autoimmune disease, hydroxychloroquine is an effective first-line therapy for IA secondary to ICI therapy.
CANIT0002232	30709339	Basic research	Glioblastoma multiforme	Glioblastoma multiforme	EFO:0000519	Brain	INGR1 ( P15260); 	INGR1; 	IFNG plus Temozolomide	IFNG	Immune cytokine plus Chemotherapy	IFNG (DB00033); Temozolomide (DB00853); 	Cell lines	N/A	Basic research	The resullts indicate a significant downregulation of the JAK/STAT pathway and immune response in recurrent tumors. The cell model showed an upregulation of PD-L1 after IFNG treatment, while additional temozolomide treatment lead to a reduction of PD-L1 expression and JAK/STAT pathway activation. These findings were confirmed in specimens of de-novo and recurrent glioblastoma.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Feb 1	Crosslink between Temozolomide and PD-L1 immune-checkpoint inhibition in glioblastoma multiforme.	 BMC Cancer	BACKGROUND: In recent years, PD-1/PD-L1 immune checkpoint inhibitors have improved cancer therapy in many tumor types, but no benefit of immune checkpoint therapy has been found in glioblastoma multiforme (GBM). Based on the results of our earlier work, which showed a reduction of PD-L1 expression in patients treated with temozolomide (TMZ), we aimed to investigate the link between TMZ therapy and the immune control point target PD-L1.METHODS: RNA-sequencing data from de-novo and recurrent glioblastoma were analyzed by AutoPipe algorithm. Results were confirmed either in a cell model by two primary and one established GBM cell line and specimens of de-novo and recurrent GBM. PD-L1 and pathway activation of the JAK/STAT pathway was analyzed by quantitative real-time PCR and western blot.RESULTS: We found a significant downregulation of the JAK/STAT pathway and immune response in recurrent tumors. The cell model showed an upregulation of PD-L1 after IFN¦Ã treatment, while additional TMZ treatment lead to a reduction of PD-L1 expression and JAK/STAT pathway activation. These findings were confirmed in specimens of de-novo and recurrent glioblastoma.CONCLUSIONS: Our results suggest that TMZ therapy leads to a down-regulation of PD-L1 in primary GBM cells. These results support the clinical findings where PD-L1 is significantly reduced in recurrent GBMs. If the target is diminished, it may also lead to impaired efficacy of PD-1/PD-L1 inhibitors such as nivolumab.
CANIT0002233	30712477	Clinical research	Metastatic nonsquamous non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus pemetrexed plus platinum	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); pemetrexed (DB00642); platinum (DB12257); 	N/A	N/A	Meta-analysis	Pembrolizumab + pemetrexed + platinum is likely the most efficacious first-line regimen for metastatic metastatic nonsquamous non-small-cell lung cancer (NSq-NSCLC).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Pembrolizumab plus chemotherapy for first-line treatment of metastatic nonsquamous non-small-cell lung cancer: a network meta-analysis.	 Immunotherapy	AIM: A systematic review and network meta-analysis were conducted to evaluate the efficacy of pembrolizumab + pemetrexed + platinum relative to other regimens in metastatic nonsquamous non-small-cell lung cancer (NSq-NSCLC).PATIENTS & METHODS: Eligible studies evaluated first-line regimens in NSq-NSCLC patients without known targetable mutations. Relative treatment effects were synthesized with random effects proportional hazards Bayesian network meta-analyses.RESULTS: The hazard ratio (HR) for overall survival (OS) for pembrolizumab + pemetrexed + platinum was statistically significant over all platinum-doublet (HR range: 0.42-0.61), platinum-doublet + bevacizumab (HR range: 0.44-0.53) and platinum-doublet + atezolizumab regimens (HR range: 0.56-0.62). Additionally, pembrolizumab + pemetrexed + platinum numerically improved OS over atezolizumab + paclitaxel + carboplatin + bevacizumab (HR: 0.65; 95% credible interval: 0.43, 1.01). Pembrolizumab + pemetrexed + platinum had 95.6% probability of being the best treatment regimen for OS.CONCLUSION: Pembrolizumab + pemetrexed + platinum is likely the most efficacious first-line regimen for metastatic NSq-NSCLC.
CANIT0002234	30718052	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by surgery	N/A	Immune checkpoint therapy followed by Surgery	Nivolumab (DB09035); 	22	N/A	Phase I trial	Neoadjuvant therapy with nivolumab was not associated with unexpected perioperative morbidity or mortality. More than half of the video-assisted thoracoscopic surgery/robotic cases were converted to thoracotomy, often because of hilar inflammation and fibrosis.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer.	 J Thorac Cardiovasc Surg	OBJECTIVE: We conducted a phase I trial of neoadjuvant nivolumab, a monoclonal antibody to the programmed cell death protein 1 checkpoint receptor, in patients with resectable non-small cell lung cancer. We analyzed perioperative outcomes to assess the safety of this strategy.METHODS: Patients with untreated stage I-IIIA non-small cell lung cancer underwent neoadjuvant therapy with 2 cycles of nivolumab (3 mg/kg), 4 and 2 weeks before resection. Patients underwent invasive mediastinal staging as indicated and post-treatment computed tomography. Primary study end points were safety and feasibility of neoadjuvant nivolumab followed by pulmonary resection. Data on additional surgical details were collected through chart review.RESULTS: Of 22 patients enrolled, 20 underwent resection. One was unresectable; another had small cell histologic subtype. There were no delays to surgical resection. Median time from first treatment to surgery was 33 (range, 17-43) days. There were 15 lobectomies, 2 pneumonectomies, 1 bilobectomy, 1 sleeve lobectomy, and 1 wedge resection. Of 13 procedures attempted via a video-assisted thoracoscopic surgery or robotic approach, 7 (54%) required thoracotomy. Median operative time was 228 (range, 132-312) minutes; estimated blood loss was 100 (range, 25-1000) mL; length of hospital stay was 4 (range, 2-17) days. There was no operative mortality. Morbidity occurred in 10 of 20 patients (50%). The most common postoperative complication was atrial arrhythmia (6/20; 30%). Major pathologic response was identified in 9 of 20 patients (45%).CONCLUSIONS: Neoadjuvant therapy with nivolumab was not associated with unexpected perioperative morbidity or mortality. More than half of the video-assisted thoracoscopic surgery/robotic cases were converted to thoracotomy, often because of hilar inflammation and fibrosis.
CANIT0002235	30726175	Clinical research	Merkel cell carcinoma	Merkel cell skin cancer	EFO:1001471	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	50	N/A	Multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017)	The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors.	Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Mar 20	Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy.	 J Clin Oncol	PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited.PATIENTS AND METHODS: In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults na ve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.RESULTS: Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death.CONCLUSION: Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.
CANIT0002236	30729336	Case report	HPV-negative anorectal squamous cell carcinoma	Anorectal squamous cell carcinoma	EFO:1000081	Anus	PD-1 (Q15116); 	PD-1; 	Cisplatin-based chemoradiation therapy followed by pembrolizumab	N/A	Chemoradiotherapy followed by Immune checkpoint therapy	Pembrolizumab (DB09037); cisplatin (DB00515); 	1	N/A	Case	We report a HPV-negative anorectal squamous cell carcinoma which, despite cisplatin-based chemoradiation therapy, showed progression. Interestingly, after identification of its mismatch repair-deficiency (MLH1/PMS2-absent, MSH2/MSH6-intact), pembrolizumab-based immunotherapy was initiated, leading to a marked clinical response.	N/A	N/A	N/A	Mismatch-repair status (NCIT:C20639); 	DNA mismatch repair-deficient	Mutational status	 2019 Jun	A mismatch repair-deficient and HPV-negative anorectal squamous cell carcinoma.	 Virchows Arch	Invasive primary squamous cell carcinomas involving the anorectal region are challenging to manage. Microsatellite instability has been shown to impact clinical courses and outcomes of patients affected by many types of carcinomas. To the best of our knowledge, there are no reports on microsatellite instability in anorectal squamous cell carcinomas. Here, we report a HPV-negative anorectal squamous cell carcinoma which, despite cisplatin-based chemoradiation therapy, showed progression. Interestingly, after identification of its mismatch repair-deficiency (MLH1/PMS2-absent, MSH2/MSH6-intact), pembrolizumab-based immunotherapy was initiated, leading to a marked clinical response. This unique case illustrates that microsatellite instability testing and immunotherapy targeting immune checkpoint blockade should be considered for managing anorectal squamous cell carcinomas that fail conventional chemoradiation therapies or when patients are non-surgical candidates. This report provides the first evidence of microsatellite instability in anorectal squamous cell carcinomas and supports the role for microsatellite instability testing in this cancer type to optimize patient management.
CANIT0002237	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002238	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Elimination of neoepitopes ()	Elimination of neoepitopes	Gene expression signature on/in tumor cell	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002239	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PTEN (P60484); 	PTEN mutation	Mutational status	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002240	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PTPN11 (Q06124); 	PTPN11 mutation	Mutational status	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002241	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	T-cell clonal diversity	Tumor-infiltrating immune cell	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002242	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Immune microenvironment (NCIT:C48199); 	Tumor microenvironment profiles	Tumor-infiltrating immune cell	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002243	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002244	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Elimination of neoepitopes ()	Elimination of neoepitopes	Gene expression signature on/in tumor cell	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002245	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Immune microenvironment (NCIT:C48199); 	Tumor microenvironment profiles	Tumor-infiltrating immune cell	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002246	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PTEN (P60484); 	PTEN mutation	Mutational status	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002247	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PTPN11 (Q06124); 	PTPN11 mutation	Mutational status	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002248	30742119	Clinical research	Glioblastomas	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	66	N/A	N/A	Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-cell repertoire (NCIT:C129657); T-Lymphocyte (NCIT:C12476); 	T-cell clonal diversity	Tumor-infiltrating immune cell	 2019 Mar	Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.	 Nat Med	Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.
CANIT0002249	30742122	Clinical research	Recurrent, surgically resectable glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Surgery followed by Pembrolizumab with continued adjuvant therapy	Sugery followed by Adjuvant, post-surgical pembrolizumab	Surgery followed by Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	16	Randomized, multi-institution	Downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Cell cycle regulation (NCIT:C19598); 	Cell-cycle-related gene expression within the tumor	Gene expression signature on/in tumor cell	 2019 Mar	Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.	 Nat Med	Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-¦Ã-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
CANIT0002250	30742122	Clinical research	Recurrent, surgically resectable glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Surgery followed by Pembrolizumab with continued adjuvant therapy	Sugery followed by Adjuvant, post-surgical pembrolizumab	Surgery followed by Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	16	Randomized, multi-institution	Neoadjuvant PD-1 blockade was associated with upregulation of INFG-related gene expression These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	INFG (Q30DS9); 	IFNG-related gene expression within the tumor	Gene expression signature on/in tumor cell	 2019 Mar	Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.	 Nat Med	Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-¦Ã-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
CANIT0002251	30742122	Clinical research	Recurrent, surgically resectable glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Surgery followed by Pembrolizumab with continued adjuvant therapy	Sugery followed by Adjuvant, post-surgical pembrolizumab	Surgery followed by Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	16	Randomized, multi-institution	A decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Monocyte counts (NCIT:C12547); 	A decreasing monocytic population	Cell percentage/counts in blood	 2019 Mar	Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.	 Nat Med	Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-¦Ã-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
CANIT0002252	30742122	Clinical research	Recurrent, surgically resectable glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Surgery followed by Pembrolizumab with continued adjuvant therapy	Sugery followed by Adjuvant, post-surgical pembrolizumab	Surgery followed by Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	16	Randomized, multi-institution	Decreased PD-1 expression on peripheral blood T cells was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	Decreased PD-1 expression on peripheral blood T-cell 	Gene expression signature on/in immune cell	 2019 Mar	Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.	 Nat Med	Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-¦Ã-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
CANIT0002253	30742122	Clinical research	Recurrent, surgically resectable glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Surgery followed by Pembrolizumab with continued adjuvant therapy	Sugery followed by Adjuvant, post-surgical pembrolizumab	Surgery followed by Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	16	Randomized, multi-institution	Focal induction of programmed death-ligand 1 in the tumor microenvironment was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	Focal induction of programmed death-ligand 1 in the tumor microenvironment	Gene expression signature on/in immune cell	 2019 Mar	Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.	 Nat Med	Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-¦Ã-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
CANIT0002254	30742122	Clinical research	Recurrent, surgically resectable glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Surgery followed by Pembrolizumab with continued adjuvant therapy	Sugery followed by Adjuvant, post-surgical pembrolizumab	Surgery followed by Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	16	Randomized, multi-institution	Enhanced clonal expansion of T cells was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	Enhanced clonal expansion of T-cell 	Immune response	 2019 Mar	Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.	 Nat Med	Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-¦Ã-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
CANIT0002255	30742122	Clinical research	Recurrent, surgically resectable glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Surgery followed by Pembrolizumab with continued adjuvant therapy	Sugery followed by Adjuvant, post-surgical pembrolizumab	Surgery followed by Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	16	Randomized, multi-institution	Neoadjuvant PD-1 blockade was associated with upregulation of T cell-related gene expression. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	T-cell - related gene expression within the tumor	Gene expression signature on/in tumor cell	 2019 Mar	Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.	 Nat Med	Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-¦Ã-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
CANIT0002256	30747241	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Radiochemotherapy followed by Adoptive transfer of ex vivo TKD/IL-2-activated NK cells	N/A	Immune checkpoint therapy plus Radiotherapy followed by Cell immunotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	1	N/A	Case	Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood.	N/A	N/A	N/A	CD3 (P07766); CD94 (Q13241); NKG2D (P26718); Natural killer-cells (NCIT:C98762); 	Increased CD3-/NKG2D(+)/CD94(+) NK cell counts in the peripheral blood.	Gene expression signature on/in immune cell	 2019 Apr	Radiochemotherapy combined with NK cell transfer followed by second-line PD-1 inhibition in a patient with NSCLC stage IIIb inducing long-term tumor control: a case study.	 Strahlenther Onkol	BACKGROUND: Membrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient.PATIENT: Following simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy.RESULTS: Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood.CONCLUSION: A combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.
CANIT0002257	30747241	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Radiochemotherapy followed by Adoptive transfer of ex vivo TKD/IL-2-activated NK cells	N/A	Immune checkpoint therapy plus Radiotherapy followed by Cell immunotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	1	N/A	Case	Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood.	N/A	N/A	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD8(+)-to-CD4(+) T-cell ratios	Gene expression signature on/in immune cell	 2019 Apr	Radiochemotherapy combined with NK cell transfer followed by second-line PD-1 inhibition in a patient with NSCLC stage IIIb inducing long-term tumor control: a case study.	 Strahlenther Onkol	BACKGROUND: Membrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient.PATIENT: Following simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy.RESULTS: Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood.CONCLUSION: A combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.
CANIT0002258	30747241	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Radiochemotherapy followed by Adoptive transfer of ex vivo TKD/IL-2-activated NK cells	N/A	Immune checkpoint therapy plus Radiotherapy followed by Cell immunotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	1	N/A	Case	Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood.	N/A	N/A	N/A	CD3 (P07766); CD56 (P13591); Natural killer-cells (NCIT:C98762); 	CD3-/CD56bright to CD3-/CD56dim NK cell ratios in the peripheral blood.	Gene expression signature on/in immune cell	 2019 Apr	Radiochemotherapy combined with NK cell transfer followed by second-line PD-1 inhibition in a patient with NSCLC stage IIIb inducing long-term tumor control: a case study.	 Strahlenther Onkol	BACKGROUND: Membrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient.PATIENT: Following simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy.RESULTS: Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood.CONCLUSION: A combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.
CANIT0002259	30747241	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Radiochemotherapy followed by Adoptive transfer of ex vivo TKD/IL-2-activated NK cells	N/A	Immune checkpoint therapy plus Radiotherapy followed by Cell immunotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	1	N/A	Case	Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood.	N/A	N/A	N/A	Treg cells (CL:0000815); 	Reduced regulatory T-cells in the peripheral blood.	Gene expression signature on/in immune cell	 2019 Apr	Radiochemotherapy combined with NK cell transfer followed by second-line PD-1 inhibition in a patient with NSCLC stage IIIb inducing long-term tumor control: a case study.	 Strahlenther Onkol	BACKGROUND: Membrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient.PATIENT: Following simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy.RESULTS: Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood.CONCLUSION: A combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.
CANIT0002260	30753264	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	91	N/A	N/A	The feature selection process allowed identifying a subset of approximately 20 of 770 genes that associated with clinical outcome. We utilized the training cohort to derive prediction models based on the endpoint of best response following immunotherapy. In the validation cohort, these models successfully identified all ¡°top responders¡±. Concordant prediction of clinical benefit by our models identified a subgroup of patients that benefits from immunotherapy (p=0.035, HR=0.32). PD-L1 immunohistochemistry appeared to confer an orthogonal layer of information: Incorporating PD-L1 TPS provided a combined prediction with an even stronger predictive value (favorable/intermediate/unfavorable, p=0.006). 	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Apr 1	Machine learning-based predictors for immune checkpoint inhibitor therapy of non-small-cell lung cancer.	 Ann Oncol	Unable to provide
CANIT0002261	30758859	Clinical research	Acral and mucosal melanoma	Acral melanoma	MONDO:0003865	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); 	3	N/A	Retrospective analysis	Two of the three patients of acral melanoma with radiotherapy (RT) and ipilimumab had stable disease and one had progressive disease (RR and DCR were 0% and 66.6%, respectively). 	Vitiligo developed after RT 	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Efficacy of combined radiotherapy and anti-programmed death 1 therapy in acral and mucosal melanoma.	 J Dermatol	Some studies showed that clinical response to immune check point inhibitors is lower in acral and mucosal melanoma than in cutaneous melanoma. Although the synergistic effect of radiotherapy (RT) and ipilimumab has been reported in patients with brain metastasis, the efficacy of combined RT and anti-programmed death 1 (PD-1) therapy for acral and mucosal melanoma is unclear. The present study aimed to evaluate the efficacy of combined RT and anti-PD-1 therapy for acral and mucosal melanoma. We retrospectively analyzed patients with acral or mucosal melanoma who were treated with anti-PD-1 and RT at Sapporo Medical University Hospital. In 10 patients (acral, 3; mucosal, 7), the response rate (RR) and the disease control rate (DCR) were 40% and 60%, respectively. As regards mucosal melanoma, four of the seven patients had achieved complete response + partial response, and three had progressive disease (RR = 57.1%). Meanwhile, two of the three patients with acral melanoma had stable disease and one had progressive disease (RR and DCR were 0% and 66.6%, respectively). Except for the patients treated with palliative RT for bone metastasis in the present study, the RR was 50% (4/8 patients), and the DCR was 75% (6/8 patients). Vitiligo developed after RT in five (50%) patients at a median duration of 2 months after RT. The clinical response and the high occurrence of vitiligo suggest that the combination of RT and anti-PD-1 therapy could be effective in some patients with mucosal melanoma.
CANIT0002262	30758859	Clinical research	Acral and mucosal melanoma	Mucosal melanoma	MONDO:0000544	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); 	7	N/A	Retrospective analysis	As regards mucosal melanoma, four of the seven patients with radiotherapy (RT) and ipilimumab had achieved complete response + partial response, and three had progressive disease (RR = 57.1%). Except for the patients treated with palliative RT for bone metastasis in the present study, the RR was 50% (4/8 patients), and the DCR was 75% (6/8 patients). The clinical response and the high occurrence of vitiligo suggest that the combination of RT and anti-PD-1 therapy could be effective in some patients with mucosal melanoma.	Vitiligo developed after RT 	N/A	N/A	Vitiligo (NCIT:C26915); 	High occurrence of vitiligo	Adverse events	 2019 Apr	Efficacy of combined radiotherapy and anti-programmed death 1 therapy in acral and mucosal melanoma.	 J Dermatol	Some studies showed that clinical response to immune check point inhibitors is lower in acral and mucosal melanoma than in cutaneous melanoma. Although the synergistic effect of radiotherapy (RT) and ipilimumab has been reported in patients with brain metastasis, the efficacy of combined RT and anti-programmed death 1 (PD-1) therapy for acral and mucosal melanoma is unclear. The present study aimed to evaluate the efficacy of combined RT and anti-PD-1 therapy for acral and mucosal melanoma. We retrospectively analyzed patients with acral or mucosal melanoma who were treated with anti-PD-1 and RT at Sapporo Medical University Hospital. In 10 patients (acral, 3; mucosal, 7), the response rate (RR) and the disease control rate (DCR) were 40% and 60%, respectively. As regards mucosal melanoma, four of the seven patients had achieved complete response + partial response, and three had progressive disease (RR = 57.1%). Meanwhile, two of the three patients with acral melanoma had stable disease and one had progressive disease (RR and DCR were 0% and 66.6%, respectively). Except for the patients treated with palliative RT for bone metastasis in the present study, the RR was 50% (4/8 patients), and the DCR was 75% (6/8 patients). Vitiligo developed after RT in five (50%) patients at a median duration of 2 months after RT. The clinical response and the high occurrence of vitiligo suggest that the combination of RT and anti-PD-1 therapy could be effective in some patients with mucosal melanoma.
CANIT0002263	30760168	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus pemetrexed plus docetaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); docetaxel (DB01248); pemetrexed (DB00642); 	1	N/A	Case	We present a case of a 78-year-old man who was diagnosed with stage IV non-small cell lung adenocarcinoma with an EGFR exon 20 mutations treated with pemetrexed, nivolumab, and then docetaxel. He has lived over four years after his initial diagnosis. This case illustrates the importance of genetic testing of patients to evaluate for specific gene mutations. It highlights the fact that these patients with exon 20 mutations are not sensitive to tyrosine kinase inhibitor treatment and often respond better to chemotherapeutic agents.	N/A	N/A	N/A	EGFR (P00533); 	EGFR exon 20 mutation	Mutational status	 2020 Jan	Treatment exceeds expectations in a patient with non-small cell lung adenocarcinoma with an EGFR exon 20 mutation.	 J Oncol Pharm Pract	Non-small cell lung adenocarcinoma is the most common type of lung cancer but is often difficult to treat. New treatment options have emerged with the class of tyrosine kinase inhibitors, but it has been found that certain genetic mutations in the epidermal growth factor receptor (EGFR) receptor are not as sensitive to this treatment as others. We present a case of a 78-year-old man who was diagnosed with stage IV non-small cell lung adenocarcinoma with an EGFR exon 20 mutations treated with pemetrexed, nivolumab, and then docetaxel. He has lived over four years after his initial diagnosis. This case illustrates the importance of genetic testing of patients to evaluate for specific gene mutations. It highlights the fact that these patients with exon 20 mutations are not sensitive to tyrosine kinase inhibitor treatment and often respond better to chemotherapeutic agents.
CANIT0002264	30762312	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	252	N/A	Retrospective analysis	In patients with PD-L1 expression in >= 1% of their tumor cells, the PFS of patients with malignant pleural effusion (MPE) was significantly shorter than of patients without MPE (median PFS 3.1 vs. 6.5 months, HR 2.0, 95% confidence interval 1.0-3.5; P = 0.021). The presence of MPE was independently associated with a shorter PFS and OS in multivariate analysis.	Malignant pleural effusion	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Apr	Malignant pleural effusion as a predictor of the efficacy of anti-PD-1 antibody in patients with non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: The aim of this study was to evaluate the usefulness of the presence of malignant pleural effusion (MPE) as a negative predictor of anti-PD-1 antibody efficacy.METHODS: A retrospective review of patients with advanced or recurrent non-small cell lung cancer treated with an anti-PD-1 antibody between December 2015 and March 2018 at the National Cancer Center Hospital, Japan, was conducted. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and without MPE. Additional survival analysis according to PD-L1 expression status was conducted. Univariate and multivariate analyses were performed.RESULTS: A total of 252 patients were identified before the commencement of anti-PD-1 antibody treatment: 33 with MPE and 219 without MPE. PFS and OS were significantly shorter in patients with MPE than in patients without MPE (median PFS 3.0 vs. 5.8 months, hazard ratio [HR] 1.7, P = 0.014; median OS 7.9 vs. 15.8 months, HR 2.1, P = 0.001). In patients with PD-L1 expression in >= 1% of their tumor cells, the PFS of patients with MPE was significantly shorter than of patients without MPE (median PFS 3.1 vs. 6.5 months, HR 2.0, 95% confidence interval 1.0-3.5; P = 0.021). The presence of MPE was independently associated with a shorter PFS and OS in multivariate analysis.CONCLUSION: The presence of MPE in patients administered an anti-PD-1 antibody is associated with shorter PFS and OS, regardless of the presence of PD-L1 expression >= 1% of tumor cells.
CANIT0002265	30762312	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	252	N/A	Retrospective analysis	PFS and OS were significantly shorter in patients with malignant pleural effusion (MPE) than in patients without MPE (median PFS 3.0 vs. 5.8 months, hazard ratio [HR] 1.7, P = 0.014; median OS 7.9 vs. 15.8 months, HR 2.1, P = 0.001). In patients with PD-L1 expression in >= 1% of their tumor cells, the PFS of patients with MPE was significantly shorter than of patients without MPE (median PFS 3.1 vs. 6.5 months, HR 2.0, 95% confidence interval 1.0-3.5; P = 0.021). The presence of MPE was independently associated with a shorter PFS and OS in multivariate analysis.	Malignant pleural effusion	N/A	N/A	Malignant Pleural Effusion (NCIT:C9432); 	Malignant pleural effusion	Disease status	 2019 Apr	Malignant pleural effusion as a predictor of the efficacy of anti-PD-1 antibody in patients with non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: The aim of this study was to evaluate the usefulness of the presence of malignant pleural effusion (MPE) as a negative predictor of anti-PD-1 antibody efficacy.METHODS: A retrospective review of patients with advanced or recurrent non-small cell lung cancer treated with an anti-PD-1 antibody between December 2015 and March 2018 at the National Cancer Center Hospital, Japan, was conducted. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and without MPE. Additional survival analysis according to PD-L1 expression status was conducted. Univariate and multivariate analyses were performed.RESULTS: A total of 252 patients were identified before the commencement of anti-PD-1 antibody treatment: 33 with MPE and 219 without MPE. PFS and OS were significantly shorter in patients with MPE than in patients without MPE (median PFS 3.0 vs. 5.8 months, hazard ratio [HR] 1.7, P = 0.014; median OS 7.9 vs. 15.8 months, HR 2.1, P = 0.001). In patients with PD-L1 expression in >= 1% of their tumor cells, the PFS of patients with MPE was significantly shorter than of patients without MPE (median PFS 3.1 vs. 6.5 months, HR 2.0, 95% confidence interval 1.0-3.5; P = 0.021). The presence of MPE was independently associated with a shorter PFS and OS in multivariate analysis.CONCLUSION: The presence of MPE in patients administered an anti-PD-1 antibody is associated with shorter PFS and OS, regardless of the presence of PD-L1 expression >= 1% of tumor cells.
CANIT0002266	30765258	Clinical research	Trastuzumab-resistant, advanced HER2-positive breast cancer	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); HER2 (P04626); 	PD-1; HER2	Pembrolizumab plus trastuzumab	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); trastuzumab (DB00072); 	58	N/A	Single-arm, multicentre, phase 1b-2 trial	Six (15%, 90% CI 7-29) of 40 PD-L1-positive patients with trastuzumab-resistant, advanced HER2-positive breast cancer achieved an objective response. There were no objective responders among the PD-L1-negative patients.Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients.	The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3-5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3-5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Mar	Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial.	 Lancet Oncol	BACKGROUND: HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer.METHODS: We did this single-arm, multicentre, phase 1b-2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed.FINDINGS: Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13.6 months (IQR 11.6-18.4) for patients with PD-L1-positive tumours, and 12.2 months (7.9-12.2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7-29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3-5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3-5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2.INTERPRETATION: Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients.FUNDING: Merck, International Breast Cancer Study Group.
CANIT0002267	30765392	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	35	N/A	N/A	We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR, 1.72; 95% confidence interval, 1.10-2.68; P = 0.017). No relationship was seen in cohorts of patients with NSCLC who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be due to NK-cell dysfunction.	N/A	N/A	N/A	KIR3DS1 (Q14943); 	Genetic variant of KIR3DS1	Mutational status	 2019 May 15	A Variant of a Killer Cell Immunoglobulin-like Receptor Is Associated with Resistance to PD-1 Blockade in Lung Cancer.	 Clin Cancer Res	PURPOSE: PD-(L)1-blocking antibodies have clinical activity in metastatic non-small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways.EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells were collected from 35 patients with NSCLC receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and nonresponders to treatment. Findings were confirmed in additional cohorts of patients with NSCLC receiving immune checkpoint blockade.RESULTS: We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR, 1.72; 95% confidence interval, 1.10-2.68; P = 0.017). No relationship was seen in cohorts of patients with NSCLC who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be due to NK-cell dysfunction.CONCLUSIONS: We identified an association of the KIR3DS1 allelic variant with response to PD-1-targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. Although the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive markers for response to PD-1-targeted immunotherapy.
CANIT0002268	30767428	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	148	N/A	N/A	From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery. Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.	N/A	N/A	N/A	Treatment history (NCIT:C160179); Ipilimumab (DB06186); 	Prior treatment with ipilimumab	Disease status	 2019 Jul	Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti-PD-1 antibodies.	 Pigment Cell Melanoma Res	BACKGROUND: Brain radiotherapy is used in the management of melanoma brain metastases (MBM) and can result in radionecrosis. Anti-PD-1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer-term survivors with MBM treated with this combination.METHODS: Patients with MBM treated with radiotherapy and anti-PD-1 who survived >1 year were identified to determine radionecrosis incidence (Cohort A, n = 135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (Cohort B, n = 148).RESULTS: From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery.CONCLUSIONS: Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.
CANIT0002269	30767428	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	148	N/A	N/A	From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery. Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Jul	Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti-PD-1 antibodies.	 Pigment Cell Melanoma Res	BACKGROUND: Brain radiotherapy is used in the management of melanoma brain metastases (MBM) and can result in radionecrosis. Anti-PD-1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer-term survivors with MBM treated with this combination.METHODS: Patients with MBM treated with radiotherapy and anti-PD-1 who survived >1 year were identified to determine radionecrosis incidence (Cohort A, n = 135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (Cohort B, n = 148).RESULTS: From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery.CONCLUSIONS: Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.
CANIT0002270	30768970	Clinical research	Lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab or nivolumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); nivolumab (DB09035); 	105	N/A	N/A	Elderly patients were characterized by increased numbers of CD8+ T cells and impaired cytolytic molecule expression. The observed immune signature was also associated with a loss of clonal neoantigens and the accumulation of immunosuppressive elements. These findings show a unique immune microenvironment in senescence and support biomarker-guided candidate identification for anti-PD-1/PD-L1 therapeutic strategies for elderly patients with lung adenocarcinoma.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8(+) T-cells	Gene expression signature on/in immune cell	 2019 May	Impaired Cytolytic Activity and Loss of Clonal Neoantigens in Elderly Patients With Lung Adenocarcinoma.	 J Thorac Oncol	INTRODUCTION: Whether the efficacy of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors declines with senescence remains controversial for lung adenocarcinoma (LUAD). Responsiveness to anti-PD-1/PD-L1 therapy is thought to rely on neoantigen exposure and immune elements in the tumor microenvironment. In this study, we explored the features of the tumor immune microenvironment in elderly patients with treatment-na ve LUAD.METHODS: Transcriptome profiles and clinical characteristics of patients with LUAD were retrieved from The Cancer Genome Atlas as a discovery cohort. Immune cell infiltration (quantified by a single-sample gene set enrichment analysis), immunoregulatory molecule expression, and mutational patterns (from The Cancer Immunome Atlas) were compared between young and elderly patients. Immune cell infiltration was verified by immunohistochemistry using a validation cohort including 105 treatment-na ve patients with LUAD. A tissue microarray consisting of 120 LUAD patients was used in the immunohistochemistry validation.RESULTS: Activated CD8+ T cell numbers increased slightly with age, but cytolytic molecules in T cells (granzyme B [GZMB], perforin 1 [PRF1], granzyme A [GZMA], granzyme M [GZMM], and granulysin [GNLY]) gradually declined. PD-L1 expression was not associated with age; however, a number of immunosuppressive elements beyond PD-L1 were upregulated in aging patients, including regulatory T cells and co-inhibitory molecules, for example, TIM-3, TIGIT, and HHLA2. Finally, senescence was accompanied by a loss of clonal neoantigens, which is believed to be correlated with responsiveness to immune checkpoint inhibitors.CONCLUSIONS: Elderly patients were characterized by increased numbers of CD8+ T cells and impaired cytolytic molecule expression. The observed immune signature was also associated with a loss of clonal neoantigens and the accumulation of immunosuppressive elements. These findings show a unique immune microenvironment in senescence and support biomarker-guided candidate identification for anti-PD-1/PD-L1 therapeutic strategies for elderly patients with LUAD.
CANIT0002271	30780002	Clinical research	Non-Small Cell Lung Cancer and Brain Metastases	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	1025	N/A	Retrospective analysis	In the Brain metastasis (BM) subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS. Stable patients with BM without baseline corticosteroids has the best prognosis.	N/A	N/A	N/A	Corticosteroids (NCIT:C211); 	Corticosteroid use	Exposure factors/status	 2019 Jul	Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors.	 J Thorac Oncol	INTRODUCTION: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.METHODS: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.RESULTS: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p < 0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS.CONCLUSION: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis.
CANIT0002272	30780002	Clinical research	Non-Small Cell Lung Cancer and Brain Metastases	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	1025	N/A	Retrospective analysis	In the Brain metastasis (BM) subgroup multivariate analysis, stable BMs (HR = 0.62) and higher Disease-specific Graded Prognostic Assessment (ds-GPA) classification (HR = 0.48-0.52) were associated with improved OS. Stable patients with BM without a good ds-GPA classification has the best prognosis.	N/A	N/A	N/A	Disease-specific Graded Prognostic Assessment Score (NCIT:C140884); 	Disease-specific Graded Prognostic Assessment (ds-GPA) score	Disease status	 2019 Jul	Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors.	 J Thorac Oncol	INTRODUCTION: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.METHODS: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.RESULTS: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p < 0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS.CONCLUSION: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis.
CANIT0002273	30780002	Clinical research	Non-Small Cell Lung Cancer and Brain Metastases	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	1025	N/A	Retrospective analysis	In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS.In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2019 Jul	Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors.	 J Thorac Oncol	INTRODUCTION: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.METHODS: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.RESULTS: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p < 0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS.CONCLUSION: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis.
CANIT0002274	30785829	Clinical research	Advanced/metastatic non-small-cell lung cancer (NSCLC)	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	288	N/A	Phase II trial	Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.	Grade 3 to 4 treatment-related adverse events occurred in 29% of patients.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Apr 20	First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers.	 J Clin Oncol	PURPOSE: CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB).PATIENTS AND METHODS: Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point.RESULTS: Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, >= 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, >= 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients.CONCLUSION: Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.
CANIT0002275	30785829	Clinical research	Advanced/metastatic non-small-cell lung cancer (NSCLC)	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	288	N/A	Phase II trial	Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.	Grade 3 to 4 treatment-related adverse events occurred in 29% of patients.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Apr 20	First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers.	 J Clin Oncol	PURPOSE: CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB).PATIENTS AND METHODS: Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point.RESULTS: Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, >= 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, >= 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients.CONCLUSION: Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.
CANIT0002276	30789633	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	550	546	Phase 3 randomized clinical trial	In this model, nivolumab plus ipilimumab was estimated to be cost-effective compared with sunitinib for intermediate- and poor-risk patients withmetastatic renal cell carcinoma (mRCC) at a willingness-to-pay threshold from $100 000 to $150 000 per QALY.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Apr 1	First-line Nivolumab Plus Ipilimumab vs Sunitinib for Metastatic Renal Cell Carcinoma: A Cost-effectiveness Analysis.	 JAMA Oncol	IMPORTANCE: Recently, new drugs have been approved for the first-line treatment of metastatic renal cell carcinoma (mRCC). Nivolumab plus ipilimumab significantly increases overall survival for intermediate- and poor-risk patients with mRCC. However, considering the high cost of nivolumab plus ipilimumab, there is a need to assess its value by considering both efficacy and cost.OBJECTIVE: To evaluate the cost-effectiveness of nivolumab plus ipilimumab vs sunitinib in the first-line setting for intermediate- and poor-risk patients with mRCC from the US payer perspective.DESIGN, SETTING, AND PARTICIPANTS: A Markov model was developed to compare the lifetime cost and effectiveness of nivolumab plus ipilimumab vs sunitinib in the first-line treatment of mRCC using outcomes data from the CheckMate 214 phase 3 randomized clinical trial, which included 1096 patients with mRCC (median age, 62 years) and compared nivolumab plus ipilimumab vs sunitinib as first-line treatment of mRCC. In the analysis, patients were modeled to receive sunitinib or nivolumab plus ipilimumab for 4 doses followed by nivolumab monotherapy.MAIN OUTCOMES AND MEASURES: Life-years, quality-adjusted life-years (QALYs), and lifetime costs were estimated, at a willingness-to-pay threshold of $100 000 to $150 000 per QALY. Univariable, 2-way, and probabilistic sensitivity analyses were performed to evaluate the model uncertainty. Additional subgroup analyses were performed.RESULTS: Nivolumab plus ipilimumab provided an additional 0.96 QALYs, at a cost of $108 363 per QALY. Sensitivity analyses found the results to be most sensitive to overall survival hazard ratio (0.63; 95% CI, 0.44-0.89) and mean patient weight (70 kg, range, 40-200 kg). Other variables, such as the cost of nivolumab plus ipilimumab (mean, $32 213.44; range, $25 770.75-$38 656.13), utility values for nivolumab plus ipilimumab (mean, 0.82; range, 0.65-0.98), and proportion receiving nivolumab in sunitinib arm (mean, 0.27; range, 0.22-0.32), had a moderate or minor influence on model results. Subgroup analyses demonstrated that nivolumab plus ipilimumab was most cost-effective for patients with programmed cell death 1 ligand 1 expression of at least 1% ($86 390 per QALY).CONCLUSIONS AND RELEVANCE: In this model, nivolumab plus ipilimumab was estimated to be cost-effective compared with sunitinib for intermediate- and poor-risk patients with mRCC at a willingness-to-pay threshold from $100 000 to $150 000 per QALY.
CANIT0002277	30792455	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	42	N/A	Retrospective analysis	Sarcopenia was significantly associated with poorer progression-free survival (PFS) (median, 2.1 vs. 6.8 months, p = 0.004). Compared to patients with sarcopenia, those without sarcopenia had a higher overall response rate (40.0% vs. 9.1%, p = 0.025) and 1-year PFS rate (38.1% vs. 10.1%).	N/A	N/A	N/A	Sarcopenia ()	Sarcopenia	Adverse events	 2019 Feb 21	Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study.	 Sci Rep	The aim of this study was to investigate the clinical impact of sarcopenia on the efficacy of programmed death (PD)-1 inhibitors. We retrospectively reviewed the medical records of all patients treated with nivolumab or pembrolizumab between January 2016 and September 2018 for previously treated advanced non-small cell lung cancer (NSCLC). The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on baseline computed tomography was assessed to calculate the psoas muscle index (PMI). Sarcopenia was defined based on PMI cut-off values for Asian adults (6.36 cm2/m2 for males and 3.92 cm2/m2 for females). A total of 42 patients were analysed. The prevalence of sarcopenia was 52.4%. Sarcopenia was significantly associated with poorer progression-free survival (PFS) (median, 2.1 vs. 6.8 months, p = 0.004). Compared to patients with sarcopenia, those without sarcopenia had a higher overall response rate (40.0% vs. 9.1%, p = 0.025) and 1-year PFS rate (38.1% vs. 10.1%). In conclusion, sarcopenia at baseline as determined using computed tomography is a significant predictor of worse outcome in patients with advanced NSCLC receiving PD-1 blockade. Screening for sarcopenia may help identify patients more likely to achieve a long-term response in routine clinical practice.
CANIT0002278	30796424	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	8947	N/A	Retrospective analysis	Overall across 8947 patients, Time-to-treatment discontinuation (TTD) was more closely associated with PFS (r = 0.87, 95% CI 0.86-0.87) than with OS (0.68, 95% CI 0.67-0.69). Early TTD (PFS-TTD >= 3 months) occurred in 7.7% of patients overall, and was more common with chemo monotherapy (15.0%) while late TTD (TTD-PFS >= 3 months) occurred in 6.0% of patients overall, and was more common in EGFR-positive and ALK-positive patients (12.4% and 22.9%). In oncogene-targeted subgroups (EGFR positive and ALK positive), median TTDs (13.4 and 14.1 months) exceeded median PFS (11.4 and 11.3 months).	N/A	N/A	N/A	Therapy cycles (); 	Time-to-treatment discontinuation	Exposure factors/status	 2019 May 1	Analysis of time-to-treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer.	 Ann Oncol	BACKGROUND: Pragmatic end points, such as time-to-treatment discontinuation (TTD), defined as the date of starting a medication to the date of treatment discontinuation or death has been proposed as a potential efficacy end point for real-world evidence (RWE) trials, where imaging evaluation is less structured and standardized.PATIENTS AND METHODS: We studied 18 randomized clinical trials of patients with metastatic non-small-cell lung cancer (mNSCLC), initiated after 2007 and submitted to U.S. Food and Drug Administration. TTD was calculated as date of randomization to date of discontinuation or death and compared to progression-free survival (PFS) and overall survival (OS) across all patients, as well as in treatment-defined subgroups [EGFR mutation-positive treated with tyrosine kinase inhibitor (TKI), EGFR wild-type treated with TKI, ALK-positive treated with TKI, immune checkpoint inhibitor (ICI), chemotherapy doublet with maintenance, chemotherapy monotherapy].RESULTS: Overall across 8947 patients, TTD was more closely associated with PFS (r = 0.87, 95% CI 0.86-0.87) than with OS (0.68, 95% CI 0.67-0.69). Early TTD (PFS-TTD >= 3 months) occurred in 7.7% of patients overall, and was more common with chemo monotherapy (15.0%) while late TTD (TTD-PFS >= 3 months) occurred in 6.0% of patients overall, and was more common in EGFR-positive and ALK-positive patients (12.4% and 22.9%). In oncogene-targeted subgroups (EGFR positive and ALK positive), median TTDs (13.4 and 14.1 months) exceeded median PFS (11.4 and 11.3 months).CONCLUSIONS: At the patient level, TTD is associated with PFS across therapeutic classes. Median TTD exceeds median PFS for biomarker-selected patients receiving oncogene-targeted therapies. TTD should be prospectively studied further as an end point for pragmatic randomized RWE trials only for continuously administered therapies.
CANIT0002279	30809973	Clinical research	152 patients 	Non-small cell lung carcinoma	EFO:0003060	Lung	VEGFR2 (P35968); 	VEGFR2; 	Nivolumab followed by ramucirumab plus docetaxel	N/A	Immune checkpoint therapy plus Target therapy plus Chemotherapy	Nivolumab (DB09035); ramucirumab (DB05578); docetaxel (DB01248); 	152	N/A	Retrospective analysis	Ramucirumab plus docetaxel achieved a higher response rate when administered immediately after nivolumab failure compared to regimens without prior nivolumab administration	Gastrointestinal adverse events were frequently observed in 19 patients	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Improved efficacy of ramucirumab plus docetaxel after nivolumab failure in previously treated non-small cell lung cancer patients.	 Thorac Cancer	BACKGROUND: It is unclear whether the chemotherapy response improves after exposure to immunotherapy. Antiangiogenic agents have been shown to stimulate the immune system and cause synergistic effects that stimulate tumor shrinkage. We conducted a retrospective study to evaluate improvement of the efficacy of ramucirumab plus docetaxel after the failure of nivolumab as a PD-1 inhibitor.METHODS: From February 2016 to December 2017, 152 patients with non-small cell lung cancer (NSCLC) administered nivolumab in our institution were identified. We reviewed the records of 20 NSCLC patients administered ramucirumab plus docetaxel after nivolumab failure. The overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were investigated. Pegylated granulocyte colony-stimulating factor was prophylactically administered to 18 patients (90%) after the administration of ramucirumab plus docetaxel.RESULTS: The median age of the patients was 70 (range: 55-77) years. Twelve patients were male and eight were female. The histology was adenocarcinoma in 16 patients, squamous cell carcinoma in three, and other in one. The ORR of ramucirumab plus docetaxel was 60%, and the PFS and OS were 169 and 343 days, respectively. Among the 20 patients, 12 achieved a partial response, giving an ORR of 60.0%. Six patients had stable disease and two had progressive disease. The disease control rate was 90%. Gastrointestinal adverse events were frequently observed in 19 patients.CONCLUSIONS: Ramucirumab plus docetaxel achieved a higher response rate when administered immediately after nivolumab failure compared to regimens without prior nivolumab administration.
CANIT0002280	30810218	Case report	Eruptive porokeratosis	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Among the different clinical subtypes of porokeratosis, the case could be classified as eruptive pruritic papular porokeratosis, a form that evolves rapidly, is associated with pruritus, is not related to family history and photodamaged skin. Eruptive porokeratosis under nivolumab adjuvant treatment for melanoma.	Pruritic lesions	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Eruptive porokeratosis under nivolumab adjuvant treatment for melanoma.	 Int J Dermatol	Unable to provide
CANIT0002281	30811629	Case report	A 65-year-old white woman	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We present a patient with locally advanced cutaneous squamous cell carcinoma (cSCC) of the left upper lip and columella treated with pembrolizumab, highlighting both its use in the treatment of an advanced cSCC and the unique histologic findings of multiple keratin granulomata with adjacent lymphocytic aggregates and fibrosis	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Multiple keratin granulomata: A potential histologic clue to cutaneous squamous cell carcinoma responding to programmed cell death protein 1 inhibitor therapy.	 J Cutan Pathol	We present histologic features of a locally advanced cutaneous squamous cell carcinoma (cSCC) treated with the programmed cell death protein-1 (PD-1) antagonist, pembrolizumab, with a partial response. This contributes to a growing body of literature supporting the efficacy of pembrolizumab in treatment of surgically unresectable cSCC. We also provide a detailed description of the histologic features, particularly keratin granulomata with adjacent lymphocytic aggregates and fibrosis, observed in cSCC under treatment with a PD-1 antagonist.
CANIT0002282	30814440	Case report	Breast cancer	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	In our recent case of a 52-year-old female doctor suffering from breast cancer having metastasized to the lung and liver, it was decided to use nivolumab to prevent the disease progressing after excisional surgeries and multiple chemotherapies. One month after completing the nivolumab course, fatigue, hypoglycemia and hypotension developed and isolated ACTH deficiency (IAD) was diagnosed. A further month later, under steroid supplementation, hyperglycemia emerged alongside thirst and polydipsia, prompting a diagnosis of fulminant type 1 diabetes (FT1D). Her susceptibility to type 1 diabetes was examined by HLA haplotype and CTLA4 gene polymorphism analyses. Polymorphisms CT60G>A and +49G>A in CTLA4 both generated a GG genotype. Our patient manifested one of the rarest combinations of autoimmune disease induced by nivolumab. Whereas the HLA haplotype was unsusceptible to autoimmune type 1 diabetes, polymorphisms of CTLA4, the antibody of which frequently causes hypophysitis, were susceptible to FT1D. Peripheral modulation of activated T cells, mainly by PD-1 antibodies, induced FT1D associated with IAD in patients with CTLA4 polymorphism. This case reveals hints of the T-cell etiology in T1D and evidence of CTLA4 involvement in IAD.	Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody	N/A	N/A	N/A	N/A	N/A	 2019 Apr 25	Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody-insight into the pathogenesis of autoimmune endocrinopathy.	 Endocr J	Therapeutic blocking antibodies against programmed death 1 (PD1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are applied for advanced cancer therapy, but induce a wide range of immune-related adverse events. In our recent case of a 52-year-old female doctor suffering from breast cancer having metastasized to the lung and liver, it was decided to use nivolumab to prevent the disease progressing after excisional surgeries and multiple chemotherapies. One month after completing the nivolumab course, fatigue, hypoglycemia and hypotension developed and isolated ACTH deficiency (IAD) was diagnosed. A further month later, under steroid supplementation, hyperglycemia emerged alongside thirst and polydipsia, prompting a diagnosis of fulminant type 1 diabetes (FT1D). Her susceptibility to type 1 diabetes was examined by HLA haplotype and CTLA4 gene polymorphism analyses. Polymorphisms CT60G>A and +49G>A in CTLA4 both generated a GG genotype. Our patient manifested one of the rarest combinations of autoimmune disease induced by nivolumab. Whereas the HLA haplotype was unsusceptible to autoimmune type 1 diabetes, polymorphisms of CTLA4, the antibody of which frequently causes hypophysitis, were susceptible to FT1D. Peripheral modulation of activated T cells, mainly by PD-1 antibodies, induced FT1D associated with IAD in patients with CTLA4 polymorphism. This case reveals hints of the T-cell etiology in T1D and evidence of CTLA4 involvement in IAD.
CANIT0002283	30835875	Case report	Metastatic melanoma with adrenal metastasis	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab plus TACE Surgery	N/A	Immune checkpoint therapy plus Surgery	Nivolumab (DB09035); 	1	N/A	Case	TACE would be one good option for patients showing localized progression of adrenal metastatic site, especially for those undergoing ICI treatment	Pain and slight fever	N/A	N/A	Metastasis (NCIT:C19151); 	Localized progression of adrenal metastatic site	Disease status	 2019 Aug	Successful control of adrenal metastasis with transcatheter arterial chemoembolization in metastatic melanoma patient undergoing treatment with immune checkpoint inhibitor.	 J Dermatol	Unable to provide
CANIT0002284	30837448	Case report	An elderly female	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The patient was not a candidate for chemotherapy due to kidney failure. On the basis of ongoing separate trials on different immunotherapies, she was started on nivolumab. Treating metastatic cutaneous squamous cell carcinoma is a challenge considering the absence of phase III trials due to the rarity of this disease. Historically, platinum with or without 5-FU (fluorouracil), bleomycin, doxorubicin, and retinoic acid were used with variable responses. Data on epidermal growth factor receptor (EGFR) inhibitors on EGFR expressing tumors are available. However, even with the most recent reports on immunotherapy in patients with high programmed death-1 expression or high mutation burden, it is difficult to achieve good response.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar 6	Uncommon Presentation of Metastatic Squamous Cell Carcinoma of the Skin and Treatment Challenges.	 Am J Case Rep	BACKGROUND Squamous cell carcinoma is one of the most common keratinocytic skin cancers, the other being basal cell carcinoma. It is the second most common skin cancer after melanoma. Cutaneous squamous cell carcinoma is mostly a localized disease. The metastatic presentation is rare even in the presence of invasive disease. The metastatic potential depends on the presence of high-risk features at the time of diagnosis. Lung, liver, and bone are the frequent sites of metastasis. Local and locoregional disease undergoes excision with or without adjuvant radiation. However, we lack proper treatment paradigms for this metastatic disease. CASE REPORT We are reporting a case of an elderly female with a history of high-risk localized cutaneous squamous cell carcinoma treated with complete local excision and radiation presenting 5 years later with extensive disease to the lung and liver, abdominal nodes, and spinal fracture. The patient was not a candidate for chemotherapy due to kidney failure. On the basis of ongoing separate trials on different immunotherapies, she was started on nivolumab. CONCLUSIONS Treating metastatic cutaneous squamous cell carcinoma is a challenge considering the absence of phase III trials due to the rarity of this disease. Historically, platinum with or without 5-FU (fluorouracil), bleomycin, doxorubicin, and retinoic acid were used with variable responses. Data on epidermal growth factor receptor (EGFR) inhibitors on EGFR expressing tumors are available. However, even with the most recent reports on immunotherapy in patients with high programmed death-1 expression or high mutation burden, it is difficult to achieve good response.
CANIT0002285	30838402	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	N/A	N/A	N/A	In the illustrative dataset, the net survival benefit favored ipilimumab [¦¤(0) = 15.8%, 95% confidence interval = 4.6% to 27.3%, P = .006]. This favorable effect was maintained when the analysis was focused on long-term survival differences (eg, >12 months, ¦¤(12) = 12.5% (95% confidence interval = 4.4% to 20.6%, P = .002). Under the scenarios of a delayed treatment effect and cure rate, the power of the net survival benefit test compared favorably to the standard log-rank test power and was comparable to the power of the weighted log-rank test for large values of the threshold of clinical relevance.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov 1	Assessing Long-Term Survival Benefits of Immune Checkpoint Inhibitors Using the Net Survival Benefit.	 J Natl Cancer Inst	Unable to provide
CANIT0002286	30849967	Clinical research	70 patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	46	24	Multivariate analysis	The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. serum level of NSE was not significant for monitoring the efficacy of nivolumab.	N/A	N/A	N/A	NSE (Q96MF7); 	Serum NSE levels	Gene expression signature in serum	 2019 Mar 8	The role of CEA, CYFRA21-1 and NSE in monitoring tumor response to Nivolumab in advanced non-small cell lung cancer (NSCLC) patients.	 J Transl Med	BACKGROUND: CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung cancer, respectively. Their role in cancer immunotherapy needs to be elucidated.METHODS: Patients with advanced non-small cell lung cancer (NSCLC) were treated with nivolumab 3 mg/kg every 2 weeks within the Italian Nivolumab Expanded Access Program. Blood samples were collected at baseline, at each cycle up to cycle 5 and then every two cycles until patient's withdrawn from the study. All patients underwent a CT-scan after every 4 cycles of treatment and responses were classified according to RECIST 1.1. The biomarkers serum levels were measured with a chemiluminescent microparticle immunoassay for CEA and with an immuno radiometric assay for CYFRA21-1 and NSE. The markers values at baseline and after 4 cycles were used to analyze the relationship between their variation over baseline and the tumor response, evaluated as disease control rate (DCR: CR + PR + SD), and survival (PFS and OS).RESULTS: A total of 70 patients were evaluable for the analysis. Overall, a disease control was obtained in 24 patients (35.8%, 4 PR + 20 SD). After 4 cycles of nivolumab a CEA or CYFRA21-1 reduction >= 20% over the baseline was significantly associated with DCR (CEA, p = 0.021; CYFRA21-1, p < 0.001), PFS (CEA, p = 0.028; CYFRA21-1, p < 0.001) and OS (CEA, p = 0.026; CYFRA21-1, p = 0.019). Multivariate analysis confirmed the ability of CYFRA21-1 reduction >= 20% to predict DCR (p = 0.002) and PFS (p < 0.001).CONCLUSION: The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab.
CANIT0002287	30849967	Clinical research	70 patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	46	24	Multivariate analysis	The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab	N/A	N/A	N/A	CEA (P06731); 	Serum CEA levels	Gene expression signature in serum	 2019 Mar 8	The role of CEA, CYFRA21-1 and NSE in monitoring tumor response to Nivolumab in advanced non-small cell lung cancer (NSCLC) patients.	 J Transl Med	BACKGROUND: CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung cancer, respectively. Their role in cancer immunotherapy needs to be elucidated.METHODS: Patients with advanced non-small cell lung cancer (NSCLC) were treated with nivolumab 3 mg/kg every 2 weeks within the Italian Nivolumab Expanded Access Program. Blood samples were collected at baseline, at each cycle up to cycle 5 and then every two cycles until patient's withdrawn from the study. All patients underwent a CT-scan after every 4 cycles of treatment and responses were classified according to RECIST 1.1. The biomarkers serum levels were measured with a chemiluminescent microparticle immunoassay for CEA and with an immuno radiometric assay for CYFRA21-1 and NSE. The markers values at baseline and after 4 cycles were used to analyze the relationship between their variation over baseline and the tumor response, evaluated as disease control rate (DCR: CR + PR + SD), and survival (PFS and OS).RESULTS: A total of 70 patients were evaluable for the analysis. Overall, a disease control was obtained in 24 patients (35.8%, 4 PR + 20 SD). After 4 cycles of nivolumab a CEA or CYFRA21-1 reduction >= 20% over the baseline was significantly associated with DCR (CEA, p = 0.021; CYFRA21-1, p < 0.001), PFS (CEA, p = 0.028; CYFRA21-1, p < 0.001) and OS (CEA, p = 0.026; CYFRA21-1, p = 0.019). Multivariate analysis confirmed the ability of CYFRA21-1 reduction >= 20% to predict DCR (p = 0.002) and PFS (p < 0.001).CONCLUSION: The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab.
CANIT0002288	30849967	Clinical research	70 patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	46	24	Multivariate analysis	The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab	N/A	N/A	N/A	CYFRA21-1	Serum lCYFRA21-1 levels	Gene expression signature in serum	 2019 Mar 8	The role of CEA, CYFRA21-1 and NSE in monitoring tumor response to Nivolumab in advanced non-small cell lung cancer (NSCLC) patients.	 J Transl Med	BACKGROUND: CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung cancer, respectively. Their role in cancer immunotherapy needs to be elucidated.METHODS: Patients with advanced non-small cell lung cancer (NSCLC) were treated with nivolumab 3 mg/kg every 2 weeks within the Italian Nivolumab Expanded Access Program. Blood samples were collected at baseline, at each cycle up to cycle 5 and then every two cycles until patient's withdrawn from the study. All patients underwent a CT-scan after every 4 cycles of treatment and responses were classified according to RECIST 1.1. The biomarkers serum levels were measured with a chemiluminescent microparticle immunoassay for CEA and with an immuno radiometric assay for CYFRA21-1 and NSE. The markers values at baseline and after 4 cycles were used to analyze the relationship between their variation over baseline and the tumor response, evaluated as disease control rate (DCR: CR + PR + SD), and survival (PFS and OS).RESULTS: A total of 70 patients were evaluable for the analysis. Overall, a disease control was obtained in 24 patients (35.8%, 4 PR + 20 SD). After 4 cycles of nivolumab a CEA or CYFRA21-1 reduction >= 20% over the baseline was significantly associated with DCR (CEA, p = 0.021; CYFRA21-1, p < 0.001), PFS (CEA, p = 0.028; CYFRA21-1, p < 0.001) and OS (CEA, p = 0.026; CYFRA21-1, p = 0.019). Multivariate analysis confirmed the ability of CYFRA21-1 reduction >= 20% to predict DCR (p = 0.002) and PFS (p < 0.001).CONCLUSION: The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab.
CANIT0002289	30850565	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We describe the clinical course of a 64-year-old woman with stage IVa lung adenocarcinoma who presented with over 1 month of fatigue, unintentional weight loss and emesis. She initiated treatment with nivolumab immunotherapy 1 year prior and had been tolerating the treatment well. A comprehensive workup revealed multiple endocrinological abnormalities consistent with hypophysitis leading to hypopituitarism in the form of central adrenal insufficiency and hypogonadism as well as a partially empty sella on imaging.	Nivolumab-induced hypophysitis leading to hypopituitarism and secondary empty sella syndrome	N/A	N/A	N/A	N/A	N/A	 2019 Mar 7	Nivolumab-induced hypophysitis leading to hypopituitarism and secondary empty sella syndrome in a patient with non-small cell lung cancer.	 BMJ Case Rep	We describe the clinical course of a 64-year-old woman with stage IVa lung adenocarcinoma who presented with over 1 month of fatigue, unintentional weight loss and emesis. She initiated treatment with nivolumab immunotherapy 1 year prior and had been tolerating the treatment well. A comprehensive workup revealed multiple endocrinological abnormalities consistent with hypophysitis leading to hypopituitarism in the form of central adrenal insufficiency and hypogonadism as well as a partially empty sella on imaging. This case demonstrates that while receiving novel forms of treatment such as immunotherapy, patients should be monitored closely for a wide range of adverse effects.
CANIT0002290	30850589	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	37	N/A	N/A	Here we report that cigarette smoke and the carcinogen benzo(a)pyrene (BaP) induce PD-L1 expression on lung epithelial cells in vitro and in vivo, which is mediated by aryl hydrocarbon receptor (AhR). Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer. In 37 patients treated with anti-PD-1 antibody pembrolizumab, 13/16 (81.3%) patients who achieve partial response or stable disease express high levels of AhR, whereas 12/16 (75%) patients with progression disease exhibit low levels of AhR in tumor tissues. AhR inhibitors exert significant antitumor activity and synergize with anti-PD-L1 antibody in lung cancer mouse models.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	AHR (P35869); 	Aryl hydrocarbon receptor levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Mar 8	The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy.	 Nat Commun	Whether tobacco carcinogens enable exposed cells immune escape resulting in carcinogenesis, and why patients who smoke respond better to immunotherapies than non-smokers, remains poorly understood. Here we report that cigarette smoke and the carcinogen benzo(a)pyrene (BaP) induce PD-L1 expression on lung epithelial cells in vitro and in vivo, which is mediated by aryl hydrocarbon receptor (AhR). Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer. In 37 patients treated with anti-PD-1 antibody pembrolizumab, 13/16 (81.3%) patients who achieve partial response or stable disease express high levels of AhR, whereas 12/16 (75%) patients with progression disease exhibit low levels of AhR in tumor tissues. AhR inhibitors exert significant antitumor activity and synergize with anti-PD-L1 antibody in lung cancer mouse models. These results demonstrate that tobacco smoke enables lung epithelial cells to escape from adaptive immunity to promote tumorigenesis, and AhR predicts the response to immunotherapy and represents an attractive therapeutic target.
CANIT0002291	30850839	Basic research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	These findings show that BLT immune humanized mice can demonstrate immune-mediated adverse effects of antiPD1 therapy, and may represent a model that can be used to better understand toxicity of this class of drugs.	Both BLT-humanized strains showed adverse reactions similar to those reported in humans, including pneumonitis and hepatitis, with nephritis, dermatitis and adrenalitis also noted in some individuals. Additional histopathologic findings included pancreatic atrophy, myositis, and osteomyelitis in some animals.	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 May 1	BLT-Immune Humanized Mice as a Model for Nivolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains.	 Toxicol Sci	Checkpoint inhibitors represent a new class of therapeutics in the treatment of cancer that has demonstrated remarkable clinical effectiveness. However, some patients have experienced serious immune-mediated adverse effects including pneumonitis, hepatitis, colitis, nephritis, dermatitis, encephalitis, and adrenal or pituitary insufficiency. These adverse events were not predicted by nonclinical studies. To determine if bone marrow-liver-thymus (BLT) immune humanized mice could demonstrate these adverse effects, we studied the effect of nivolumab on 2 strains of BLT-humanized mice, NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac (NOG) and NOD.Cg-Prkdcscid Il2rgtm1Sug Tg(SV40/HTLV-IL3, CSF2)10-7Jic/JicTac (NOG-EXL). Mice were treated with 2.5, 5.0, or 10.0 mg/kg nivolumab or saline twice weekly for 28 days. BLT-NOG mice had significantly reduced survival compared with BLT-NOG-EXL mice. In spite of the difference in survival, both BLT-humanized strains showed adverse reactions similar to those reported in humans, including pneumonitis and hepatitis, with nephritis, dermatitis and adrenalitis also noted in some individuals. Additional histopathologic findings included pancreatic atrophy, myositis, and osteomyelitis in some animals. T-cell activation increased with concomitant loss of PD-1 detection. These findings show that BLT immune humanized mice can demonstrate immune-mediated adverse effects of antiPD1 therapy, and may represent a model that can be used to better understand toxicity of this class of drugs.
CANIT0002292	30852924	Clinical research	BRAF-mutant advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Cobimetinib plus vemurafenib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	124	247	Meta-analysis	After adjusting, nivolumab + ipilimumab showed improved OS versus vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36-0.89); OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar.	Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab and 59.5% with vemurafenib + cobimetinib.	N/A	N/A	N/A	N/A	N/A	 2019 May	Comparative efficacy of combination immunotherapy and targeted therapy in the treatment of BRAF-mutant advanced melanoma: a matching-adjusted indirect comparison.	 Immunotherapy	AIM: Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors (dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma.METHODS: Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (CheckMate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall survival (OS), progression-free survival and objective response rates were assessed.RESULTS: After adjusting, nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64; 95% CI: 0.46-0.89) or vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36-0.89); OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar. Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab, 31.6% with dabrafenib + trametinib and 59.5% with vemurafenib + cobimetinib.CONCLUSION: Nivolumab + ipilimumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increasing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary to prospectively validate these findings.
CANIT0002293	30852924	Clinical research	BRAF-mutant advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Dabrafenib plus trametinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	124	563	Meta-analysis	After adjusting, nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64; 95% CI: 0.46-0.89) ; OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar.Nivolumab + ipilimumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increasing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary to prospectively validate these findings.	Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab and 31.6% with dabrafenib + trametinib	N/A	N/A	N/A	N/A	N/A	 2019 May	Comparative efficacy of combination immunotherapy and targeted therapy in the treatment of BRAF-mutant advanced melanoma: a matching-adjusted indirect comparison.	 Immunotherapy	AIM: Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors (dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma.METHODS: Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (CheckMate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall survival (OS), progression-free survival and objective response rates were assessed.RESULTS: After adjusting, nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64; 95% CI: 0.46-0.89) or vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36-0.89); OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar. Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab, 31.6% with dabrafenib + trametinib and 59.5% with vemurafenib + cobimetinib.CONCLUSION: Nivolumab + ipilimumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increasing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary to prospectively validate these findings.
CANIT0002294	30853817	Case report	Non-small-cell lung carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); 	1	N/A	Case	We present a patient with type 1 diabetes mellitus secondary to immunotherapy, together with an overview of the associated literature. Patients who develop type 1 diabetes mellitus experience a rapid course, and diabetic ketoacidosis is commonly the presenting symptom. Insulin is currently the treatment of choice; oral antidiabetics or corticosteroids do not assist in management.	Diabetes mellitus	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Diabetes mellitus secondary to treatment with immune checkpoint inhibitors.	 Curr Oncol	Cancer immunotherapy has been one of the highlights in the advancement of cancer care. Certain immune checkpoint inhibitors bind to PD-1 on T cells and mediate an antitumour immune response. Given that immune checkpoint inhibitors are becoming part of standard care, a new class of adverse events-immune-related adverse events-has emerged. Among them is endocrine toxicity, most commonly targeting the thyroid, pituitary, or adrenal glands. New-onset diabetes mellitus has been reported in fewer than 1% of patients. We present a patient with type 1 diabetes mellitus secondary to immunotherapy, together with an overview of the associated literature. Patients who develop type 1 diabetes mellitus experience a rapid course, and diabetic ketoacidosis is commonly the presenting symptom. Insulin is currently the treatment of choice; oral antidiabetics or corticosteroids do not assist in management. Several predictive factors are under investigation, but physician awareness and prompt management are key to a positive outcome.
CANIT0002295	30862448	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	19	N/A	N/A	In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness.	Inflammatory myopathy	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Inflammatory myopathy associated with PD-1 inhibitors.	 J Autoimmun	OBJECTIVE: To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy).METHODS: We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects.RESULTS: In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness.CONCLUSIONS: Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.
CANIT0002296	30864291	Clinical research	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); EGFR (P00533); 	PD-1; EGFR	Pembrolizumab or nivolumab plus different kinds of EGFR-tyrosine kinase inhibitor	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Four out of the 26 patients developed interstitial lung disease (ILD) during EGFR-TKI treatment: three patients during the administration of osimertinib immediately after, and one during afatinib immediately before treatment with an anti-PD-1 antibody. Three of 12 patients who underwent EGFR-TKI therapy immediately after anti-PD-1 antibody treatment experienced osimertinib-induced ILD. ILD was not observed in the five patients administered an anti-PD-1 antibody followed by first or second-generation EGFR-TKIs.	Interstitial lung disease	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Different incidence of interstitial lung disease according to different kinds of EGFR-tyrosine kinase inhibitors administered immediately before and/or after anti-PD-1 antibodies in lung cancer.	 Thorac Cancer	BACKGROUND: The aim of our study was to retrospectively assess the incidence of interstitial lung disease (ILD) related to EGFR-tyrosine kinase inhibitor (TKI) treatment immediately before and/or after the administration of a PD-1 antibody.METHODS: We analyzed the data of 26 patients who underwent treatment with EGFR-TKIs immediately before and/or after the administration of an anti-PD-1 antibody.RESULTS: Four out of the 26 patients developed ILD during EGFR-TKI treatment: three patients during the administration of osimertinib immediately after, and one during afatinib immediately before treatment with an anti-PD-1 antibody. Three of 12 patients who underwent EGFR-TKI therapy immediately after anti-PD-1 antibody treatment experienced osimertinib-induced ILD. ILD was not observed in the five patients administered an anti-PD-1 antibody followed by first or second-generation EGFR-TKIs.CONCLUSION: ILD was observed in the treatment sequence of an anti-PD-1 antibody followed by osimertinib, but not with first or second-generation EGFR-TKIs.
CANIT0002297	30866995	Basic research	Gastric cancer	Gastric cancer	MONDO:0001056	Stomach	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus rapamycin	N/A	Immune checkpoint therapy	N/A	Cell lines	N/A	Basic research	Mechanistic target of rapamycin (mTOR) inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type gastric cancer (GCs) which may develop from intestinal-type GCs.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Mar 12	A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors.	 J Exp Clin Cancer Res	BACKGROUND: Mechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most diffuse-type GCs were genomically stable (GS). Pathological analysis suggested that some diffuse-type GCs developed from intestinal-type GCs.METHODS: We established patient-derived xenograft (PDX) lines from diffuse-type GCs, and searched for drugs that suppressed their growth. Diffuse-type GCs were classified into subtypes by their gene expression profiles.RESULTS: mTOR inhibitor temsirolimus strongly suppressed the growth of PDX-derived diffuse-type GC-initiating cells, which was regulated via Wnt-mTOR axis. These cells were microsatellite unstable (MSI) or chromosomally unstable (CIN), inconsistent with TCGA report. Diffuse-type GCs in TCGA cohort could be classified into two clusters, and GS subtype was major in cluster I while CIN and MSI subtypes were predominant in cluster II where PDX-derived diffuse-type GC cells were included. We estimated that about 9 and 55% of the diffuse-type GCs in cluster II were responders to mTOR inhibitors and checkpoint inhibitors, respectively, by identifying PIK3CA mutations and MSI condition in TCGA cohort. These ratios were far greater than those of diffuse-type GCs in cluster I or intestinal-type GCs. Further analysis suggested that diffuse-type GCs in cluster II developed from intestinal-type GCs while those in cluster I from normal gastric epithelial cells.CONCLUSION: mTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs.
CANIT0002298	30870272	Clinical research	Patients with melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	5	N/A	Retrospective analysis	In this case series, it is encouraging to note that the initial acute neurological symptoms were often transient. Nevertheless, pretherapeutic brain imaging to exclude occult brain metastases and stratify the risk of intracerebral oedema and haemorrhage should be considered.	Acute neurological adverse events	N/A	N/A	N/A	N/A	N/A	 2019 Oct	Acute neurological adverse events during immune checkpoint inhibition therapy in patients with melanoma brain metastases.	 Melanoma Res	The common adverse effects of immune checkpoint blockade therapy are well recognised. However, neurological adverse effects of checkpoint inhibitor therapy are less widely appreciated, and their clinical management remains challenging. Therefore, we report our experience of managing acute, life-threatening neurological toxicity during immune checkpoint inhibitor therapy. Five male patients with stage IV melanoma underwent anti-programmed cell death protein 1 therapy (monotherapy or combination therapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies) and developed severe neurological symptoms and signs including headache, hemiparesis and dysarthria. The initial diagnosis of brain metastases actually occurred after initiation of checkpoint inhibitor therapy in three of the patients, whereas two patients had pre-existing central nervous metastases and developed cerebral oedema and haemorrhage during immunotherapy. A rapidly fatal outcome occurred in two patients treated with immunotherapy following the development of BRAF-inhibitor and MEK-inhibitor resistance. Four of the patients died owing to neurological complications, and one achieved a complete cerebral response. Immunotherapy and tumour progression can both result in the development of neurological symptoms and signs, making it difficult to determine causality. However, the temporal relationship between the development of neurological symptoms and the first administration of therapy means that patients should be closely monitored for the development of neurological sequelae, which may even herald the presence of occult brain metastases. The decision on whether to continue immunotherapy must balance the risks of symptom - versus disease progression. However, in our case series, it is encouraging to note that the initial acute neurological symptoms were often transient. Nevertheless, pretherapeutic brain imaging to exclude occult brain metastases and stratify the risk of intracerebral oedema and haemorrhage should be considered.
CANIT0002299	30874885	Case report	Pyogenic granuloma with lymphonodal and pulmonal metastases	Pyogenic ranuloma	MONDO:0022096	Soft tissue	PD-1 (Q15116); 	PD-1; 	Sugery plus cabozantinib followed by Nivolumab	N/A	Surgery plus Target therapy followed by Immune checkpoint therapy	Nivolumab (DB09035); cabozantinib (DB08875); 	1	N/A	Case	After 4 weeks the tumor showed a local recurrence and histologically a local relapse was found. Therefore, a change in the systemic therapy was initiated (nivolumab). In the follow-up of 18 months no recurrence of the palpebral tumor occurred. A stable disease condition of the clear cell renal cell carcinoma was achieved. Even if the clinical aspect of an inflammatory tumor of the lids seems to be clear, a histopathological examination is still necessary. An interdisciplinary approach with reevaluation of the systemic therapy led to an improvement of the patient treatment	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov	[Periocular metastasis as differential diagnosis of pyogenic granuloma and therapeutic marker of a systemic disease].	 Ophthalmologe	BACKGROUND: A pyogenic granuloma is a frequent palpebral pseudotumor. Showing a typical clinical picture after an inflammation (hordeolum, chalazion) it can be easily diagnosed and sometimes a histopathological analysis is thought to be unnecessary.METHODS: A case report of a patient suffering from a palpebral metastasis of a clear cell renal cell carcinoma (cRCC) as an atypical differential diagnosis of an inflammatory pseudotumor of the eyelid is presented.RESULTS: A 72-year-old man presented for surgical treatment of a pyogenic granuloma. The medial portion of the inferior eyelid showed a nodular and pediculate lesion of the tarsal conjunctiva. At the time of presentation the patient was receiving adjuvant systemic treatment with cabozantinib because of lymphonodal and pulmonal metastases of the cRCC. The tumor was resected and the histopathological examination revealed a sarcomatoid dedifferentiated metastasis of the cRCC. After 4 weeks the tumor showed a local recurrence and histologically a local relapse was found. Therefore, a change in the systemic therapy was initiated (nivolumab). In the follow-up of 18 months no recurrence of the palpebral tumor occurred. A stable disease condition of the cRCC was achieved.CONCLUSION: Even if the clinical aspect of an inflammatory tumor of the lids seems to be clear, a histopathological examination is still necessary. An interdisciplinary approach with reevaluation of the systemic therapy led to an improvement of the patient treatment.
CANIT0002300	30876831	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	550	N/A	Multicohort, open-label, phase 1 study	Pembrolizumab provides durable response and long-term effects on overall survival, with tolerable safety, for treatment naive and previously treated patients with advanced non-small-cell lung cancer expressing PD-L1.	Grade 3-5 treatment-related adverse events occurred in 66 patients (12%), and 30 (6%) discontinued owing to a treatment-related adverse event. The most frequent grade 3-4 treatment-related adverse events were pneumonitis (10 [2%] of 550) and fatigue (5 [1%] of 550). Overall, 227 patients (41%) of 550 had serious adverse events, of which 50 (9%) were treatment related.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 tumour proportion score >=50%	Gene expression signature on/in tumor cell	 2019 Apr	Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study.	 Lancet Respir Med	BACKGROUND: The anti-programmed death 1 monoclonal antibody pembrolizumab has shown antitumour activity and is a first-line and second-line treatment option for patients with programmed death ligand 1 (PD-L1)-expressing advanced non-small-cell lung cancer. We report updated 3-year safety and efficacy outcomes from the phase 1 study, KEYNOTE-001.METHODS: KEYNOTE-001 is a multicohort, open-label, phase 1 study of pembrolizumab (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks) in treatment naive or previously treated patients with locally advanced or metastatic non-small-cell lung cancer with measurable disease at baseline. Two cohorts were randomly assigned to a pembrolizumab dose by use of a computer-generated randomisation schedule at cohort-dependent ratios, and a further four cohorts were assigned to a pembrolizumab dose without randomisation. We present 3-year outcomes for the full analysis set of patients who received at least one dose of study treatment, pooled for all pembrolizumab doses. The primary efficacy endpoint was proportion of patients with objective response, analysed here as investigator-assessed response according to immune-related response criteria. Secondary efficacy endpoints included overall survival, duration of response, and progression-free survival. Safety endpoints included incidence of adverse events. This study is registered at ClinicalTrials.gov, number NCT01295827, and is ongoing.FINDINGS: Between May 8, 2012 and July 13, 2014, 550 patients (101 treatment naive and 449 previously treated) were enrolled. Median follow-up was 34.5 months at data cutoff (Sept 1, 2016). At 36 months, investigator-assessed objective response according to immune-related response criteria was achieved for 41 of 101 treatment naive patients (41% [95% CI 30.9-50.8]; median duration of response was 16.7 months [95% CI 12.6-not reached]) and 102 of 449 previously treated patients (23% [18.9-26.9]; 33.3 ([22.5-not reached]). The Kaplan-Meier estimate of overall survival at 36 months was 26.4% (95% CI 14.3-40.1) for treatment naive patients and 19.0% (15.0-23.4) for previously treated patients, with median overall survival of 22.3 months (95% CI 17.1-31.5) and 10.5 months (8.6-13.2). PD-L1 tumour proportion score >=50% was associated with longer median overall survival (95% CI) versus tumour proportion score 1-49% (treatment naive: 34.9 [20.3-not reached] vs 19.5 [10.7-26.3] months; previously treated: 15.4 [10.5-18.5] vs 8.5 [6.0-12.7] months). Grade 3-5 treatment-related adverse events occurred in 66 patients (12%), and 30 (6%) discontinued owing to a treatment-related adverse event. The most frequent grade 3-4 treatment-related adverse events were pneumonitis (10 [2%] of 550) and fatigue (5 [1%] of 550). Overall, 227 patients (41%) of 550 had serious adverse events, of which 50 (9%) were treatment related.INTERPRETATION: Pembrolizumab provides durable response and long-term effects on overall survival, with tolerable safety, for treatment naive and previously treated patients with advanced non-small-cell lung cancer expressing PD-L1.FUNDING: Merck Sharp & Dohme Corp.
CANIT0002301	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	57	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	AJCC stage (NCIT:C39315 ); 	AJCC stage	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002302	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	57	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002303	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	57	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002304	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	57	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Number of metastatic sites	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002305	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	57	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002306	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	57	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Prior therapies	Exposure factors/status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002307	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	57	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	Diameter of largest tumor (tumor bulk)	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002308	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	AJCC stage (NCIT:C39315 ); 	AJCC stage	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002309	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002310	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002311	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Number of metastatic sites	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002312	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002313	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Prior therapies	Exposure factors/status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002314	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	Diameter of largest tumor (tumor bulk)	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002315	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	AJCC stage (NCIT:C39315 ); 	AJCC stage	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002316	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002317	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002318	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Number of metastatic sites	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002319	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002320	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Prior therapies	Exposure factors/status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002321	30882548	Clinical research	Metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	303	N/A	N/A	Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	Diameter of largest tumor (tumor bulk)	Disease status	 2019 Jul/Aug	Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.	 J Immunother	Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor <=2 cm had a 53% RR, whereas those with largest tumor >2 cm had a 38% RR (P=0.009). Those with liver metastases had lower RR (25% vs. 43%; P=0.002). RR to anti-PD-1 was greater in patients with <=10 metastases compared with those with >10 (39% vs. 27%; P=0.027). In multivariable analyses, size of the largest tumor was independently associated with PFS (P=0.0005), OS (P<0.0001), and RR (P=0.02), whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS (P=0.035) and RR (P=0.009) but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.
CANIT0002322	30885338	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	42	N/A	Retrospective analysis	Immune checkpoint inhibitors (ICIs) were discontinued in 15 of 42 treatment responders because of severe immune-related adverse events. Tumor burden was a significant independent predictor of severe immune-related adverse events (p = 0.03). The odds ratio of severe immune-related adverse events and tumor burden over 90 mm was 8.62 (95% confidence interval = 1.96-37.9, p = 0.004).	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	Tumor burden	Disease status	 2019 Apr	The association between tumor burden and severe immune-related adverse events in non-small cell lung cancer patients responding to immune-checkpoint inhibitor treatment.	 Lung Cancer	OBJECTIVES: The use of immune checkpoint inhibitors (ICIs) for advanced non-small cell lung cancer (NSCLC) has demonstrated survival benefits, although some treatment responders (defined as patients with non-progressive disease) are forced to discontinue treatment because of severe immune-related adverse events (irAEs). An association between treatment efficacy and irAEs has been reported. However, it is unclear which treatment responders are likely to develop severe irAEs. We aimed to examine risk factors for ICI-related severe irAEs in patients with NSCLC.MATERIALS AND METHODS: Between February 2016 and October 2018, we retrospectively evaluated 42 patients with NSCLC at our institution who responded to ICI treatment. Tumor burden was measured as the sum of the unidimensional diameters of up to five target lesions, according to the Response Evaluation Criteria in Solid Tumors version 1.1.RESULTS: ICIs were discontinued in 15 of 42 treatment responders because of severe irAEs. Tumor burden was a significant independent predictor of severe irAEs (p = 0.03). The odds ratio of severe irAEs and tumor burden over 90 mm was 8.62 (95% confidence interval = 1.96-37.9, p = 0.004).CONCLUSION: A high tumor burden was a risk factor for severe irAEs in patients with NSCLC who responded to ICI treatment.
CANIT0002323	30885351	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	83	N/A	Retrospective analysis	Progression-free survival (2.9 versus 3.8 months, p = 0.03) and overall survival (11.6 versus 15.8 months, p = 0.03) were significantly shorter in patients positive for Antinuclear antibodies (ANA) than in those without ANA.	Of the 83 patients analyzed, 18 (21.7%) were positive for Antinuclear antibodies (ANA). The incidence of immune-related adverse events (irAEs) did not differ significantly between patients with ANA (6/18, 33.3%) and those negative for ANA (21/65, 32.3%), although it tended to increase as the ANA titer increased.	N/A	N/A	Antinuclear Antibodies (NCIT:C74916); 	Antinuclear antibodies	Gene expression signature in serum	 2019 Apr	Safety and efficacy of PD-1 inhibitors in non-small cell lung cancer patients positive for antinuclear antibodies.	 Lung Cancer	OBJECTIVES: To examine the possible effects of antinuclear antibodies (ANA) on the safety and efficacy of programmed cell death-1 (PD-1) inhibitors in patients with advanced non-small cell lung cancer (NSCLC).PATIENTS AND METHODS: Clinical data including ANA status were reviewed retrospectively for patients with advanced NSCLC who received monotherapy with a PD-1 inhibitor.RESULTS: Of the 83 patients analyzed, 18 (21.7%) were positive for ANA. The incidence of immune-related adverse events (irAEs) did not differ significantly between patients with ANA (6/18, 33.3%) and those negative for ANA (21/65, 32.3%), although it tended to increase as the ANA titer increased. Progression-free survival (2.9 versus 3.8 months, p =  0.03) and overall survival (11.6 versus 15.8 months, p =  0.03) were significantly shorter in patients positive for ANA than in those without ANA.CONCLUSION: PD-1 inhibitors can be administered safely in advanced NSCLC patients positive for ANA without obvious exacerbation of autoimmune disease, although patients with a high titer of such antibodies may warrant close monitoring. However, the presence of ANA might be associated with a poor outcome of such treatment.
CANIT0002324	30885353	Clinical research	Previously treated advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	51	N/A	Phase 1/2 KEYNOTE-021 study	In patients with heavily pretreated advanced NSCLC, pembrolizumab plus ipilimumab showed evidence of antitumor activity, but was associated with meaningful toxicity. Among patients who received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg (n = 44), ORR was 30% (95% CI, 17%-45%), but not statistically significantly >20% (P = 0.0858). Median progression-free survival in this group was 4.1 (95% CI, 1.4-5.8) months; median overall survival was 10.9 (95% CI, 6.1-23.7) months.	No dose-limiting toxicities occurred at any dose level. With pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg, incidences of treatment-related adverse events, grade 3-5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions were 64%, 29%, and 42%, respectively.	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non-small-cell lung cancer: KEYNOTE-021 cohorts D and H.	 Lung Cancer	OBJECTIVES: Combination immunotherapy may result in improved antitumor activity compared with single-agent treatment. We report results from dose-finding and dose-expansion cohorts of the phase 1/2 KEYNOTE-021 study that evaluated combination therapy with anti programmed death 1 (PD-1) antibody pembrolizumab plus anti cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in patients with previously treated advanced non-small-cell lung cancer (NSCLC).MATERIALS AND METHODS: Eligibility criteria stipulated histologically/cytologically confirmed advanced NSCLC and treatment failure on >=1 prior systemic therapy (platinum-based chemotherapy or targeted therapy for patients with EGFR/ALK aberrations). In the dose-finding cohort, patients initially received pembrolizumab 10 mg/kg plus ipilimumab 1 or 3 mg/kg once every 3 weeks for 4 cycles followed by pembrolizumab 10 mg/kg monotherapy for up to 2 years. Based on emerging published data, subsequent patients received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg. Objective response rate (ORR; primary efficacy endpoint) was assessed per RECIST version 1.1 by blinded, independent central review. Phase 2 hypothesis that ORR would be greater than the 20% rate for historical controls was evaluated using the exact binomial test.RESULTS: Fifty-one patients were enrolled; 71% received >=2 prior lines of therapy. No dose-limiting toxicities occurred at any dose level. Among patients who received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg (n = 44), ORR was 30% (95% CI, 17%-45%), but not statistically significantly >20% (P = 0.0858). Median progression-free survival in this group was 4.1 (95% CI, 1.4-5.8) months; median overall survival was 10.9 (95% CI, 6.1-23.7) months. With pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg, incidences of treatment-related adverse events, grade 3-5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions were 64%, 29%, and 42%, respectively.CONCLUSIONS: In patients with heavily pretreated advanced NSCLC, pembrolizumab plus ipilimumab showed evidence of antitumor activity, but was associated with meaningful toxicity.
CANIT0002325	30885550	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	559	N/A	Retrospective analysis	Our study confirmed that immune-related adverse events (irAEs)  are concordantly related to higher overall response rate (ORR), longer progression-free survival (PFS), and longer overall survival (OS) with anti-PD-1 immunotherapy in patients with NSCLC.	A total of 559 patients were enrolled; 231 patients (41.3%) developed irAEs of any grade and 50 patients (8.9%) G3/G4 events; 191 of them (82.6%) developed single-site irAEs and 40 (17.4%) multiple-site irAEs.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2019 Jul	Correlations Between the Immune-related Adverse Events Spectrum and Efficacy of Anti-PD1 Immunotherapy in NSCLC Patients.	 Clin Lung Cancer	BACKGROUND: Immune-related adverse events (irAEs) developed during immunotherapy with anti-PD-1 agents, could be a predictive surrogate marker of clinical benefit in patients with advanced non-small-cell lung cancer (NSCLC).METHODS: Patients with NSCLC, treated with anti-PD-1 agents, were retrospectively evaluated. Univariate and multivariate analyses were performed to evaluate the relationships between types of irAEs (differentiated according to system/organ involved and to single-site/multiple-site), overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). We further performed a 6-week landmark analysis.RESULTS: A total of 559 patients were enrolled; 231 patients (41.3%) developed irAEs of any grade and 50 patients (8.9%) G3/G4 events; 191 of them (82.6%) developed single-site irAEs and 40 (17.4%) multiple-site irAEs. At multivariate analysis, higher ORR was related to irAEs of any grade (P < .0001), single-site irAEs (P < .0001), endocrine (P = .0043) and skin irAEs (P = .0005). Longer PFS was related to irAEs of any grade (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0374), endocrine irAEs (P = .0084) and skin irAEs (P = .0001). Longer OS was related to irAEs of any grade (P < .0001), single-site irAEs (P < .0001), endocrine irAEs (P = .0044), gastrointestinal irAEs (P = .0437), skin irAEs (P = .0006), and others irAEs (P = .0378). At the 6-week landmark analysis, irAEs of any grade was confirmed an independent predictor of higher ORR, longer PFS, and longer OS.CONCLUSION: Our study confirmed that irAEs are concordantly related to higher ORR, longer PFS, and longer OS with anti-PD-1 immunotherapy in patients with NSCLC.
CANIT0002326	30885937	Basic research	Sarcoma	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab plus GLV-1h68	N/A	Immune checkpoint therapy plus oncolytic virus	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	Viral isolated limb perfusion (ILP) augments the response to PD-1 blockade, transforming this locoregional therapy into a potentially effective systemic treatment for sarcoma and warrants translational evaluation. Enhanced therapy was associated with marked modulation of the tumor microenvironment, with an increase in the number and penetrance of intratumoral CD8+ T cells. GLV-1h68 was capable of inducing markers of immunogenic cell death in human sarcoma cell lines.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Intratumoral CD8(+) T-cells	Gene expression signature on/in immune cell	 2019 Jun 1	PD-1 Blockade Following Isolated Limb Perfusion with Vaccinia Virus Prevents Local and Distant Relapse of Soft-tissue Sarcoma.	 Clin Cancer Res	PURPOSE: The prevention and treatment of metastatic sarcoma are areas of significant unmet need. Immune checkpoint inhibitor monotherapy has shown little activity in sarcoma and there is great interest in identifying novel treatment combinations that may augment responses. In vitro and in vivo, we investigated the potential for an oncolytic vaccinia virus (GLV-1h68) delivered using isolated limb perfusion (ILP) to promote antitumor immune responses and augment response to PD-1 blockade in sarcoma.Experimental Design: In an established animal model of extremity sarcoma, we evaluated the potential of locoregional delivery of a vaccinia virus (GLV-1h68) alongside biochemotherapy (melphalan/TNFa) in ILP. Complementary in vitro assays for markers of immunogenic cell death were performed in sarcoma cell lines.RESULTS: PD-1 monotherapy had minimal efficacy in vivo, mimicking the clinical scenario. Pretreatment with GLV-1h68 delivered by ILP (viral ILP) significantly improved responses. Furthermore, when performed prior to surgery and radiotherapy, viral ILP and PD-1 blockade prevented both local and distant relapse, curing a previously treatment-refractory model. Enhanced therapy was associated with marked modulation of the tumor microenvironment, with an increase in the number and penetrance of intratumoral CD8+ T cells and expansion and activation of dendritic cells. GLV-1h68 was capable of inducing markers of immunogenic cell death in human sarcoma cell lines.CONCLUSIONS: Viral ILP augments the response to PD-1 blockade, transforming this locoregional therapy into a potentially effective systemic treatment for sarcoma and warrants translational evaluation.
CANIT0002327	30885937	Basic research	Sarcoma	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab plus GLV-1h68	N/A	Immune checkpoint therapy plus oncolytic virus	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	Viral isolated limb perfusion (ILP) augments the response to PD-1 blockade, transforming this locoregional therapy into a potentially effective systemic treatment for sarcoma and warrants translational evaluation. Enhanced therapy was associated with marked modulation of the tumor microenvironment, with an increase in expansion and activation of dendritic cells. GLV-1h68 was capable of inducing markers of immunogenic cell death in human sarcoma cell lines.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Dendritic cells (NCIT:C12583); 	Expansion and activation of dendritic cells	Cell percentage/counts in blood	 2019 Jun 1	PD-1 Blockade Following Isolated Limb Perfusion with Vaccinia Virus Prevents Local and Distant Relapse of Soft-tissue Sarcoma.	 Clin Cancer Res	PURPOSE: The prevention and treatment of metastatic sarcoma are areas of significant unmet need. Immune checkpoint inhibitor monotherapy has shown little activity in sarcoma and there is great interest in identifying novel treatment combinations that may augment responses. In vitro and in vivo, we investigated the potential for an oncolytic vaccinia virus (GLV-1h68) delivered using isolated limb perfusion (ILP) to promote antitumor immune responses and augment response to PD-1 blockade in sarcoma.Experimental Design: In an established animal model of extremity sarcoma, we evaluated the potential of locoregional delivery of a vaccinia virus (GLV-1h68) alongside biochemotherapy (melphalan/TNFa) in ILP. Complementary in vitro assays for markers of immunogenic cell death were performed in sarcoma cell lines.RESULTS: PD-1 monotherapy had minimal efficacy in vivo, mimicking the clinical scenario. Pretreatment with GLV-1h68 delivered by ILP (viral ILP) significantly improved responses. Furthermore, when performed prior to surgery and radiotherapy, viral ILP and PD-1 blockade prevented both local and distant relapse, curing a previously treatment-refractory model. Enhanced therapy was associated with marked modulation of the tumor microenvironment, with an increase in the number and penetrance of intratumoral CD8+ T cells and expansion and activation of dendritic cells. GLV-1h68 was capable of inducing markers of immunogenic cell death in human sarcoma cell lines.CONCLUSIONS: Viral ILP augments the response to PD-1 blockade, transforming this locoregional therapy into a potentially effective systemic treatment for sarcoma and warrants translational evaluation.
CANIT0002328	30895946	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	9887	N/A	N/A	PD-L1 expression and tumor mutational burden (TMB) are not significantly correlated within most cancer subtypes, and they show only a marginal association at the tumor sample level (Pearson's correlation 0.084). Across distinct tumor types, PD-L1 expression and TMB have nonoverlapping effects on the response rate to PD-1/PD-L1 inhibitors and can broadly be used to categorize the immunologic subtypes of cancer.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Mar 21	PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers.	 JCI Insight	BACKGROUND: PD-L1 expression and tumor mutational burden (TMB) have emerged as important biomarkers of response to immune checkpoint inhibitor (ICI) therapy. These biomarkers have each succeeded and failed in predicting responders for different cancer types. We sought to describe the PD-L1 expression landscape across the spectrum of ICI-responsive human cancers, and to determine the relationship between PD-L1 expression, TMB, and response rates to ICIs.METHODS: We assessed 9887 clinical samples for PD-L1 expression and TMB.RESULTS: PD-L1 expression and TMB are not significantly correlated within most cancer subtypes, and they show only a marginal association at the tumor sample level (Pearson's correlation 0.084). Across distinct tumor types, PD-L1 expression and TMB have nonoverlapping effects on the response rate to PD-1/PD-L1 inhibitors and can broadly be used to categorize the immunologic subtypes of cancer.CONCLUSION: Our results indicate that PD-L1 expression and TMB may each inform the use of ICIs, point to different mechanisms by which PD-L1 expression regulates ICI responsiveness, and identify new opportunities for therapeutic development.FUNDING: Funding was provided by Foundation Medicine Inc., the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the Viragh Foundation, the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924), the NIH Center Core Grant (P30 CA006973), the Norman & Ruth Rales Foundation, and the Conquer Cancer Foundation.
CANIT0002329	30895946	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ8); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	9887	N/A	N/A	PD-L1 expression and tumor mutational burden (TMB) are not significantly correlated within most cancer subtypes, and they show only a marginal association at the tumor sample level (Pearson's correlation 0.084). Across distinct tumor types, PD-L1 expression and TMB have nonoverlapping effects on the response rate to PD-1/PD-L1 inhibitors and can broadly be used to categorize the immunologic subtypes of cancer.	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Mar 21	PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers.	 JCI Insight	BACKGROUND: PD-L1 expression and tumor mutational burden (TMB) have emerged as important biomarkers of response to immune checkpoint inhibitor (ICI) therapy. These biomarkers have each succeeded and failed in predicting responders for different cancer types. We sought to describe the PD-L1 expression landscape across the spectrum of ICI-responsive human cancers, and to determine the relationship between PD-L1 expression, TMB, and response rates to ICIs.METHODS: We assessed 9887 clinical samples for PD-L1 expression and TMB.RESULTS: PD-L1 expression and TMB are not significantly correlated within most cancer subtypes, and they show only a marginal association at the tumor sample level (Pearson's correlation 0.084). Across distinct tumor types, PD-L1 expression and TMB have nonoverlapping effects on the response rate to PD-1/PD-L1 inhibitors and can broadly be used to categorize the immunologic subtypes of cancer.CONCLUSION: Our results indicate that PD-L1 expression and TMB may each inform the use of ICIs, point to different mechanisms by which PD-L1 expression regulates ICI responsiveness, and identify new opportunities for therapeutic development.FUNDING: Funding was provided by Foundation Medicine Inc., the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the Viragh Foundation, the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924), the NIH Center Core Grant (P30 CA006973), the Norman & Ruth Rales Foundation, and the Conquer Cancer Foundation.
CANIT0002330	30896626	Case report	Lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Edoxaban followed by pembrolizumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Pembrolizumab (DB09037); edoxaban (DB09075); 	1	N/A	Case	A 63-year-old female was diagnosed with lung adenocarcinoma (cT2aN3M1b stage IVa) along with having asymptomatic venous thromboembolism (VTE); thus, 60 mg/day edoxaban administration was initiated. In addition, 1st-line chemotherapy generated a partial antitumoral response. However, owing to lung cancer progression, a secondary treatment with pembrolizumab administration was initiated. The patient suddenly experienced aphasia 11 days after pembrolizumab administration. Therefore,direct oral anticoagulants (DOACs) should be replaced with heparin to prevent arterial thromboembolism (ATE)  when cancer and coagulation become uncontrollable with DOAC.	Aphasia	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Cerebral embolism during edoxaban administration for venous thromboembolism in a patient with lung adenocarcinoma: A case report.	 Medicine (Baltimore)	RATIONALE: The efficacy of direct oral anticoagulants (DOACs) in the treatment and prophylaxis of cancer-related venous thromboembolism (VTE) is reportedly similar to that of heparin. However, the effect of DOACs on the prophylaxis of cancer-related arterial thromboembolism (ATE) remains unclear. To our knowledge, we present the 1st case where cerebral ATE was encountered during edoxaban administration for VTE in a patient with lung adenocarcinoma.PATIENT CONCERNS: In March 2017, a 63-year-old female was diagnosed with lung adenocarcinoma (cT2aN3M1b stage IVa) along with having asymptomatic VTE; thus, 60 mg/day edoxaban administration was initiated. In addition, 1st-line chemotherapy generated a partial antitumoral response. However, owing to lung cancer progression, a secondary treatment with pembrolizumab administration was initiated. The patient suddenly experienced aphasia 11 days after pembrolizumab administration.DIAGNOSIS: The patient was diagnosed as multiple cerebral ATE using brain magnetic resonance imaging. However, VTE recurrence was not observed. Based on the findings of lung cancer progression and increased coagulation, cerebral ATE was diagnosed as Trousseau syndrome.INTERVENTIONS: DOAC administration was switched to heparin administration.OUTCOMES: Coagulation profile normalized and aphasia improved without any further disease symptoms.LESSONS: We considered that DOACs are effective for the treatment and prophylaxis of VTE but may be insufficient for ATE prevention. Therefore, DOACs should be replaced with heparin to prevent ATE when cancer and coagulation become uncontrollable with DOAC.
CANIT0002331	30900155	Clinical research	Advanced pulmonary adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	178	N/A	Retrospective analysis	Among 178 patients with EGFR-mutant (n = 38) or wild-type (WT) (n = 140) tumors, the EGFR mutation group had a lower objective response rate (ORR) (15.8% vs. 32.9%, p = 0.04) than the EGFR WT group. EGFR mutation and weak/negative PD-L1 expression were associated with a significantly shorter median PFS than EGFR WT (1.9 vs. 3.0 months, p = 0.04) and strong PD-L1 expression (1.6 vs. 3.9 months, p = 0.007), respectively. In multivariate analysis, EGFR mutation predicted worse ORR [hazard ratio (HR) 3.15; 95% confidence interval (CI) 1.15-8.63] and PFS (HR 1.75, 95% CI 1.11-2.75), as did weak/negative PD-L1 expression (ORR, HR 3.46, 95% CI 1.62-7.37; and PFS, HR 1.72, 95% CI 1.17-2.53).Together with PD-L1 expression, EGFR mutation status is an important factor to predict the efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary adenocarcinoma.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2019 May	Impact of EGFR mutation on the clinical efficacy of PD-1 inhibitors in patients with pulmonary adenocarcinoma.	 J Cancer Res Clin Oncol	PURPOSE: We evaluated the predictive role of EGFR mutation on the efficacy of PD-1/PD-L1 inhibitor therapy in patients with advanced pulmonary adenocarcinoma while considering clinical factors such as PD-L1 expression, gender, and smoking status.METHODS: Patients were required to have available data for EGFR mutation, PD-L1 expression, and efficacy of PD-1/PD-L1 inhibitors.RESULTS: Among 178 patients with EGFR-mutant (n = 38) or wild-type (WT) (n = 140) tumors, the EGFR mutation group had a lower objective response rate (ORR) (15.8% vs. 32.9%, p = 0.04) than the EGFR WT group, similar to the pattern observed for other factors: weak/negative PD-L1 expression vs. strong PD-L1 expression (17.3% vs. 39.2%, p = 0.001); never smokers vs. smokers (19.4% vs. 35.1%, p = 0.03); and females vs. males (21.0% vs. 33.6%, p = 0.08). EGFR mutation and weak/negative PD-L1 expression were associated with a significantly shorter median PFS than EGFR WT (1.9 vs. 3.0 months, p = 0.04) and strong PD-L1 expression (1.6 vs. 3.9 months, p = 0.007), respectively. In multivariate analysis, EGFR mutation predicted worse ORR [hazard ratio (HR) 3.15; 95% confidence interval (CI) 1.15-8.63] and PFS (HR 1.75, 95% CI 1.11-2.75), as did weak/negative PD-L1 expression (ORR, HR 3.46, 95% CI 1.62-7.37; and PFS, HR 1.72, 95% CI 1.17-2.53).CONCLUSIONS: Together with PD-L1 expression, EGFR mutation status is an important factor to predict the efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary adenocarcinoma.
CANIT0002332	30900155	Clinical research	Advanced pulmonary adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	178	N/A	Retrospective analysis	It is observed objective response rate (ORR) of females vs. males (21.0% vs. 33.6%, p = 0.08). 	N/A	N/A	N/A	Gender (NCIT:C17357); 	Males	Personal feature	 2019 May	Impact of EGFR mutation on the clinical efficacy of PD-1 inhibitors in patients with pulmonary adenocarcinoma.	 J Cancer Res Clin Oncol	PURPOSE: We evaluated the predictive role of EGFR mutation on the efficacy of PD-1/PD-L1 inhibitor therapy in patients with advanced pulmonary adenocarcinoma while considering clinical factors such as PD-L1 expression, gender, and smoking status.METHODS: Patients were required to have available data for EGFR mutation, PD-L1 expression, and efficacy of PD-1/PD-L1 inhibitors.RESULTS: Among 178 patients with EGFR-mutant (n = 38) or wild-type (WT) (n = 140) tumors, the EGFR mutation group had a lower objective response rate (ORR) (15.8% vs. 32.9%, p = 0.04) than the EGFR WT group, similar to the pattern observed for other factors: weak/negative PD-L1 expression vs. strong PD-L1 expression (17.3% vs. 39.2%, p = 0.001); never smokers vs. smokers (19.4% vs. 35.1%, p = 0.03); and females vs. males (21.0% vs. 33.6%, p = 0.08). EGFR mutation and weak/negative PD-L1 expression were associated with a significantly shorter median PFS than EGFR WT (1.9 vs. 3.0 months, p = 0.04) and strong PD-L1 expression (1.6 vs. 3.9 months, p = 0.007), respectively. In multivariate analysis, EGFR mutation predicted worse ORR [hazard ratio (HR) 3.15; 95% confidence interval (CI) 1.15-8.63] and PFS (HR 1.75, 95% CI 1.11-2.75), as did weak/negative PD-L1 expression (ORR, HR 3.46, 95% CI 1.62-7.37; and PFS, HR 1.72, 95% CI 1.17-2.53).CONCLUSIONS: Together with PD-L1 expression, EGFR mutation status is an important factor to predict the efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary adenocarcinoma.
CANIT0002333	30900155	Clinical research	Advanced pulmonary adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	178	N/A	Retrospective analysis	It is observed objective response rate (ORR) of  never smokers vs. smokers (19.4% vs. 35.1%, p = 0.03).	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 May	Impact of EGFR mutation on the clinical efficacy of PD-1 inhibitors in patients with pulmonary adenocarcinoma.	 J Cancer Res Clin Oncol	PURPOSE: We evaluated the predictive role of EGFR mutation on the efficacy of PD-1/PD-L1 inhibitor therapy in patients with advanced pulmonary adenocarcinoma while considering clinical factors such as PD-L1 expression, gender, and smoking status.METHODS: Patients were required to have available data for EGFR mutation, PD-L1 expression, and efficacy of PD-1/PD-L1 inhibitors.RESULTS: Among 178 patients with EGFR-mutant (n = 38) or wild-type (WT) (n = 140) tumors, the EGFR mutation group had a lower objective response rate (ORR) (15.8% vs. 32.9%, p = 0.04) than the EGFR WT group, similar to the pattern observed for other factors: weak/negative PD-L1 expression vs. strong PD-L1 expression (17.3% vs. 39.2%, p = 0.001); never smokers vs. smokers (19.4% vs. 35.1%, p = 0.03); and females vs. males (21.0% vs. 33.6%, p = 0.08). EGFR mutation and weak/negative PD-L1 expression were associated with a significantly shorter median PFS than EGFR WT (1.9 vs. 3.0 months, p = 0.04) and strong PD-L1 expression (1.6 vs. 3.9 months, p = 0.007), respectively. In multivariate analysis, EGFR mutation predicted worse ORR [hazard ratio (HR) 3.15; 95% confidence interval (CI) 1.15-8.63] and PFS (HR 1.75, 95% CI 1.11-2.75), as did weak/negative PD-L1 expression (ORR, HR 3.46, 95% CI 1.62-7.37; and PFS, HR 1.72, 95% CI 1.17-2.53).CONCLUSIONS: Together with PD-L1 expression, EGFR mutation status is an important factor to predict the efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary adenocarcinoma.
CANIT0002334	30900155	Clinical research	Advanced pulmonary adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	178	N/A	Retrospective analysis	Among 178 patients with EGFR-mutant (n = 38) or wild-type (WT) (n = 140) tumors, the EGFR mutation group had a lower objective response rate (ORR) (15.8% vs. 32.9%, p = 0.04) than the EGFR WT group, similar to the pattern observed for other factor: weak/negative PD-L1 expression vs. strong PD-L1 expression (17.3% vs. 39.2%, p = 0.001). EGFR mutation and weak/negative PD-L1 expression were associated with a significantly shorter median PFS than EGFR WT (1.9 vs. 3.0 months, p = 0.04) and strong PD-L1 expression (1.6 vs. 3.9 months, p = 0.007), respectively. In multivariate analysis, EGFR mutation predicted worse ORR [hazard ratio (HR) 3.15; 95% confidence interval (CI) 1.15-8.63] and PFS (HR 1.75, 95% CI 1.11-2.75), as did weak/negative PD-L1 expression (ORR, HR 3.46, 95% CI 1.62-7.37; and PFS, HR 1.72, 95% CI 1.17-2.53). Together with PD-L1 expression, EGFR mutation status is an important factor to predict the efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary adenocarcinoma.	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2019 May	Impact of EGFR mutation on the clinical efficacy of PD-1 inhibitors in patients with pulmonary adenocarcinoma.	 J Cancer Res Clin Oncol	PURPOSE: We evaluated the predictive role of EGFR mutation on the efficacy of PD-1/PD-L1 inhibitor therapy in patients with advanced pulmonary adenocarcinoma while considering clinical factors such as PD-L1 expression, gender, and smoking status.METHODS: Patients were required to have available data for EGFR mutation, PD-L1 expression, and efficacy of PD-1/PD-L1 inhibitors.RESULTS: Among 178 patients with EGFR-mutant (n = 38) or wild-type (WT) (n = 140) tumors, the EGFR mutation group had a lower objective response rate (ORR) (15.8% vs. 32.9%, p = 0.04) than the EGFR WT group, similar to the pattern observed for other factors: weak/negative PD-L1 expression vs. strong PD-L1 expression (17.3% vs. 39.2%, p = 0.001); never smokers vs. smokers (19.4% vs. 35.1%, p = 0.03); and females vs. males (21.0% vs. 33.6%, p = 0.08). EGFR mutation and weak/negative PD-L1 expression were associated with a significantly shorter median PFS than EGFR WT (1.9 vs. 3.0 months, p = 0.04) and strong PD-L1 expression (1.6 vs. 3.9 months, p = 0.007), respectively. In multivariate analysis, EGFR mutation predicted worse ORR [hazard ratio (HR) 3.15; 95% confidence interval (CI) 1.15-8.63] and PFS (HR 1.75, 95% CI 1.11-2.75), as did weak/negative PD-L1 expression (ORR, HR 3.46, 95% CI 1.62-7.37; and PFS, HR 1.72, 95% CI 1.17-2.53).CONCLUSIONS: Together with PD-L1 expression, EGFR mutation status is an important factor to predict the efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary adenocarcinoma.
CANIT0002335	30911841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	155	N/A	Retrospective analysis	The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS.	61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	EGFR/ALK (P00533); 	ALK rearrangement	Mutational status	 2019 Jun	Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.	 J Cancer Res Clin Oncol	PURPOSE: Immune checkpoint inhibitors (ICI) have shown marked responses in patients with non-small cell lung cancer (NSCLC) in clinical trials. However, because such trials comprise cohorts selected based on specific criteria, it is unclear if their results represent routine clinical practice.METHODS: We examined 155 patients with advanced NSCLC who were administered either nivolumab or pembrolizumab at Yonsei Cancer Center, Korea between March 2014 and January 2019. Patient characteristics, EGFR/ALK mutation status, metastatic locations, response to ICIs, and adverse events were retrospectively analyzed.RESULTS: The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS. Furthermore, 61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.CONCLUSIONS: The real-world ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials despite the patients' different baseline characteristics. Our findings can aid in establishing effective immunotherapeutic management of NSCLC in routine clinical practice.
CANIT0002336	30911841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	155	N/A	Retrospective analysis	The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS.	61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2019 Jun	Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.	 J Cancer Res Clin Oncol	PURPOSE: Immune checkpoint inhibitors (ICI) have shown marked responses in patients with non-small cell lung cancer (NSCLC) in clinical trials. However, because such trials comprise cohorts selected based on specific criteria, it is unclear if their results represent routine clinical practice.METHODS: We examined 155 patients with advanced NSCLC who were administered either nivolumab or pembrolizumab at Yonsei Cancer Center, Korea between March 2014 and January 2019. Patient characteristics, EGFR/ALK mutation status, metastatic locations, response to ICIs, and adverse events were retrospectively analyzed.RESULTS: The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS. Furthermore, 61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.CONCLUSIONS: The real-world ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials despite the patients' different baseline characteristics. Our findings can aid in establishing effective immunotherapeutic management of NSCLC in routine clinical practice.
CANIT0002337	30911841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	155	N/A	Retrospective analysis	The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS.	61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2019 Jun	Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.	 J Cancer Res Clin Oncol	PURPOSE: Immune checkpoint inhibitors (ICI) have shown marked responses in patients with non-small cell lung cancer (NSCLC) in clinical trials. However, because such trials comprise cohorts selected based on specific criteria, it is unclear if their results represent routine clinical practice.METHODS: We examined 155 patients with advanced NSCLC who were administered either nivolumab or pembrolizumab at Yonsei Cancer Center, Korea between March 2014 and January 2019. Patient characteristics, EGFR/ALK mutation status, metastatic locations, response to ICIs, and adverse events were retrospectively analyzed.RESULTS: The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS. Furthermore, 61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.CONCLUSIONS: The real-world ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials despite the patients' different baseline characteristics. Our findings can aid in establishing effective immunotherapeutic management of NSCLC in routine clinical practice.
CANIT0002338	30911841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	155	N/A	Retrospective analysis	The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS.	61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2019 Jun	Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.	 J Cancer Res Clin Oncol	PURPOSE: Immune checkpoint inhibitors (ICI) have shown marked responses in patients with non-small cell lung cancer (NSCLC) in clinical trials. However, because such trials comprise cohorts selected based on specific criteria, it is unclear if their results represent routine clinical practice.METHODS: We examined 155 patients with advanced NSCLC who were administered either nivolumab or pembrolizumab at Yonsei Cancer Center, Korea between March 2014 and January 2019. Patient characteristics, EGFR/ALK mutation status, metastatic locations, response to ICIs, and adverse events were retrospectively analyzed.RESULTS: The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS. Furthermore, 61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.CONCLUSIONS: The real-world ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials despite the patients' different baseline characteristics. Our findings can aid in establishing effective immunotherapeutic management of NSCLC in routine clinical practice.
CANIT0002339	30911841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	155	N/A	Retrospective analysis	The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS.	61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Jun	Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.	 J Cancer Res Clin Oncol	PURPOSE: Immune checkpoint inhibitors (ICI) have shown marked responses in patients with non-small cell lung cancer (NSCLC) in clinical trials. However, because such trials comprise cohorts selected based on specific criteria, it is unclear if their results represent routine clinical practice.METHODS: We examined 155 patients with advanced NSCLC who were administered either nivolumab or pembrolizumab at Yonsei Cancer Center, Korea between March 2014 and January 2019. Patient characteristics, EGFR/ALK mutation status, metastatic locations, response to ICIs, and adverse events were retrospectively analyzed.RESULTS: The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS. Furthermore, 61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.CONCLUSIONS: The real-world ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials despite the patients' different baseline characteristics. Our findings can aid in establishing effective immunotherapeutic management of NSCLC in routine clinical practice.
CANIT0002340	30911841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	155	N/A	Retrospective analysis	The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS.	61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Jun	Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.	 J Cancer Res Clin Oncol	PURPOSE: Immune checkpoint inhibitors (ICI) have shown marked responses in patients with non-small cell lung cancer (NSCLC) in clinical trials. However, because such trials comprise cohorts selected based on specific criteria, it is unclear if their results represent routine clinical practice.METHODS: We examined 155 patients with advanced NSCLC who were administered either nivolumab or pembrolizumab at Yonsei Cancer Center, Korea between March 2014 and January 2019. Patient characteristics, EGFR/ALK mutation status, metastatic locations, response to ICIs, and adverse events were retrospectively analyzed.RESULTS: The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent >= 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4-31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893-4.21) and 10.25 (95% CI 5.39-15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS. Furthermore, 61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis.CONCLUSIONS: The real-world ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials despite the patients' different baseline characteristics. Our findings can aid in establishing effective immunotherapeutic management of NSCLC in routine clinical practice.
CANIT0002341	30911859	Clinical research	Advanced gastric/gastroesophageal junction cancer	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	56	N/A	Multicohort, phase II, nonrandomized KEYNOTE-059 study	The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy).Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma.	In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis).	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study.	 Gastric Cancer	BACKGROUND: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab +/- chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented.METHODS: Patients >= 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score >= 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy).RESULTS: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy).CONCLUSIONS: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma.CLINICAL TRIAL: ClinicalTrials.gov NCT02335411.
CANIT0002342	30911859	Clinical research	Advanced gastric/gastroesophageal junction cancer	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	56	N/A	Multicohort, phase II, nonrandomized KEYNOTE-059 study	The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy). Pembrolizumab demonstrated antitumor activity and was well tolerated in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma.	In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. 	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study.	 Gastric Cancer	BACKGROUND: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab +/- chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented.METHODS: Patients >= 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score >= 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy).RESULTS: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy).CONCLUSIONS: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma.CLINICAL TRIAL: ClinicalTrials.gov NCT02335411.
CANIT0002343	30913364	Clinical research	Thirty patients were administered docetaxel©\based chemotherapy and 21 patients were administered S©\1 in any line after nivolumab. Twenty©\four patients were administered docetaxel©\based chemotherapy and 15 patients were administered S©\1 immediately after nivolumab. Sixty©\six patients were administered docetaxel and 23 patients were administered S©\1 without ICIs. 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by chemotherapy	N/A	Immune checkpoint therapy followed by Chemotherapy	Nivolumab (DB09035); chemotherapy (NCIT:C15632); 	N/A	N/A	N/A	Subsequent cytotoxic chemotherapy, especially immediately after nivolumab treatment, demonstrated better treatment efficacy than that of regimens without ICI pretreatment	N/A	N/A	N/A	N/A	N/A	N/A	 2019 May	Efficacy of subsequent docetaxel +/- ramucirumab and S-1 after nivolumab for patients with advanced non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: Cytotoxic chemotherapy for advanced non-small cell lung cancer (NSCLC) as second-line or subsequent treatment generally results in a poor treatment outcome. Several reports have indicated that subsequent cytotoxic chemotherapy in patients who have received immune checkpoint inhibitors (ICIs) might have relatively better efficacy.METHODS: The clinical data of advanced NSCLC patients treated with nivolumab during clinical practice at the National Cancer Center Hospital between 17 December 2015 and 31 August 2017 were consecutively reviewed, and the treatment outcomes of docetaxel-based chemotherapy (docetaxel +/- ramucirumab) or S-1 after nivolumab were analyzed. The results were then compared with those of advanced NSCLC patients treated with docetaxel or S-1 but not ICIs during clinical practice between 17 December 2014 and 16 December 2015.RESULTS: Thirty patients were administered docetaxel-based chemotherapy and 21 patients were administered S-1 in any line after nivolumab. Twenty-four patients were administered docetaxel-based chemotherapy and 15 patients were administered S-1 immediately after nivolumab. Sixty-six patients were administered docetaxel and 23 patients were administered S-1 without ICIs. The objective response rate, disease control rate, and median progression-free survival duration were 28.6%, 53.6%, and 5.26 months for patients receiving docetaxel-based chemotherapy or S-1 immediately after nivolumab treatment; 24.3%, 51.4%, and 3.88 months for patients receiving docetaxel-based chemotherapy or S-1 in any line after nivolumab; and 16.4%, 56.7%, and 2.74 months, for patients receiving docetaxel or S-1 without ICIs, respectively.CONCLUSION: Subsequent cytotoxic chemotherapy, especially immediately after nivolumab, has better treatment efficacy than that of regimens without ICI pretreatment.
CANIT0002344	30917841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	102	N/A	N/A	Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2019 Mar 27	A nomogram to predict survival in non-small cell lung cancer patients treated with nivolumab.	 J Transl Med	BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection.METHODS: Patients with stage IIIB-IV NSCLC receiving nivolumab at Sant'Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process.RESULTS: A total of 102 patients were included in this study. The median age was 69 years (range 44-85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.CONCLUSION: We developed a nomogram based on easily available and inexpensive clinical factors showing a good performance in predicting individual OS probability among NSCLC patients treated with nivolumab. This prognostic device could be valuable to clinicians in more accurately driving treatment decision in daily practice as well as enrollment onto clinical trials.
CANIT0002345	30917841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	102	N/A	N/A	Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2019 Mar 27	A nomogram to predict survival in non-small cell lung cancer patients treated with nivolumab.	 J Transl Med	BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection.METHODS: Patients with stage IIIB-IV NSCLC receiving nivolumab at Sant'Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process.RESULTS: A total of 102 patients were included in this study. The median age was 69 years (range 44-85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.CONCLUSION: We developed a nomogram based on easily available and inexpensive clinical factors showing a good performance in predicting individual OS probability among NSCLC patients treated with nivolumab. This prognostic device could be valuable to clinicians in more accurately driving treatment decision in daily practice as well as enrollment onto clinical trials.
CANIT0002346	30917841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	102	N/A	N/A	Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Lung metastasis	Disease status	 2019 Mar 27	A nomogram to predict survival in non-small cell lung cancer patients treated with nivolumab.	 J Transl Med	BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection.METHODS: Patients with stage IIIB-IV NSCLC receiving nivolumab at Sant'Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process.RESULTS: A total of 102 patients were included in this study. The median age was 69 years (range 44-85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.CONCLUSION: We developed a nomogram based on easily available and inexpensive clinical factors showing a good performance in predicting individual OS probability among NSCLC patients treated with nivolumab. This prognostic device could be valuable to clinicians in more accurately driving treatment decision in daily practice as well as enrollment onto clinical trials.
CANIT0002347	30917841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	102	N/A	N/A	Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Lymph nodes only involvement	Disease status	 2019 Mar 27	A nomogram to predict survival in non-small cell lung cancer patients treated with nivolumab.	 J Transl Med	BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection.METHODS: Patients with stage IIIB-IV NSCLC receiving nivolumab at Sant'Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process.RESULTS: A total of 102 patients were included in this study. The median age was 69 years (range 44-85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.CONCLUSION: We developed a nomogram based on easily available and inexpensive clinical factors showing a good performance in predicting individual OS probability among NSCLC patients treated with nivolumab. This prognostic device could be valuable to clinicians in more accurately driving treatment decision in daily practice as well as enrollment onto clinical trials.
CANIT0002348	30917841	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	102	N/A	N/A	Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Mar 27	A nomogram to predict survival in non-small cell lung cancer patients treated with nivolumab.	 J Transl Med	BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection.METHODS: Patients with stage IIIB-IV NSCLC receiving nivolumab at Sant'Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process.RESULTS: A total of 102 patients were included in this study. The median age was 69 years (range 44-85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age >= 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.CONCLUSION: We developed a nomogram based on easily available and inexpensive clinical factors showing a good performance in predicting individual OS probability among NSCLC patients treated with nivolumab. This prognostic device could be valuable to clinicians in more accurately driving treatment decision in daily practice as well as enrollment onto clinical trials.
CANIT0002349	30918156	Case report	A 72-year-old patient with lung cancer 	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	T-cell activation by nivolumab treatment might not be directly associated with acute interstitial lung disease (ILD) exacerbation, and that treatable organized pneumonia pattern might be a major pulmonary complication of nivolumab in patients with pre-existing ILD, similar to patients without underlying ILD	 pneumonitis with an organized pneumonia (OP) pattern	N/A	N/A	Interstitial lung disease (NCIT:C27006); 	Pre-existing interstitial lung disease	Disease status	2019	Organizing Pneumonia after Nivolumab Treatment in a Patient with Pathologically Proven Idiopathic Pulmonary Fibrosis.	 J Nippon Med Sch	Acute exacerbation of pre-existing interstitial lung disease (ILD) associated with systemic anticancer therapy is recognized as a life-threatening adverse event of lung cancer treatment. Programmed cell death 1 (PD-1) checkpoint inhibitors, such as nivolumab, often induce pneumonitis in patients with cancer; however, the tolerance and safety of nivolumab for advanced lung cancer with ILD are unclear. We report a 72-year-old patient with lung cancer with pathologically proven idiopathic pulmonary fibrosis who was treated with nivolumab. She demonstrated pneumonitis with an organized pneumonia (OP) pattern, but no acute exacerbation of ILD featuring a diffuse alveolar damage (DAD) pattern. She was successfully treated with corticosteroid therapy, and maintained good disease control after the discontinuation of nivolumab. She also showed pseudoprogression of the primary tumor, implying infiltration of T-cells into the lung. These findings suggest that T-cell activation by nivolumab treatment might not be directly associated with acute ILD exacerbation, and that treatable OP might be a major pulmonary complication of nivolumab in patients with pre-existing ILD, similar to patients without underlying ILD.
CANIT0002350	30922394	Clinical research	A total of 139 patients (79 atients treated with anti-PD-1 monotherapy and 60 patients treated with ipilimumab plus nivolumab)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	79	N/A	Retrospective analysis	 the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination)	N/A	N/A	N/A	Body mass index (NCIT:C16358); 	Body mass index	Personal feature	 2019 Mar 29	Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.METHODS: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.RESULTS: Overweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.CONCLUSIONS: The findings support the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).
CANIT0002351	30922394	Clinical research	A total of 139 patients (79 atients treated with anti-PD-1 monotherapy and 61 patients treated with ipilimumab plus nivolumab)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	79	N/A	Retrospective analysis	 the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination)	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2019 Mar 29	Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.METHODS: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.RESULTS: Overweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.CONCLUSIONS: The findings support the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).
CANIT0002352	30922394	Clinical research	A total of 139 patients (79 atients treated with anti-PD-1 monotherapy and 62 patients treated with ipilimumab plus nivolumab)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	79	N/A	Retrospective analysis	 the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination)	N/A	N/A	N/A	Creatinine (NCIT:C399); 	Serum creatinine levels	Metabolite	 2019 Mar 29	Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.METHODS: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.RESULTS: Overweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.CONCLUSIONS: The findings support the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).
CANIT0002353	30922394	Clinical research	A total of 139 patients (79 atients treated with anti-PD-1 monotherapy and 60 patients treated with ipilimumab plus nivolumab)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	79	N/A	Retrospective analysis	 the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination)	N/A	N/A	N/A	Body mass index (NCIT:C16358); 	Body mass index	Personal feature	 2019 Mar 29	Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.METHODS: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.RESULTS: Overweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.CONCLUSIONS: The findings support the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).
CANIT0002354	30922394	Clinical research	A total of 139 patients (79 atients treated with anti-PD-1 monotherapy and 61 patients treated with ipilimumab plus nivolumab)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	79	N/A	Retrospective analysis	 the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination)	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2019 Mar 29	Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.METHODS: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.RESULTS: Overweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.CONCLUSIONS: The findings support the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).
CANIT0002355	30922394	Clinical research	A total of 139 patients (79 atients treated with anti-PD-1 monotherapy and 62 patients treated with ipilimumab plus nivolumab)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	79	N/A	Retrospective analysis	 the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination)	N/A	N/A	N/A	Creatinine (NCIT:C399); 	Serum creatinine levels	Metabolite	 2019 Mar 29	Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.METHODS: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.RESULTS: Overweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.CONCLUSIONS: The findings support the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).
CANIT0002356	30922394	Clinical research	A total of 139 patients (79 atients treated with anti-PD-1 monotherapy and 63 patients treated with ipilimumab plus nivolumab)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	79	N/A	Retrospective analysis	 the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination)	N/A	N/A	N/A	Body mass index (NCIT:C16358); 	Body mass index	Personal feature	 2019 Mar 29	Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.METHODS: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.RESULTS: Overweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.CONCLUSIONS: The findings support the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).
CANIT0002357	30922394	Clinical research	A total of 139 patients (79 atients treated with anti-PD-1 monotherapy and 64 patients treated with ipilimumab plus nivolumab)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	79	N/A	Retrospective analysis	 the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination)	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2019 Mar 29	Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.METHODS: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.RESULTS: Overweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.CONCLUSIONS: The findings support the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).
CANIT0002358	30922394	Clinical research	A total of 139 patients (79 atients treated with anti-PD-1 monotherapy and 65 patients treated with ipilimumab plus nivolumab)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	79	N/A	Retrospective analysis	 the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination)	N/A	N/A	N/A	Creatinine (NCIT:C399); 	Serum creatinine levels	Metabolite	 2019 Mar 29	Complex inter-relationship of body mass index, gender and serum creatinine on survival: exploring the obesity paradox in melanoma patients treated with checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting.METHODS: Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models.RESULTS: Overweight/Class-I (25- < 35 kg/m2) obese patients had a significantly lower risk of mortality (adjusted-HR:0.26; 95%CI:0.1-0.71; p-value = 0.008) and progressive disease (adjusted-HR:0.43; 95%CI:0.19-0.95; p-value:0.038) compared to normal-weight (18.5- < 25 kg/m2). Class II/III obesity (compared to normal-weight) had an adjusted HR of 0.42 (95%CI: 0.1-1.77; p-value: 0.238) for OS and 1 (95%CI:0.34-2.94; p-value:0.991) for PFS. Exploration of interactions for OS showed that the association was predominantly driven by males (adjusted-HRmales:0.11; 95%CI:0.03-0.4; adjusted-HRfemales: 0.56; 95%CI:0.16-1.89; p-valueinteraction:0.044); the association was not seen in patients with serum creatinine< 0.9 mg/dL (adjusted-HR:0.43; 95%CI:0.15-1.24; p-valueinteraction:0.020), who were predominantly females. These observations were made in both the anti-PD-1 monotherapy (n = 79) and combination therapy (anti-PD-1/CTLA-4, n = 60) cohorts.CONCLUSIONS: The findings support the existence of an obesity paradox restricted to overweight/Class-I obesity in the real-world setting; the association was driven predominantly by males who largely had higher serum creatinine levels, a surrogate for skeletal muscle mass in the setting of metastatic disease. These observations suggest that sarcopenia (low skeletal muscle mass) or direct measures of body mass composition may be more suitable predictors of survival in melanoma patients treated with PD-1 blockade (monotherapy/combination).
CANIT0002359	30922878	Clinical research	 non-squamous non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab plus carboplatin plus paclitaxel	Bevacizumab plus carboplatin plus paclitaxel	Immune checkpoint therapy plus Chemotherapy	Atezolizumab (DB11595); bevacizumab (DB00112); carboplatin (DB00958); paclitaxel (DB01229); 	402	400	Randomised, open-label phase 3 trial	Improved survival was noted for patients treated with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) compared with those given  the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.	In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2019 May	Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.	 Lancet Respir Med	BACKGROUND: The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups.METHODS: IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov, number NCT02366143, and is ongoing.FINDINGS: Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17.0-NE) with ABCP (34 of 400) and 18.7 months (95% CI 13.4-NE) with BCP (45 of 400; hazard ratio [HR] 0.61 [95% CI 0.29-1.28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17.5 months [95% CI 11.7-NE] with BCP [32 of 400]; HR 0.31 [95% CI 0.11-0.83]) and in the intention-to-treat population (19.8 months [17.4-24.2] vs 14.9 months [13.4-17.1]; HR 0.76 [0.63-0.93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13.3 months [11.6-NE] with ABCP [52 of 400] vs 9.4 months [7.9-11.7] with BCP [57 of 400]; HR 0.52 [0.33-0.82]). Median overall survival was 21.4 months (95% CI 13.8-NE) with ACP versus 18.7 months (95% CI 13.4-NE) with BCP in EGFR-positive patients (HR 0.93 [95% CI 0.51-1.68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0.90 [95% CI 0.47-1.74]), in the intention-to-treat population (HR 0.85 [0.71-1.03]), or in patients with baseline liver metastases (HR 0.87 [0.57-1.32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.INTERPRETATION: Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.FUNDING: F. Hoffmann-La Roche, Genentech.
CANIT0002360	30922878	Clinical research	 non-squamous non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab plus carboplatin plus paclitaxel	Bevacizumab plus carboplatin plus paclitaxel	Immune checkpoint therapy plus Chemotherapy	Atezolizumab (DB11595); bevacizumab (DB00112); carboplatin (DB00958); paclitaxel (DB01229); 	402	400	Randomised, open-label phase 3 trial	Improved survival was noted for patients treated with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) compared with those given  the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.	In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2019 May	Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.	 Lancet Respir Med	BACKGROUND: The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups.METHODS: IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov, number NCT02366143, and is ongoing.FINDINGS: Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17.0-NE) with ABCP (34 of 400) and 18.7 months (95% CI 13.4-NE) with BCP (45 of 400; hazard ratio [HR] 0.61 [95% CI 0.29-1.28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17.5 months [95% CI 11.7-NE] with BCP [32 of 400]; HR 0.31 [95% CI 0.11-0.83]) and in the intention-to-treat population (19.8 months [17.4-24.2] vs 14.9 months [13.4-17.1]; HR 0.76 [0.63-0.93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13.3 months [11.6-NE] with ABCP [52 of 400] vs 9.4 months [7.9-11.7] with BCP [57 of 400]; HR 0.52 [0.33-0.82]). Median overall survival was 21.4 months (95% CI 13.8-NE) with ACP versus 18.7 months (95% CI 13.4-NE) with BCP in EGFR-positive patients (HR 0.93 [95% CI 0.51-1.68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0.90 [95% CI 0.47-1.74]), in the intention-to-treat population (HR 0.85 [0.71-1.03]), or in patients with baseline liver metastases (HR 0.87 [0.57-1.32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.INTERPRETATION: Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.FUNDING: F. Hoffmann-La Roche, Genentech.
CANIT0002361	30922878	Clinical research	 non-squamous non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab plus carboplatin plus paclitaxel	Bevacizumab plus carboplatin plus paclitaxel	Immune checkpoint therapy plus Target therapy plus Chemotherapy	Atezolizumab (DB11595); bevacizumab (DB00112); carboplatin (DB00958); paclitaxel (DB01229); 	400	400	Randomised, open-label phase 3 trial	Improved survival was noted for patients treated with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) compared with those given  the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.	In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2019 May	Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.	 Lancet Respir Med	BACKGROUND: The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups.METHODS: IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov, number NCT02366143, and is ongoing.FINDINGS: Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17.0-NE) with ABCP (34 of 400) and 18.7 months (95% CI 13.4-NE) with BCP (45 of 400; hazard ratio [HR] 0.61 [95% CI 0.29-1.28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17.5 months [95% CI 11.7-NE] with BCP [32 of 400]; HR 0.31 [95% CI 0.11-0.83]) and in the intention-to-treat population (19.8 months [17.4-24.2] vs 14.9 months [13.4-17.1]; HR 0.76 [0.63-0.93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13.3 months [11.6-NE] with ABCP [52 of 400] vs 9.4 months [7.9-11.7] with BCP [57 of 400]; HR 0.52 [0.33-0.82]). Median overall survival was 21.4 months (95% CI 13.8-NE) with ACP versus 18.7 months (95% CI 13.4-NE) with BCP in EGFR-positive patients (HR 0.93 [95% CI 0.51-1.68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0.90 [95% CI 0.47-1.74]), in the intention-to-treat population (HR 0.85 [0.71-1.03]), or in patients with baseline liver metastases (HR 0.87 [0.57-1.32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.INTERPRETATION: Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.FUNDING: F. Hoffmann-La Roche, Genentech.
CANIT0002362	30922878	Clinical research	 non-squamous non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab plus carboplatin plus paclitaxel	Bevacizumab plus carboplatin plus paclitaxel	Immune checkpoint therapy plus Target therapy plus Chemotherapy	Atezolizumab (DB11595); bevacizumab (DB00112); carboplatin (DB00958); paclitaxel (DB01229); 	400	400	Randomised, open-label phase 3 trial	Improved survival was noted for patients treated with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) compared with those given  the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.	In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2019 May	Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.	 Lancet Respir Med	BACKGROUND: The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups.METHODS: IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov, number NCT02366143, and is ongoing.FINDINGS: Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17.0-NE) with ABCP (34 of 400) and 18.7 months (95% CI 13.4-NE) with BCP (45 of 400; hazard ratio [HR] 0.61 [95% CI 0.29-1.28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17.5 months [95% CI 11.7-NE] with BCP [32 of 400]; HR 0.31 [95% CI 0.11-0.83]) and in the intention-to-treat population (19.8 months [17.4-24.2] vs 14.9 months [13.4-17.1]; HR 0.76 [0.63-0.93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13.3 months [11.6-NE] with ABCP [52 of 400] vs 9.4 months [7.9-11.7] with BCP [57 of 400]; HR 0.52 [0.33-0.82]). Median overall survival was 21.4 months (95% CI 13.8-NE) with ACP versus 18.7 months (95% CI 13.4-NE) with BCP in EGFR-positive patients (HR 0.93 [95% CI 0.51-1.68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0.90 [95% CI 0.47-1.74]), in the intention-to-treat population (HR 0.85 [0.71-1.03]), or in patients with baseline liver metastases (HR 0.87 [0.57-1.32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group.INTERPRETATION: Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study.FUNDING: F. Hoffmann-La Roche, Genentech.
CANIT0002363	30923820	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	185	N/A	Academic real-world cohort study	In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of disease progression (PD) or treatment limiting toxicity (TLT) , the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a complete response (CR), and being treated for >6 months, the risk of relapse after treatment discontinuation was low. Patients achieving a partial response (PR) or stable disease (SD) as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul 1	Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma.	 Ann Oncol	BACKGROUND: Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established.PATIENTS AND METHODS: This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N = 167) or nivolumab (N = 18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia.RESULTS: Median time on treatment was 12 months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18 months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12 months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response.CONCLUSIONS: In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6 months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients.CLINICAL TRIAL REGISTRATION: NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970 cond=melanoma&cntry=BE&city=Jette&rank=3).
CANIT0002364	30924739	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	99	N/A	Retrospective analysis	Reasons for admission in the study population were comparable to those identified in the general cancer population, with immune related adverse events being associated with a minority of both total and potentially preventable admissions.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	Characteristics of hospitalizations among patients receiving immune checkpoint inhibitors at a community teaching hospital.	 J Oncol Pharm Pract	PURPOSE: As immune checkpoint inhibitors continue to acquire new indications, it is important to understand the impact their use has on patients. This study adds to current literature by presenting an analysis of hospitalizations in this population. The primary objective was to assess the reasons for an emergency department visit or hospital admission in patients who receive immune checkpoint inhibitors. Secondary objectives included identifying the frequency of suspected or confirmed immune related adverse events, types of immune related adverse events, number of preventable admissions, duration of immunotherapy, and length of stay.METHODS: This study was a retrospective, multi-center, chart review of patients hospitalized after receiving an immune checkpoint inhibitor. The population included patients aged 18 and above who received at least one dose of an immune checkpoint inhibitor at a network facility and had a documented admission within one year following the initiation of immunotherapy. Descriptive statistics were performed along with inferential comparisons and a Poisson regression to determine if the immune checkpoint blocker or cancer type predicted admission or reason for admission.RESULTS: The 99 patients who met inclusion criteria had a total of 202 admissions. Of these patients, 56 (56.6%) had multiple admissions within the year following initiation of immunotherapy. The most common diagnoses on initial admissions were shortness of breath, pain, and pneumonia. A total of 104 admissions (51.5%) were considered potentially preventable. Suspected or confirmed immune related adverse events were identified in 15.6% of all admissions. There were no significant predictors of admissions or reason for admission.CONCLUSION: Reasons for admission in the study population were comparable to those identified in the general cancer population, with immune related adverse events being associated with a minority of both total and potentially preventable admissions.
CANIT0002365	30925541	Case report	An 87-year-old woman	Squamous cell carcinoma	EFO:0000707	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	In an attempt to palliate this invasive tumor, the patient received 8 infusions of pembrolizumab (Keytruda; anti-PD1, immunotherapy agent). Six months after, external examination showed significant regression of the lesion with cicatrization down to the temporal fossa with an exposed, escharred lateral zygomatic arch and lateral frontal bone	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Sep/Oct	Massive Periocular Squamous Cell Carcinoma With Response to Pembrolizumab (Keytruda).	 Ophthalmic Plast Reconstr Surg	Unable to provide
CANIT0002366	30925943	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	71	N/A	N/A	Overall, BDX008+ patients had significantly better overall survival (OS) (HR = 0.50, P = 0.016) and a trend for better progression-free survival (PFS) (HR = 0.61, P = 0.060) than BDX008- patients. BDX008 classification was statistically significant in the analyses adjusted for mutation status, LDH, and line of treatment (P = 0.009 for OS and 0.031 for PFS). BRAF WT BDX008+ patients had markedly long median OS of 32.5 months and 53% landmark 2 years survival, with statistically significantly superior OS as compared to BDX008- patients (HR = 0.41, P = 0.032). The difference between BDX008+ and BDX008- in PFS in BRAF WT patients and in OS and PFS in BRAF MUT patients did not reach statistical significance, though numerically was consistent with overall results. The test demonstrated significant interaction with neutrophil-to-lymphocyte ratio (NLR) (PFS P = 0.041, OS P = 0.004). BDX008 as a biomarker selecting for benefit from immune checkpoint blockade, especially in patients with wild type BRAF and in subgroups with low NLR, warrants further evaluation.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	BRAF (P15056); 	BRAF wild type	Mutational status	 2019 Mar 29	Proteomic test for anti-PD-1 checkpoint blockade treatment of metastatic melanoma with and without BRAF mutations.	 J Immunother Cancer	The therapeutic landscape in metastatic melanoma has changed dramatically in the last decade, with the success of immune checkpoint inhibitors resulting in durable responses for a large number of patients. For patients with BRAF mutations, combinations of BRAF and MEK inhibitors demonstrated response rates and benefit comparable to those from immune checkpoint inhibitors, providing the rationale for sequential treatment with targeted and immunotherapies and raising the question of optimal treatment sequencing.Biomarkers for the selection of anti-PD-1 therapy in BRAF wild type (BRAF WT) and in BRAF mutated (BRAF MUT) patients help development of alternative treatments for patients unlikely to benefit, and might lead to better understanding of the interaction of checkpoint inhibition and targeted therapy. In this paper we evaluate the performance of a previously developed serum proteomic test, BDX008, in metastatic melanoma patients treated with anti-PD-1 agents and investigate the role of BRAF mutation status. BDX008, a pre-treatment proteomic test associated with acute phase reactants, wound healing and complement activation, stratifies patients into two groups, BDX008+ and BDX008-, with better and worse outcomes on immunotherapy.Serum samples were available from 71 patients treated with anti-PD1 inhibitors; 25 patients had BRAF mutations, 39 were wild type. Overall, BDX008+ patients had significantly better overall survival (OS) (HR = 0.50, P = 0.016) and a trend for better progression-free survival (PFS) (HR = 0.61, P = 0.060) than BDX008- patients. BDX008 classification was statistically significant in the analyses adjusted for mutation status, LDH, and line of treatment (P = 0.009 for OS and 0.031 for PFS). BRAF WT BDX008+ patients had markedly long median OS of 32.5 months and 53% landmark 2 years survival, with statistically significantly superior OS as compared to BDX008- patients (HR = 0.41, P = 0.032). The difference between BDX008+ and BDX008- in PFS in BRAF WT patients and in OS and PFS in BRAF MUT patients did not reach statistical significance, though numerically was consistent with overall results. The test demonstrated significant interaction with neutrophil-to-lymphocyte ratio (NLR) (PFS P = 0.041, OS P = 0.004). BDX008 as a biomarker selecting for benefit from immune checkpoint blockade, especially in patients with wild type BRAF and in subgroups with low NLR, warrants further evaluation.
CANIT0002367	30925943	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	71	N/A	N/A	Overall, BDX008+ patients had significantly better overall survival (OS) (HR = 0.50, P = 0.016) and a trend for better progression-free survival (PFS) (HR = 0.61, P = 0.060) than BDX008- patients. BDX008 classification was statistically significant in the analyses adjusted for mutation status, LDH, and line of treatment (P = 0.009 for OS and 0.031 for PFS). BRAF WT BDX008+ patients had markedly long median OS of 32.5 months and 53% landmark 2 years survival, with statistically significantly superior OS as compared to BDX008- patients (HR = 0.41, P = 0.032). The difference between BDX008+ and BDX008- in PFS in BRAF WT patients and in OS and PFS in BRAF MUT patients did not reach statistical significance, though numerically was consistent with overall results. The test demonstrated significant interaction with neutrophil-to-lymphocyte ratio (NLR) (PFS P = 0.041, OS P = 0.004). BDX008 as a biomarker selecting for benefit from immune checkpoint blockade, especially in patients with wild type BRAF and in subgroups with low NLR, warrants further evaluation.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	BDX008 (); 	BDX008(+) patients	Gene expression signature on/in tumor cell	 2019 Mar 29	Proteomic test for anti-PD-1 checkpoint blockade treatment of metastatic melanoma with and without BRAF mutations.	 J Immunother Cancer	The therapeutic landscape in metastatic melanoma has changed dramatically in the last decade, with the success of immune checkpoint inhibitors resulting in durable responses for a large number of patients. For patients with BRAF mutations, combinations of BRAF and MEK inhibitors demonstrated response rates and benefit comparable to those from immune checkpoint inhibitors, providing the rationale for sequential treatment with targeted and immunotherapies and raising the question of optimal treatment sequencing.Biomarkers for the selection of anti-PD-1 therapy in BRAF wild type (BRAF WT) and in BRAF mutated (BRAF MUT) patients help development of alternative treatments for patients unlikely to benefit, and might lead to better understanding of the interaction of checkpoint inhibition and targeted therapy. In this paper we evaluate the performance of a previously developed serum proteomic test, BDX008, in metastatic melanoma patients treated with anti-PD-1 agents and investigate the role of BRAF mutation status. BDX008, a pre-treatment proteomic test associated with acute phase reactants, wound healing and complement activation, stratifies patients into two groups, BDX008+ and BDX008-, with better and worse outcomes on immunotherapy.Serum samples were available from 71 patients treated with anti-PD1 inhibitors; 25 patients had BRAF mutations, 39 were wild type. Overall, BDX008+ patients had significantly better overall survival (OS) (HR = 0.50, P = 0.016) and a trend for better progression-free survival (PFS) (HR = 0.61, P = 0.060) than BDX008- patients. BDX008 classification was statistically significant in the analyses adjusted for mutation status, LDH, and line of treatment (P = 0.009 for OS and 0.031 for PFS). BRAF WT BDX008+ patients had markedly long median OS of 32.5 months and 53% landmark 2 years survival, with statistically significantly superior OS as compared to BDX008- patients (HR = 0.41, P = 0.032). The difference between BDX008+ and BDX008- in PFS in BRAF WT patients and in OS and PFS in BRAF MUT patients did not reach statistical significance, though numerically was consistent with overall results. The test demonstrated significant interaction with neutrophil-to-lymphocyte ratio (NLR) (PFS P = 0.041, OS P = 0.004). BDX008 as a biomarker selecting for benefit from immune checkpoint blockade, especially in patients with wild type BRAF and in subgroups with low NLR, warrants further evaluation.
CANIT0002368	30925943	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	71	N/A	N/A	Overall, BDX008+ patients had significantly better overall survival (OS) (HR = 0.50, P = 0.016) and a trend for better progression-free survival (PFS) (HR = 0.61, P = 0.060) than BDX008- patients. BDX008 classification was statistically significant in the analyses adjusted for mutation status, LDH, and line of treatment (P = 0.009 for OS and 0.031 for PFS). BRAF WT BDX008+ patients had markedly long median OS of 32.5 months and 53% landmark 2 years survival, with statistically significantly superior OS as compared to BDX008- patients (HR = 0.41, P = 0.032). The difference between BDX008+ and BDX008- in PFS in BRAF WT patients and in OS and PFS in BRAF MUT patients did not reach statistical significance, though numerically was consistent with overall results. The test demonstrated significant interaction with neutrophil-to-lymphocyte ratio (NLR) (PFS P = 0.041, OS P = 0.004). BDX008 as a biomarker selecting for benefit from immune checkpoint blockade, especially in patients with wild type BRAF and in subgroups with low NLR, warrants further evaluation.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Mar 29	Proteomic test for anti-PD-1 checkpoint blockade treatment of metastatic melanoma with and without BRAF mutations.	 J Immunother Cancer	The therapeutic landscape in metastatic melanoma has changed dramatically in the last decade, with the success of immune checkpoint inhibitors resulting in durable responses for a large number of patients. For patients with BRAF mutations, combinations of BRAF and MEK inhibitors demonstrated response rates and benefit comparable to those from immune checkpoint inhibitors, providing the rationale for sequential treatment with targeted and immunotherapies and raising the question of optimal treatment sequencing.Biomarkers for the selection of anti-PD-1 therapy in BRAF wild type (BRAF WT) and in BRAF mutated (BRAF MUT) patients help development of alternative treatments for patients unlikely to benefit, and might lead to better understanding of the interaction of checkpoint inhibition and targeted therapy. In this paper we evaluate the performance of a previously developed serum proteomic test, BDX008, in metastatic melanoma patients treated with anti-PD-1 agents and investigate the role of BRAF mutation status. BDX008, a pre-treatment proteomic test associated with acute phase reactants, wound healing and complement activation, stratifies patients into two groups, BDX008+ and BDX008-, with better and worse outcomes on immunotherapy.Serum samples were available from 71 patients treated with anti-PD1 inhibitors; 25 patients had BRAF mutations, 39 were wild type. Overall, BDX008+ patients had significantly better overall survival (OS) (HR = 0.50, P = 0.016) and a trend for better progression-free survival (PFS) (HR = 0.61, P = 0.060) than BDX008- patients. BDX008 classification was statistically significant in the analyses adjusted for mutation status, LDH, and line of treatment (P = 0.009 for OS and 0.031 for PFS). BRAF WT BDX008+ patients had markedly long median OS of 32.5 months and 53% landmark 2 years survival, with statistically significantly superior OS as compared to BDX008- patients (HR = 0.41, P = 0.032). The difference between BDX008+ and BDX008- in PFS in BRAF WT patients and in OS and PFS in BRAF MUT patients did not reach statistical significance, though numerically was consistent with overall results. The test demonstrated significant interaction with neutrophil-to-lymphocyte ratio (NLR) (PFS P = 0.041, OS P = 0.004). BDX008 as a biomarker selecting for benefit from immune checkpoint blockade, especially in patients with wild type BRAF and in subgroups with low NLR, warrants further evaluation.
CANIT0002369	30935847	Clinical research	47 patients with metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	47	N/A	Retrospective analysis	A significant association between nivolumab-associated immune-related adverse events and prognosis in previously treated metastatic renal cell carcinoma.	Rash/pruritus	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2019 Jun	Association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab.	 Urol Oncol	OBJECTIVES: Immune-related adverse events (irAEs) develop in a subset of patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors. The relationship between presence of irAEs and prognosis in these patients remains unknown. Thus, we evaluated the prognostic impact of irAEs caused by nivolumab therapy in mRCC patients who had received prior molecular-targeted therapies.METHODS: We retrospectively evaluated 47 patients with mRCC who were treated with nivolumab after receiving at least 1 molecular-targeted therapy. The irAEs assessed in this study included cutaneous, gastrointestinal, endocrine, pulmonary, hepatobiliary, renal, and other (rheumatic disease and pancreatitis) manifestations. The grade of irAEs was defined based on the Common Terminology Criteria for Adverse Events version 4.0.RESULTS: In total, 23/47 patients (48.9%) experienced 29 irAEs. The most frequent irAE was rash/pruritus (12/23, 52.2%). The median progression-free survival (PFS) and overall survival after the initiation of nivolumab therapy were significantly longer in patients with irAEs than in those without irAEs (PFS: 13.1 vs. 4.87 months, P < 0.0001; overall survival: 26.0 vs. not reached, P = 0.0072). The multivariate analysis of PFS showed that irAE development was an independent prognostic factor (hazard ratio: 0.25, P = 0.0009). Additionally, the 2-cycle landmark analysis showed that PFS was significantly longer in patients with irAEs than in those without irAEs (median: not reached vs. 6.28 months, P = 0.0279).CONCLUSIONS: This retrospective study revealed a significant association between nivolumab-associated irAEs and prognosis in previously treated mRCC. Further prospective studies are necessary to confirm our findings.
CANIT0002370	30940117	Clinical research	Clear cell renal carcinoma	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	30	N/A	N/A	There were 18 responding lesions, and 12 non-responding lesions. We compared change in diameter and baseline maximum standardized uptake value (SUVmax) at first assessment with FDG-PET/CT, respectively. All lesions with decreased diameter and elevated SUVmax at first assessment with FDG-PET/CT showed responding at second assessment by CT scan, while most lesions with increased diameter and declined SUVmax at first assessment showed non-responding at second assessment. The multivariate logistic regression analyses revealed that only the elevation of SUVmax at 1 month was an independent predictor (P = 0.025, OR: 13.087, 95%CI: 1.373-124.716).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Apr 2	Early assessment with (18)F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography to predict short-term outcome in clear cell renal carcinoma treated with nivolumab.	 BMC Cancer	BACKGROUND: We reported previously the usefulness of 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to predict prognosis of renal cell carcinoma (RCC) treated with molecular targeted agents. Herein we describe a preliminary research of nine patients who underwent FDG-PET/CT before and after initiation of nivolumab.METHODS: Patients with metastatic RCC who were treated by nivolumab from October 2016 to March 2017 were enrolled in this study. All patients underwent FDG-PET/CT at baseline and 1 month as a first response assessment, and contrast-enhanced or non-contrast-enhanced CT scan at 4 month as a second response assessment. Logistic regression analysis was performed to assess the association of potential predictors, including age, gender, baseline diameter, baseline maximum standardized uptake value (SUVmax), lung or not lung metastasis, elevation of SUVmax at 1st assessment, and decrease in diameter at 1st assessment with the response at 2nd assessment (decrease in the diameter >= 30% or not).RESULTS: There were 9 patients and 30 lesions. Mean days of first assessment with FDG-PET/CT and second assessment by CT scan from initiation of treatment were 32.3 +/- 6.4, 115.5 +/- 14.9, respectively. Lesions whose diameter decreased >=30% at second assessment were defined as responding, and lesions whose diameter did not decrease >=30% were defined as non-responding. There were 18 responding lesions, and 12 non-responding lesions. We compared change in diameter and SUVmax at first assessment with FDG-PET/CT, respectively. All lesions with decreased diameter and elevated SUVmax at first assessment with FDG-PET/CT showed responding at second assessment by CT scan, while most lesions with increased diameter and declined SUVmax at first assessment showed non-responding at second assessment. The multivariate logistic regression analyses revealed that only the elevation of SUVmax at 1 month was an independent predictor (P = 0.025, OR: 13.087, 95%CI: 1.373-124.716).CONCLUSION: Our findings suggest that the early assessment using FDG-PET/CT can be effective to predict the response of RCC to nivolumab. However, larger prospective studies are needed to confirm these preliminary results.TRIAL REGISTRATION: Registered in University Hospital Medical Information Network in JAPAN [ UMIN0000008141 ], registration date: 11 Jun 2012.
CANIT0002371	30940209	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus steroids followed by infliximab or vedolizumab	N/A	Immune checkpoint therapy	N/A	1459	N/A	Retrospective analysis	Selective immunosuppressive therapy (SIT) should be introduced early in the disease course of immune-mediated colitis (IMC) instead of waiting until failure of steroid therapy or steroid taper. Patients who received three or more infusions of SIT had more favorable clinical outcomes.	Immune checkpoint inhibitor-induced colitis	N/A	N/A	N/A	N/A	N/A	 2019 Apr 2	Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis.	 J Immunother Cancer	BACKGROUND: Current treatment guidelines for immune-mediated colitis (IMC) recommend 4 to 6 weeks of steroids as first-line therapy, followed by selective immunosuppressive therapy (SIT) (infliximab or vedolizumab) in patients who do not respond to steroids. We assessed the effect of early SIT introduction and number of SIT infusions on clinical outcomes.METHODS: We performed a retrospective review of patients with IMC who received SIT at The University of Texas MD Anderson Cancer Center between January and December 2018. Logistic regression analyses were used to assess associations between clinical outcomes and features of IMC.RESULTS: Of the 1459 patients who received immune checkpoint inhibitors, 179 developed IMC of any grade; 84 of these 179 patients received SIT. Of the 84 patients who received SIT, 79% were males, and the mean age was 60 years (standard deviation, 14). Compared with patients who received SIT > 10 days after IMC onset, patients who received early SIT (<=10 days) required fewer hospitalizations (P = 0.03), experienced steroid taper failure less frequently (P = 0.03), had fewer steroid tapering attempts (P < 0.01), had a shorter course of steroid treatment (P = 0.09), and had a shorter duration of symptoms (P < 0.01). Patients who received one or two infusions of SIT achieved histologic remission less frequently (P = 0.09) and had higher fecal calprotectin levels after SIT (P = 0.01) compared with patients who received three or more infusions. Risk factors for IMC recurrence after weaning off steroids included: 1) needing multiple hospitalizations, 2) experiencing steroid taper failure after SIT, 3) receiving infliximab rather than vedolizumab, 4) receiving fewer than three infusions of SIT, 5) having higher fecal calprotectin levels after SIT, and 6) receiving a longer course of steroids, hospitalization and IMC symptoms. Unsuccessful weaning from steroids after SIT was associated with high IMC grades; multiple hospitalizations; steroid-resistant IMC; long interval from IMC to SIT initiation; and long duration of steroids, IMC symptoms, and hospitalization.CONCLUSION: SIT should be introduced early in the disease course of IMC instead of waiting until failure of steroid therapy or steroid taper. Patients who received three or more infusions of SIT had more favorable clinical outcomes.
CANIT0002372	30941424	Clinical research	Of 410 and 411 patients randomized to nivolumab and everolimus, 37 and 26 were Japanese, respectively.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); mTOR (P42345); 	PD-1; mTOR	Nivolumab	Everolimus	Immune checkpoint therapy	Nivolumab (DB09035); 	411	N/A	A Phase III, randomized open-label study 	Both the global and the Japanese populations experienced an improvement in quality of life with nivolumab treatment compared with everolimus. Similar proportions of patients in the global and Japanese populations received subsequent therapy	Endocrine,gastrointestinal,hepatic,pulmonary,renal,skin	N/A	N/A	N/A	N/A	N/A	 2019 Jun 1	Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the Phase III CheckMate 025 study.	 Jpn J Clin Oncol	BACKGROUND: Nivolumab treatment resulted in superior efficacy and safety versus everolimus treatment in the 2-year follow-up of the CheckMate 025 Phase III study, with consistent results in the global population and the Japanese population. Here, we report the 3-year follow-up in both groups.METHODS: Patients were randomized 1:1 to nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10 mg orally once daily until progression/intolerable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included objective response rate, progression-free survival, safety and patient-reported quality of life.RESULTS: Of 410 and 411 patients randomized to nivolumab and everolimus, 37 and 26 were Japanese, respectively. The median OS for the global population was 25.8 months with nivolumab and 19.7 months with everolimus (hazard ratio 0.74; 95.5% confidence interval [CI]: 0.63-0.88; P = 0.0005); in the Japanese population, median OS was 45.9 months and not reached (hazard ratio 1.08; 95% CI: 0.50-2.34; P = 0.85), respectively. The investigator-assessed objective response rate was 26% versus 5% with nivolumab versus everolimus (odds ratio [OR] 6.19; 95% CI: 3.82-10.06) in the global population and 43% versus 8% in the Japanese population (OR 6.80; 95% CI: 1.60-28.91; P = 0.0035), respectively. The incidence of any-grade treatment-related adverse events was lower with nivolumab versus everolimus in both the global patient population (80% versus 89%) and the Japanese population (81% versus 100%).CONCLUSIONS: At the 3-year follow-up, the efficacy and safety results of CheckMate 025 are generally consistent in the global and the Japanese populations.
CANIT0002373	30941424	Clinical research	Of 410 and 411 patients randomized to nivolumab and everolimus, 37 and 26 were Japanese, respectively.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab 	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	410	N/A	A Phase III, randomized open-label study 	Both the global and the Japanese populations experienced an improvement in quality of life with nivolumab treatment compared with everolimus. Similar proportions of patients in the global and Japanese populations received subsequent therapy	Endocrine,gastrointestinal,hepatic,pulmonary,renal,skin	N/A	N/A	N/A	N/A	N/A	 2019 Jun 1	Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the Phase III CheckMate 025 study.	 Jpn J Clin Oncol	BACKGROUND: Nivolumab treatment resulted in superior efficacy and safety versus everolimus treatment in the 2-year follow-up of the CheckMate 025 Phase III study, with consistent results in the global population and the Japanese population. Here, we report the 3-year follow-up in both groups.METHODS: Patients were randomized 1:1 to nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10 mg orally once daily until progression/intolerable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included objective response rate, progression-free survival, safety and patient-reported quality of life.RESULTS: Of 410 and 411 patients randomized to nivolumab and everolimus, 37 and 26 were Japanese, respectively. The median OS for the global population was 25.8 months with nivolumab and 19.7 months with everolimus (hazard ratio 0.74; 95.5% confidence interval [CI]: 0.63-0.88; P = 0.0005); in the Japanese population, median OS was 45.9 months and not reached (hazard ratio 1.08; 95% CI: 0.50-2.34; P = 0.85), respectively. The investigator-assessed objective response rate was 26% versus 5% with nivolumab versus everolimus (odds ratio [OR] 6.19; 95% CI: 3.82-10.06) in the global population and 43% versus 8% in the Japanese population (OR 6.80; 95% CI: 1.60-28.91; P = 0.0035), respectively. The incidence of any-grade treatment-related adverse events was lower with nivolumab versus everolimus in both the global patient population (80% versus 89%) and the Japanese population (81% versus 100%).CONCLUSIONS: At the 3-year follow-up, the efficacy and safety results of CheckMate 025 are generally consistent in the global and the Japanese populations.
CANIT0002374	30944020	Clinical research	Recurrent and/or metastatic head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	Cetuximab or docetaxel or or methotrexate	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	487	369	Phase III clinical trials (CheckMate 141 and KEYNOTE 040)	Treatment with nivolumab or pembrolizumab in R/M HNSCC patients led to an improved OS with a hazards ratio (HR) of 0.70 (95%CI 0.51-0.96; p = 0.01) and HR of 0.80 (95%CI 0.65-0.98, p = 0.0161), respectively, as compared to standard of care (SOC) chemo monotherapy regimens (specifically, cetuximab, docetaxel, or methotrexate). The gain in OS was similar in both studies, underscoring the role of anti-PD1 drugs in R/M HNSCC patients. One of the striking discrepancies between CheckMate 141 and KEYNOTE 040 was the OS observed in the control SOC arms (6.9 months median in KEYNOTE 040 versus 5.1 months in CheckMate 141), which inadvertently set a higher threshold in the bio-statistical analysis of KEYNOTE 040 so that the clinical outcome of every patient was influential in the analysis.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Apr 3	Comparative analysis of the phase III clinical trials of anti-PD1 monotherapy in head and neck squamous cell carcinoma patients (CheckMate 141 and KEYNOTE 040).	 J Immunother Cancer	Two phase III clinical trials (CheckMate 141 and KEYNOTE 040) have independently demonstrated that overall survival (OS) in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients, who have failed platinum-based therapy, can be improved with anti-PD1 monotherapy. Treatment with nivolumab or pembrolizumab in R/M HNSCC patients led to an improved OS with a hazards ratio (HR) of 0.70 (95%CI 0.51-0.96; p = 0.01) and HR of 0.80 (95%CI 0.65-0.98, p = 0.0161), respectively, as compared to standard of care (SOC) chemo monotherapy regimens (specifically, cetuximab, docetaxel, or methotrexate). The gain in OS was similar in both studies, underscoring the role of anti-PD1 drugs in R/M HNSCC patients. One of the striking discrepancies between CheckMate 141 and KEYNOTE 040 was the OS observed in the control SOC arms (6.9 months median in KEYNOTE 040 versus 5.1 months in CheckMate 141), which inadvertently set a higher threshold in the bio-statistical analysis of KEYNOTE 040 so that the clinical outcome of every patient was influential in the analysis. We perform a comparative analysis of the two studies to identify potential factors in the control arm that can impact clinical trial bio-statistical outcomes and which may have implications for future immunotherapy clinical trial designs.
CANIT0002375	30944023	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	389	N/A	N/A	Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7-6.2) and the 12-month overall survival rate was 63%. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Patients with immune-related adverse events versus without immune-related adverse events had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of immune-related adverse events displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis. The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab.	Any grade and grade 3-4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs.	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2019 Apr 3	Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program.	 J Immunother Cancer	BACKGROUND: The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval.METHODS: Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received >=1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model.RESULTS: A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7-6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3-4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis.CONCLUSIONS: The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab.
CANIT0002376	30944183	Clinical research	Metastatic urothelial cell carcinoma	Urothelial cell carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	1637	N/A	Retrospective analysis	Rates of systemic therapy initiation in the last 30 and 60 days of life were 17.0% and 29.8%, respectively. The quarterly proportion of patients who initiated immune checkpoint inhibitor therapies (CPIs) within 60 days of death increased from 1.0% to 23% during the study period (p trend < .001). After CPI approval, end-of-life CPIs initiation significantly increased among patients with poor performance status (p trend = .020) and did not significantly change among individuals with good performance status. The quarterly proportion of patients who initiated any systemic therapy at the end of life doubled (17.4% to 34.8%) during the study period, largely explained by increased CPI use. These findings suggest a dramatic rise in CPI use at the end of life in patients with mUC, a finding that may have important guideline and policy implications.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Trends in Checkpoint Inhibitor Therapy for Advanced Urothelial Cell Carcinoma at the End of Life: Insights from Real-World Practice.	 Oncologist	Several immune checkpoint inhibitor therapies (CPIs) have been approved to treat metastatic urothelial cell carcinoma (mUC). Because of the favorable toxicity profile of CPI compared with chemotherapy, oncologists may have a low threshold to prescribe CPI to patients near the end of life. We evaluated trends in initiation of end-of-life systemic therapy in 1,637 individuals in the Flatiron Health Database who were diagnosed with mUC between 2015 and 2017 and who died. Rates of systemic therapy initiation in the last 30 and 60 days of life were 17.0% and 29.8%, respectively. The quarterly proportion of patients who initiated CPI within 60 days of death increased from 1.0% to 23% during the study period (p trend < .001). After CPI approval, end-of-life CPI initiation significantly increased among patients with poor performance status (p trend = .020) and did not significantly change among individuals with good performance status. The quarterly proportion of patients who initiated any systemic therapy at the end of life doubled (17.4% to 34.8%) during the study period, largely explained by increased CPI use. These findings suggest a dramatic rise in CPI use at the end of life in patients with mUC, a finding that may have important guideline and policy implications.
CANIT0002377	30948391	Case report	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Case	We describe the cases of two cancer patients with Immune checkpoint inhibitors (ICPis)-induced colitis who had isolated histoloigical features of colitis in the absence of macroscopic disease. Sustained clinical and histological remission was induced with the topical steroid preparation, beclometasone dipropionate (Clipper), with no adverse effects.	Colitis	N/A	N/A	N/A	N/A	N/A	 2019 Apr 3	Topical beclometasone dipropionate in the management of immune checkpoint inhibitor-induced microscopic colitis.	 BMJ Case Rep	Immune checkpoint inhibitors (ICPis) have revolutionised survival outcomes for cancer patients by bolstering anti-tumour immunity. However, immune activation also occurs in non-cancer tissue, and a significant proportion of patients develop immune-mediated colitis, which can be fatal if not promptly recognised and managed. Diagnosis is often made by inflammation observed during lower gastrointestinal endoscopy. Little is known about microscopic inflammation (histological findings of inflammation in the absence of overt mucosal injury). Management strategies beyond the use of systemic corticosteroids, which incur a high burden of deleterious side effects, have not been extensively explored. We describe the cases of two cancer patients with ICPi-induced colitis who had isolated histoloigical features of colitis in the absence of macroscopic disease. Sustained clinical and histological remission was induced with the topical steroid preparation, beclometasone dipropionate (Clipper), with no adverse effects.
CANIT0002378	30948391	Case report	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We describe the cases of two cancer patients with Immune checkpoint inhibitors (ICPis)-induced colitis who had isolated histoloigical features of colitis in the absence of macroscopic disease. Sustained clinical and histological remission was induced with the topical steroid preparation, beclometasone dipropionate (Clipper), with no adverse effects.	Colitis	N/A	N/A	N/A	N/A	N/A	 2019 Apr 3	Topical beclometasone dipropionate in the management of immune checkpoint inhibitor-induced microscopic colitis.	 BMJ Case Rep	Immune checkpoint inhibitors (ICPis) have revolutionised survival outcomes for cancer patients by bolstering anti-tumour immunity. However, immune activation also occurs in non-cancer tissue, and a significant proportion of patients develop immune-mediated colitis, which can be fatal if not promptly recognised and managed. Diagnosis is often made by inflammation observed during lower gastrointestinal endoscopy. Little is known about microscopic inflammation (histological findings of inflammation in the absence of overt mucosal injury). Management strategies beyond the use of systemic corticosteroids, which incur a high burden of deleterious side effects, have not been extensively explored. We describe the cases of two cancer patients with ICPi-induced colitis who had isolated histoloigical features of colitis in the absence of macroscopic disease. Sustained clinical and histological remission was induced with the topical steroid preparation, beclometasone dipropionate (Clipper), with no adverse effects.
CANIT0002379	30950239	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus chemotherapy	Immune checkpoint therapy	Immune checkpoint therapy plus Chemotherapy	N/A	50	69	Retrospective analysis	Combing chemotherapy with immune checkpoint inhibitors improved treatment efficacy over immune checkpoint inhibitors alone. The additional efficacy of chemotherapy may differ between EGFR mutation status.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2019 May	Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: Single agent immune checkpoint inhibitors (ICIs) improve survival outcomes compared to chemotherapy for advanced non-small cell lung cancer (NSCLC), but treatment efficacy widely varies. The combination of ICIs with chemotherapy has shown promising efficacy over chemotherapy alone; however, whether this strategy is superior to single agent ICIs for the treatment of advanced NSCLC remains unknown.METHODS: The records of 109 patients with advanced NSCLC who were administered at least one cycle of ICIs were retrospectively reviewed. Patients were grouped based on the presence or absence of a chemotherapy treatment combination. Efficacy and survival outcomes were analyzed.RESULT: Sixty-nine (58.0%) patients received single agent ICIs (ICI group) and 50 (42.0%) received ICIs and chemotherapy (ICC group). The median (3.2 vs. 3.0 months; P = 0.025) and one-year (34.5 vs. 9.6%; P = 0.026) progression-free survival (PFS) rates were significantly better in the ICC than in the ICI group. The superior efficacy of ICC remained in the propensity score matched pairs (median PFS 3.2 vs. 2.6 months, P = 0.032; 1-year PFS 35.2 vs. 7.6%; P = 0.035). Eastern Cooperative Oncology Group performance status 0-1 (HR 0.37, 95% CI 0.22-0.62; P < 0.001) and the ICC group (HR 0.56, 95% CI 0.34-0.94; P = 0.028) were predictive of PFS. Subgroup-to-chemotherapy interaction revealed improved risk reduction for adenocarcinoma and EGFR mutation.CONCLUSION: Combing chemotherapy with ICIs improved treatment efficacy over ICIs alone. The additional efficacy of chemotherapy may differ between histological subtypes and EGFR mutation status.
CANIT0002380	30950239	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus chemotherapy	Immune checkpoint therapy	Immune checkpoint therapy plus Chemotherapy	N/A	50	69	Retrospective analysis	Combing chemotherapy with immune checkpoint inhibitors improved treatment efficacy over immune checkpoint inhibitors alone. The additional efficacy of chemotherapy may differ between Eastern Cooperative Oncology Group (ECOG) performance status 0-1 .	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2019 May	Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: Single agent immune checkpoint inhibitors (ICIs) improve survival outcomes compared to chemotherapy for advanced non-small cell lung cancer (NSCLC), but treatment efficacy widely varies. The combination of ICIs with chemotherapy has shown promising efficacy over chemotherapy alone; however, whether this strategy is superior to single agent ICIs for the treatment of advanced NSCLC remains unknown.METHODS: The records of 109 patients with advanced NSCLC who were administered at least one cycle of ICIs were retrospectively reviewed. Patients were grouped based on the presence or absence of a chemotherapy treatment combination. Efficacy and survival outcomes were analyzed.RESULT: Sixty-nine (58.0%) patients received single agent ICIs (ICI group) and 50 (42.0%) received ICIs and chemotherapy (ICC group). The median (3.2 vs. 3.0 months; P = 0.025) and one-year (34.5 vs. 9.6%; P = 0.026) progression-free survival (PFS) rates were significantly better in the ICC than in the ICI group. The superior efficacy of ICC remained in the propensity score matched pairs (median PFS 3.2 vs. 2.6 months, P = 0.032; 1-year PFS 35.2 vs. 7.6%; P = 0.035). Eastern Cooperative Oncology Group performance status 0-1 (HR 0.37, 95% CI 0.22-0.62; P < 0.001) and the ICC group (HR 0.56, 95% CI 0.34-0.94; P = 0.028) were predictive of PFS. Subgroup-to-chemotherapy interaction revealed improved risk reduction for adenocarcinoma and EGFR mutation.CONCLUSION: Combing chemotherapy with ICIs improved treatment efficacy over ICIs alone. The additional efficacy of chemotherapy may differ between histological subtypes and EGFR mutation status.
CANIT0002381	30950239	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus chemotherapy	Immune checkpoint therapy	Immune checkpoint therapy plus Chemotherapy	N/A	50	69	Retrospective analysis	Combing chemotherapy with immune checkpoint inhibitors improved treatment efficacy over immune checkpoint inhibitors alone. The additional efficacy of chemotherapy may differ between histological subtypes.	N/A	N/A	N/A	Squamous histology (NCIT:C19165); 	Adenocarcinoma	Disease status	 2019 May	Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: Single agent immune checkpoint inhibitors (ICIs) improve survival outcomes compared to chemotherapy for advanced non-small cell lung cancer (NSCLC), but treatment efficacy widely varies. The combination of ICIs with chemotherapy has shown promising efficacy over chemotherapy alone; however, whether this strategy is superior to single agent ICIs for the treatment of advanced NSCLC remains unknown.METHODS: The records of 109 patients with advanced NSCLC who were administered at least one cycle of ICIs were retrospectively reviewed. Patients were grouped based on the presence or absence of a chemotherapy treatment combination. Efficacy and survival outcomes were analyzed.RESULT: Sixty-nine (58.0%) patients received single agent ICIs (ICI group) and 50 (42.0%) received ICIs and chemotherapy (ICC group). The median (3.2 vs. 3.0 months; P = 0.025) and one-year (34.5 vs. 9.6%; P = 0.026) progression-free survival (PFS) rates were significantly better in the ICC than in the ICI group. The superior efficacy of ICC remained in the propensity score matched pairs (median PFS 3.2 vs. 2.6 months, P = 0.032; 1-year PFS 35.2 vs. 7.6%; P = 0.035). Eastern Cooperative Oncology Group performance status 0-1 (HR 0.37, 95% CI 0.22-0.62; P < 0.001) and the ICC group (HR 0.56, 95% CI 0.34-0.94; P = 0.028) were predictive of PFS. Subgroup-to-chemotherapy interaction revealed improved risk reduction for adenocarcinoma and EGFR mutation.CONCLUSION: Combing chemotherapy with ICIs improved treatment efficacy over ICIs alone. The additional efficacy of chemotherapy may differ between histological subtypes and EGFR mutation status.
CANIT0002382	30953972	Clinical research	Metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab or chemotherapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	1811	N/A	N/A	Consistent with clinical trial results, survival was poor in this real-world study in patients with Metastatic urothelial carcinoma (mUC), indicating a continued unmet need. As immunotherapy becomes more commonplace in the treatment of mUC, future studies are needed to understand its real-world impact on survival.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Treatment patterns and overall survival in metastatic urothelial carcinoma in a real-world, US setting.	 Cancer Epidemiol	BACKGROUND: Metastatic urothelial carcinoma (mUC) treated with chemotherapy is associated with poor survival; however, as the field of immuno-oncology continues to evolve, new immunotherapies have recently become available. The current study aimed to assess real-world characteristics, treatment patterns, and overall survival (OS) of patients with mUC treated in the United States (US).METHODS: We conducted a retrospective, observational analysis of patients with mUC from the Flatiron Health longitudinal database from 2011 to 2017. Treatment patterns of patients who started systemic first-line therapy (1 L cohort) or second-line therapy following platinum-based first-line therapy (2 L cohort) were described using medication order and administration data. Kaplan-Meier analyses were used to assess OS from the start of first- and second-line therapy in the 1 L and 2 L cohorts, respectively.RESULTS: A total of 1811 patients qualified for the 1 L cohort (median age [range], 72 [32-84] years); 476 met the criteria for the 2 L cohort (median age [range], 71 [40-84] years). The most common first- and second-line therapies were carboplatin + gemcitabine (n = 562 [34.6%]) and atezolizumab (n = 90 [13.1%]), respectively, in the 1 L cohort. Median OS was 12.7 months (95% confidence interval [CI] 11.8, 13.4) in the 1 L cohort and 8.3 months (95% CI 7.2, 8.9) in the 2 L cohort.CONCLUSIONS: Consistent with clinical trial results, survival was poor in this real-world study in patients with mUC, indicating a continued unmet need. As immunotherapy becomes more commonplace in the treatment of mUC, future studies are needed to understand its real-world impact on survival.
CANIT0002383	30954716	Case report	A 57-year-old woman	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	A case of immune thrombocytopaenia induced by pembrolizumab in a metastatic melanoma patient with a history of immune-mediated pure red cell aplasia.	Immune thrombocytopaenia	N/A	N/A	N/A	N/A	N/A	 2019 May	A case of immune thrombocytopaenia induced by pembrolizumab in a metastatic melanoma patient with a history of immune-mediated pure red cell aplasia.	 Eur J Cancer	Unable to provide
CANIT0002384	30954880	Clinical research	Advanced cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Cemiplimab	N/A	Immune checkpoint therapy	Cemiplimab (DB14707); 	33	N/A	Retrospective analysis	Alterations in NF1 trended towards being more frequent among non-responders (63% vs. 13%, p = 0.06).	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	NF1 (P21359); 	NF1 mutation	Mutational status	 2019 May	Chromosome 3q arm gain linked to immunotherapy response in advanced cutaneous squamous cell carcinoma.	 Eur J Cancer	AIMS: The activity that the immune checkpoint inhibitor (ICI) cemiplimab has recently demonstrated has led to a paradigm shift in the management of patients with advanced cutaneous squamous cell carcinoma (cSCC). To identify predictive biomarkers of response to ICIs in advanced cSCC, we studied 33 patients who received ICI therapy at the Dana-Farber/Harvard Cancer Center (DF/HCC) and analysed sequencing data for a subset of these patients.METHODS: We collected clinical data using electronic health records and genomic data using the institutional OncoPanel platform of the DF/HCC. We compared tumour genomics with data from previously sequenced cSCC cohorts.RESULTS: We observed high tumour mutational burden regardless of smoking status and response to ICI and longer median overall survival among those patients who achieved an ICI response. We compared the genetic data from our cohort with data from other cohorts that included fewer patients with distant metastatic disease. Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. In our cohort, copy number alterations (CNAs) in the 3q chromosomal arm appeared to predict response to ICI therapy.CONCLUSION: CNAs in the 21-27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to ICI and may be candidates for drug targeting in combination or sequence with ICI agents.
CANIT0002385	30954880	Clinical research	Advanced cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Cemiplimab	N/A	Immune checkpoint therapy	Cemiplimab (DB14707); 	33	N/A	Retrospective analysis	Patients with a smoking history of at least 10 pack-years were less likely to respond to ICI therapy (p < 0.01 in univariate analysis and p = 0.02 in multivariate analysis). Smokers had a lower tumour mutational burden (TMB) compared with non-smokers (median 14 vs. 54 mutations/Mb, p = 0.01).	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2019 May	Chromosome 3q arm gain linked to immunotherapy response in advanced cutaneous squamous cell carcinoma.	 Eur J Cancer	AIMS: The activity that the immune checkpoint inhibitor (ICI) cemiplimab has recently demonstrated has led to a paradigm shift in the management of patients with advanced cutaneous squamous cell carcinoma (cSCC). To identify predictive biomarkers of response to ICIs in advanced cSCC, we studied 33 patients who received ICI therapy at the Dana-Farber/Harvard Cancer Center (DF/HCC) and analysed sequencing data for a subset of these patients.METHODS: We collected clinical data using electronic health records and genomic data using the institutional OncoPanel platform of the DF/HCC. We compared tumour genomics with data from previously sequenced cSCC cohorts.RESULTS: We observed high tumour mutational burden regardless of smoking status and response to ICI and longer median overall survival among those patients who achieved an ICI response. We compared the genetic data from our cohort with data from other cohorts that included fewer patients with distant metastatic disease. Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. In our cohort, copy number alterations (CNAs) in the 3q chromosomal arm appeared to predict response to ICI therapy.CONCLUSION: CNAs in the 21-27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to ICI and may be candidates for drug targeting in combination or sequence with ICI agents.
CANIT0002386	30954880	Clinical research	Advanced cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Cemiplimab	N/A	Immune checkpoint therapy	Cemiplimab (DB14707); 	33	N/A	Retrospective analysis	The results showed high tumour mutational burden regardless of smoking status and response to immune checkpoint inhibitor (ICI) and longer median overall survival among those patients who achieved an ICI response. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 May	Chromosome 3q arm gain linked to immunotherapy response in advanced cutaneous squamous cell carcinoma.	 Eur J Cancer	AIMS: The activity that the immune checkpoint inhibitor (ICI) cemiplimab has recently demonstrated has led to a paradigm shift in the management of patients with advanced cutaneous squamous cell carcinoma (cSCC). To identify predictive biomarkers of response to ICIs in advanced cSCC, we studied 33 patients who received ICI therapy at the Dana-Farber/Harvard Cancer Center (DF/HCC) and analysed sequencing data for a subset of these patients.METHODS: We collected clinical data using electronic health records and genomic data using the institutional OncoPanel platform of the DF/HCC. We compared tumour genomics with data from previously sequenced cSCC cohorts.RESULTS: We observed high tumour mutational burden regardless of smoking status and response to ICI and longer median overall survival among those patients who achieved an ICI response. We compared the genetic data from our cohort with data from other cohorts that included fewer patients with distant metastatic disease. Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. In our cohort, copy number alterations (CNAs) in the 3q chromosomal arm appeared to predict response to ICI therapy.CONCLUSION: CNAs in the 21-27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to ICI and may be candidates for drug targeting in combination or sequence with ICI agents.
CANIT0002387	30954880	Clinical research	Advanced cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Cemiplimab	N/A	Immune checkpoint therapy	Cemiplimab (DB14707); 	33	N/A	Retrospective analysis	Copy number alterations (CNAs) in the 21-27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to immune checkpoint inhibitor (ICI) and may be candidates for drug targeting in combination or sequence with ICI agents.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CNV in in the 3q chromosomal arm ()	Copy number alterations in the 3q chromosomal arm	Mutational status	 2019 May	Chromosome 3q arm gain linked to immunotherapy response in advanced cutaneous squamous cell carcinoma.	 Eur J Cancer	AIMS: The activity that the immune checkpoint inhibitor (ICI) cemiplimab has recently demonstrated has led to a paradigm shift in the management of patients with advanced cutaneous squamous cell carcinoma (cSCC). To identify predictive biomarkers of response to ICIs in advanced cSCC, we studied 33 patients who received ICI therapy at the Dana-Farber/Harvard Cancer Center (DF/HCC) and analysed sequencing data for a subset of these patients.METHODS: We collected clinical data using electronic health records and genomic data using the institutional OncoPanel platform of the DF/HCC. We compared tumour genomics with data from previously sequenced cSCC cohorts.RESULTS: We observed high tumour mutational burden regardless of smoking status and response to ICI and longer median overall survival among those patients who achieved an ICI response. We compared the genetic data from our cohort with data from other cohorts that included fewer patients with distant metastatic disease. Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. In our cohort, copy number alterations (CNAs) in the 3q chromosomal arm appeared to predict response to ICI therapy.CONCLUSION: CNAs in the 21-27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to ICI and may be candidates for drug targeting in combination or sequence with ICI agents.
CANIT0002388	30954880	Clinical research	Advanced cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Cemiplimab	N/A	Immune checkpoint therapy	Cemiplimab (DB14707); 	33	N/A	Retrospective analysis	Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PIK3C2B (O00750); 	PIK3CA copy number alteration	Mutational status	 2019 May	Chromosome 3q arm gain linked to immunotherapy response in advanced cutaneous squamous cell carcinoma.	 Eur J Cancer	AIMS: The activity that the immune checkpoint inhibitor (ICI) cemiplimab has recently demonstrated has led to a paradigm shift in the management of patients with advanced cutaneous squamous cell carcinoma (cSCC). To identify predictive biomarkers of response to ICIs in advanced cSCC, we studied 33 patients who received ICI therapy at the Dana-Farber/Harvard Cancer Center (DF/HCC) and analysed sequencing data for a subset of these patients.METHODS: We collected clinical data using electronic health records and genomic data using the institutional OncoPanel platform of the DF/HCC. We compared tumour genomics with data from previously sequenced cSCC cohorts.RESULTS: We observed high tumour mutational burden regardless of smoking status and response to ICI and longer median overall survival among those patients who achieved an ICI response. We compared the genetic data from our cohort with data from other cohorts that included fewer patients with distant metastatic disease. Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. In our cohort, copy number alterations (CNAs) in the 3q chromosomal arm appeared to predict response to ICI therapy.CONCLUSION: CNAs in the 21-27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to ICI and may be candidates for drug targeting in combination or sequence with ICI agents.
CANIT0002389	30955977	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Platinum-based chemotherapy	Immune checkpoint therapy	Pembrolizumab (DB09037); 	637	637	Randomised, open-label, controlled, phase 3 trial	Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) populations (>=50% hazard ratio 0.69, 95% CI 0.56-0.85, p=0.0003; >=20% 0.77, 0.64-0.92, p=0.0020, and >=1% 0.81, 0.71-0.93, p=0.0018). The median surival values by TPS population were 20.0 months (95% CI 15.4-24.9) for pembrolizumab versus 12.2 months (10.4-14.2) for chemotherapy, 17.7 months (15.3-22.1) versus 13.0 months (11.6-15.3), and 16.7 months (13.9-19.7) versus 12.1 months (11.3-13.3), respectively.The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.	Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.	N/A	N/A	EGFR/ALK (P00533); 	EGFR/ALK mutational status	Mutational status	 2019 May 4	Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.	 Lancet	BACKGROUND: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.METHODS: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (>=18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (>=50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0.0122, p=0.0120, and p=0.0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894.FINDINGS: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12.8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (>=50% hazard ratio 0.69, 95% CI 0.56-0.85, p=0.0003; >=20% 0.77, 0.64-0.92, p=0.0020, and >=1% 0.81, 0.71-0.93, p=0.0018). The median surival values by TPS population were 20.0 months (95% CI 15.4-24.9) for pembrolizumab versus 12.2 months (10.4-14.2) for chemotherapy, 17.7 months (15.3-22.1) versus 13.0 months (11.6-15.3), and 16.7 months (13.9-19.7) versus 12.1 months (11.3-13.3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.INTERPRETATION: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.FUNDING: Merck Sharp & Dohme.
CANIT0002390	30955977	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Platinum-based chemotherapy	Immune checkpoint therapy	Pembrolizumab (DB09037); 	637	637	Randomised, open-label, controlled, phase 3 trial	Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) populations (>=50% hazard ratio 0.69, 95% CI 0.56-0.85, p=0.0003; >=20% 0.77, 0.64-0.92, p=0.0020, and >=1% 0.81, 0.71-0.93, p=0.0018). The median surival values by TPS population were 20.0 months (95% CI 15.4-24.9) for pembrolizumab versus 12.2 months (10.4-14.2) for chemotherapy, 17.7 months (15.3-22.1) versus 13.0 months (11.6-15.3), and 16.7 months (13.9-19.7) versus 12.1 months (11.3-13.3), respectively.The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.	Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 May 4	Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.	 Lancet	BACKGROUND: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.METHODS: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (>=18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (>=50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0.0122, p=0.0120, and p=0.0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894.FINDINGS: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12.8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (>=50% hazard ratio 0.69, 95% CI 0.56-0.85, p=0.0003; >=20% 0.77, 0.64-0.92, p=0.0020, and >=1% 0.81, 0.71-0.93, p=0.0018). The median surival values by TPS population were 20.0 months (95% CI 15.4-24.9) for pembrolizumab versus 12.2 months (10.4-14.2) for chemotherapy, 17.7 months (15.3-22.1) versus 13.0 months (11.6-15.3), and 16.7 months (13.9-19.7) versus 12.1 months (11.3-13.3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.INTERPRETATION: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.FUNDING: Merck Sharp & Dohme.
CANIT0002391	30968729	Clinical research	766 patients	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	Radical or partial nephrectomy 	Immune checkpoint therapy	Nivolumab (DB09035); 	383	383	Phase III	PD-1 blockade via modern monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic renal cell carcinoma (RCC) with preclinical evidence and early stage trials in other solid tumors supporting a potential role in the locally advanced setting, especially when given neoadjuvantly. PROSPER RCC is unique among the ongoing Phase III adjuvant trials by employing a neoadjuvant component to prime the immune system with PD-1 blockade prior to surgery. The presurgical dosing will also permit highly translational correlative work capitalizing on the availability of pre- and postnivolumab treated tissue and sera with rigorous contemporary control tissue from the observation arm. The study is powered to assess clinically meaningful end points of RFS and OS and if positive, will dramatically shift the treatment paradigm for high-risk RCC.	N/A	N/A	ECO:0007120 - animal model system study evidence used in manual assertion	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Tumor-specific CD8(+) T-cell 	Tumor-infiltrating immune cell	 2019 May	The future of perioperative therapy in advanced renal cell carcinoma: how can we PROSPER 	 Future Oncol	Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.
CANIT0002392	30968854	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Bevacizumab	Immune checkpoint therapy	Pembrolizumab (DB09037); 	9485	N/A	Meta-analysis	The study evaluated 10 phase III randomized controlled trials (RCTs) , including 9485 patients. The most relevant increase of cost € per month of OS-gain was associated with bevacizumab (66,720 €) and the lowest with the use of pembrolizumab (2734 €).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Immunotherapy in first-line for advanced non-small cell lung cancer: <br>a cost-effective choice 	 Recenti Prog Med	INTRODUCTION: The present evaluation was restricted to pivotal phase III randomized controlled trials (RCTs) in first-line for metastatic non-small cell lung cancer (NSCLC).MATERIALS AND METHODS: We calculated the pharmacological costs necessary to get the benefit in overall survival (OS), for each trial.RESULTS: Our analysis evaluated 10 phase III RCTs, including 9485 patients. The most relevant increase of cost € per month of OS-gain was associated with bevacizumab (66,720 €) and the lowest with the use of pembrolizumab (2734 €).CONCLUSION: Combining pharmacological costs of drugs with the measure of efficacy represented by OS, pembrolizumab is a cost-effective first-line treatment for patients with metastatic NSCLC.
CANIT0002393	30978241	Clinical research	EGFR-mutated Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	EGFR-tyrosine kinase inhibitors followed by nivolumab	N/A	Target therapy followed by Immune checkpoint therapy	Nivolumab (DB09035); 	9	N/A	Retrospective analysis	Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) in EGFR-mutated non-small cell lung cancer tissues were strongly correlated with better progression-free survival. 	N/A	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	A high density of CD4(+) T-cells	Gene expression signature on/in immune cell	 2019 Apr 12	Retrospective analysis of antitumor effects and biomarkers for nivolumab in NSCLC patients with EGFR mutations.	 PLoS One	Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.
CANIT0002394	30978241	Clinical research	EGFR-mutated Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	EGFR-tyrosine kinase inhibitors followed by nivolumab	N/A	Target therapy followed by Immune checkpoint therapy	Nivolumab (DB09035); 	9	N/A	Retrospective analysis	Multivariate analysis revealed that a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in EGFR-mutated non-small cell lung cancer tissues were strongly correlated with better progression-free survival. 	N/A	N/A	N/A	FOXP3 (Q9BZS1); 	A high density of Foxp3(+) on tumor cells	Gene expression signature on/in tumor cell	 2019 Apr 12	Retrospective analysis of antitumor effects and biomarkers for nivolumab in NSCLC patients with EGFR mutations.	 PLoS One	Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.
CANIT0002395	30978241	Clinical research	EGFR-mutated Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	EGFR-tyrosine kinase inhibitors followed by nivolumab	N/A	Target therapy followed by Immune checkpoint therapy	Nivolumab (DB09035); 	9	N/A	Retrospective analysis	In contrast to previous studies in wild type EGFR non-small cell lung cancer (NSCLCs), PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Apr 12	Retrospective analysis of antitumor effects and biomarkers for nivolumab in NSCLC patients with EGFR mutations.	 PLoS One	Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.
CANIT0002396	30985002	Clinical research	310 patients receiving a fixed dose of 1,200 mg administered intravenously every 3 weeks£»and one for model validation, including 459 patients with the same dosing regimen	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	769	N/A	N/A	Including tumor size kinetics in a relevant statistical framework improves the prediction of survival probability during immunotherapy treatment and may be useful to identify most-at-risk patients in real-time.	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	Tumor size	Disease status	 2019 Oct	Association Between Tumor Size Kinetics and Survival in Patients With Urothelial Carcinoma Treated With Atezolizumab: Implication for Patient Follow-Up.	 Clin Pharmacol Ther	We characterized the association between tumor size kinetics and survival in patients with advanced urothelial carcinoma treated with atezolizumab (anti-programmed death-ligand 1, Tecentriq) using a joint model. The model, developed on data from 309 patients of a phase II clinical trial, identified the time-to-tumor growth and the instantaneous changes in tumor size as the best on-treatment predictors of survival. On the validation dataset containing data from 457 patients from a phase III study, the model predicted individual survival probability using 3-month or 6-month tumor size follow-up data with an area under the receptor-occupancy curve between 0.75 and 0.84, as compared with values comprised between 0.62 and 0.75 when the model included only information available at treatment initiation. Including tumor size kinetics in a relevant statistical framework improves the prediction of survival probability during immunotherapy treatment and may be useful to identify most-at-risk patients in real-time.
CANIT0002397	30985014	Case report	A 75-year-old man, diagnosed with esophageal melanoma 6 years earlier, was referred for further management of lymph node (LN) metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Our case indicates that effector T cells may differ depending on the irAE type, CD4+ T cells in sarcoidosis and CD8+ T cells in vitiligo. Simultaneous occurrence of these two irAE suggests that antiPD-1 antibody treatment is capable of orchestrating complex immune reactions, triggering enhancement of multiple effector T-cell types	Sarcoidosis	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12478); 	CD4(+) T-cell activation	N/A	 2019 Oct	Sarcoid-like reaction and vitiligo occurring after nivolumab therapy in a patient with metastatic melanoma.	 J Dermatol	Unable to provide
CANIT0002398	30985014	Case report	A 75-year-old man, diagnosed with esophageal melanoma 6 years earlier, was referred for further management of lymph node (LN) metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Our case indicates that effector T cells may differ depending on the irAE type, CD4+ T cells in sarcoidosis and CD8+ T cells in vitiligo. Simultaneous occurrence of these two irAE suggests that antiPD-1 antibody treatment is capable of orchestrating complex immune reactions, triggering enhancement of multiple effector T-cell types	Vitiligo	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8(+) T lymphocytes	N/A	 2019 Oct	Sarcoid-like reaction and vitiligo occurring after nivolumab therapy in a patient with metastatic melanoma.	 J Dermatol	Unable to provide
CANIT0002399	30986912	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); pembrolizumab (DB09037); nivolumab (DB09035); 	32	N/A	N/A	Significant differences in the percentage of PD-L1  CD11b  myeloid cell populations were found between objective responders and non-responders. Patients with percentages of PD-L1  CD11b  cells above 30% before the start of immunotherapy showed response rates of 50%, and 70% when combined with memory CD4 T cell profiling. These findings indicate that quantification of systemic PD-L1 myeloid cell subsets could provide a simple biomarker for patient stratification, even if biopsies are scored as PD-L1 null.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); CD11B (P11215); myeloid cell (NCIT:C12549 ); 	Percentage of PD-L1 CD11b myeloid cell populations	Gene expression signature on/in immune cell	 2019 Apr 2	PD-L1 Expression in Systemic Immune Cell Populations as a Potential Predictive Biomarker of Responses to PD-L1/PD-1 Blockade Therapy in Lung Cancer.	 Int J Mol Sci	PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is known on the relevance of systemic PD-L1  cells for responses to immune checkpoint blockade. We present two clinical cases of patients with non-small cell lung cancer (NSCLC) and PD-L1-negative tumors treated with atezolizumab that showed either objective responses or progression. These patients showed major differences in the distribution of PD-L1 expression within systemic immune cells. Based on these results, an exploratory study was carried out with 32 cases of NSCLC patients undergoing PD-L1/PD-1 blockade therapies, to compare PD-L1 expression profiles and their relationships with clinical outcomes. Significant differences in the percentage of PD-L1  CD11b  myeloid cell populations were found between objective responders and non-responders. Patients with percentages of PD-L1  CD11b  cells above 30% before the start of immunotherapy showed response rates of 50%, and 70% when combined with memory CD4 T cell profiling. These findings indicate that quantification of systemic PD-L1  myeloid cell subsets could provide a simple biomarker for patient stratification, even if biopsies are scored as PD-L1 null.
CANIT0002400	30988166	Clinical research	Patients with a histologically confirmed diagnosis of RCC, melanoma, urothelial carcinoma, breast cancer, leiomyosarcoma, chondrosarcoma, or colorectal carcinoma not amenable to curative therapy were enrolled.	Breast cancer	MONDO:0007254	Breast	IL2R (A2N4P8); 	IL2R; 	Bempegaldesleukin	N/A	Immune checkpoint therapy	Bempegaldesleukin (DB15140); 	28	N/A	Multicenter phase I study	NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jun	A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2R¦Â¦Ã-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.	 Cancer Discov	NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ¦Â¦Ã to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681.
CANIT0002401	30988166	Clinical research	Patients with a histologically confirmed diagnosis of RCC, melanoma, urothelial carcinoma, breast cancer, leiomyosarcoma, chondrosarcoma, or colorectal carcinoma not amenable to curative therapy were enrolled.	Chondrosarcoma	EFO:0000333	Soft tissue	IL2R (A2N4P8); 	IL2R; 	Bempegaldesleukin	N/A	Immune checkpoint therapy	Bempegaldesleukin (DB15140); 	28	N/A	Multicenter phase I study	NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jun	A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2R¦Â¦Ã-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.	 Cancer Discov	NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ¦Â¦Ã to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681.
CANIT0002402	30988166	Clinical research	Patients with a histologically confirmed diagnosis of RCC, melanoma, urothelial carcinoma, breast cancer, leiomyosarcoma, chondrosarcoma, or colorectal carcinoma not amenable to curative therapy were enrolled.	Colorectal cancer	EFO:0005842	Intestines	IL2R (A2N4P8); 	IL2R; 	Bempegaldesleukin	N/A	Immune checkpoint therapy	Bempegaldesleukin (DB15140); 	28	N/A	Multicenter phase I study	NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jun	A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2R¦Â¦Ã-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.	 Cancer Discov	NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ¦Â¦Ã to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681.
CANIT0002403	30988166	Clinical research	Patients with a histologically confirmed diagnosis of RCC, melanoma, urothelial carcinoma, breast cancer, leiomyosarcoma, chondrosarcoma, or colorectal carcinoma not amenable to curative therapy were enrolled.	Leiomyosarcoma	EFO:0000564	Soft tissue	IL2R (A2N4P8); 	IL2R; 	Bempegaldesleukin	N/A	Immune checkpoint therapy	Bempegaldesleukin (DB15140); 	28	N/A	Multicenter phase I study	NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jun	A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2R¦Â¦Ã-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.	 Cancer Discov	NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ¦Â¦Ã to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681.
CANIT0002404	30988166	Clinical research	Patients with a histologically confirmed diagnosis of RCC, melanoma, urothelial carcinoma, breast cancer, leiomyosarcoma, chondrosarcoma, or colorectal carcinoma not amenable to curative therapy were enrolled.	Melanoma	EFO:0000756	Skin	IL2R (A2N4P8); 	IL2R; 	Bempegaldesleukin	N/A	Immune checkpoint therapy	Bempegaldesleukin (DB15140); 	28	N/A	Multicenter phase I study	NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jun	A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2R¦Â¦Ã-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.	 Cancer Discov	NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ¦Â¦Ã to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681.
CANIT0002405	30988166	Clinical research	Patients with a histologically confirmed diagnosis of RCC, melanoma, urothelial carcinoma, breast cancer, leiomyosarcoma, chondrosarcoma, or colorectal carcinoma not amenable to curative therapy were enrolled.	Renal cell carcinoma	EFO:0000681	Kidney	IL2R (A2N4P8); 	IL2R; 	Bempegaldesleukin	N/A	Immune checkpoint therapy	Bempegaldesleukin (DB15140); 	28	N/A	Multicenter phase I study	NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jun	A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2R¦Â¦Ã-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.	 Cancer Discov	NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ¦Â¦Ã to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681.
CANIT0002406	30988166	Clinical research	Patients with a histologically confirmed diagnosis of RCC, melanoma, urothelial carcinoma, breast cancer, leiomyosarcoma, chondrosarcoma, or colorectal carcinoma not amenable to curative therapy were enrolled.	Urothelial carcinoma	EFO:0008528	Bladder	IL2R (A2N4P8); 	IL2R; 	Bempegaldesleukin	N/A	Immune checkpoint therapy	Bempegaldesleukin (DB15140); 	28	N/A	Multicenter phase I study	NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jun	A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2R¦Â¦Ã-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.	 Cancer Discov	NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ¦Â¦Ã to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681.
CANIT0002407	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	6	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 11 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002408	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	6	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 9 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002409	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 10 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002410	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Cancer	EFO:0000311	Other	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	6	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 8 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002411	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Cancer	EFO:0000311	Other	PD-L1 (Q9NZQ7); TGFB1 (P01137); 	PD-L1; TGFB1	Bintrafusp alfa	N/A	Immune checkpoint therapy	Bintrafusp alfa (DB15387); 	6	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 12 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002412	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	10	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 6 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002413	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 4 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002414	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 5 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002415	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	10	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002416	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); TGFB1 (P01137); 	PD-L1; TGFB1	Bintrafusp alfa	N/A	Immune checkpoint therapy	Bintrafusp alfa (DB15387); 	10	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 7 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002417	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Recurrent respiratory papillomatosis	MONDO:0032925	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	4	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 16 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002418	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Recurrent respiratory papillomatosis	MONDO:0032925	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	4	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 14 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002419	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Recurrent respiratory papillomatosis	MONDO:0032925	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 15 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002420	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Recurrent respiratory papillomatosis	MONDO:0032925	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	4	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 13 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002421	30996010	Clinical research	Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1).	Recurrent respiratory papillomatosis	MONDO:0032925	Lung	PD-L1 (Q9NZQ7); TGFB1 (P01137); 	PD-L1; TGFB1	Bintrafusp alfa	N/A	Immune checkpoint therapy	Bintrafusp alfa (DB15387); 	4	N/A	N/A	Immune checkpoint inhibitor (ICI) therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 17 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.	Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy.	 Oncologist	BACKGROUND: The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.SUBJECTS, MATERIALS, AND METHODS: Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).RESULTS: Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD-L1) and transforming growth factor   (n = 1). Four had pre-existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti-Sj gren's Syndrome-related Antigen A (Anti-SSA) were both positive in two subjects. LSGB showed mild-to-severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD-L1) were variably positive. In direct response to the advent of the sicca immune-related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.CONCLUSION: ICI therapy is associated with an autoimmune-induced sicca syndrome distinct from Sj gren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.IMPLICATIONS FOR PRACTICE: Sicca syndrome has been reported as an immune-related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild-to-severe sialadenitis distinct from Sj gren's syndrome, with diffuse T-cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI-induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI-induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
CANIT0002422	31003911	Clinical research	363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group).	Colorectal cancer	EFO:0005842	Intestines	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab plus cobimetinib	Regorafenib	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); cobimetinib (DB05239); regorafenib (DB08896); 	183	80	A multicentre, open-label, phase III	These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cance	Grade 3-4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3-4 adverse events in the combination group were diarrhoea (20 [11%] of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group.	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.	 Lancet Oncol	BACKGROUND: Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.METHODS: IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0-1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1-21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1-21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs >=18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.FINDINGS: Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7.3 months (IQR 3.7-13.6). Median overall survival was 8.87 months (95% CI 7.00-10.61) with atezolizumab plus cobimetinib, 7.10 months (6.05-10.05) with atezolizumab, and 8.51 months (6.41-10.71) with regorafenib; the hazard ratio was 1.00 (95% CI 0.73-1.38; p=0.99) for the combination versus regorafenib and 1.19 (0.83-1.71; p=0.34) for atezolizumab versus regorafenib. Grade 3-4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3-4 adverse events in the combination group were diarrhoea (20 [11%] of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).INTERPRETATION: IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.FUNDING: F Hoffmann-La Roche Ltd/Genentech Inc.
CANIT0002423	31003911	Clinical research	363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group).	Colorectal cancer	EFO:0005842	Intestines	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Regorafenib	Immune checkpoint therapy	Atezolizumab (DB11595); 	90	80	A multicentre, open-label, phase III	These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cance	Grade 3-4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3-4 adverse events in the combination group were diarrhoea (20 [11%] of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group.	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial.	 Lancet Oncol	BACKGROUND: Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.METHODS: IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0-1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1-21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1-21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs >=18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.FINDINGS: Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7.3 months (IQR 3.7-13.6). Median overall survival was 8.87 months (95% CI 7.00-10.61) with atezolizumab plus cobimetinib, 7.10 months (6.05-10.05) with atezolizumab, and 8.51 months (6.41-10.71) with regorafenib; the hazard ratio was 1.00 (95% CI 0.73-1.38; p=0.99) for the combination versus regorafenib and 1.19 (0.83-1.71; p=0.34) for atezolizumab versus regorafenib. Grade 3-4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3-4 adverse events in the combination group were diarrhoea (20 [11%] of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).INTERPRETATION: IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.FUNDING: F Hoffmann-La Roche Ltd/Genentech Inc.
CANIT0002424	31006385	Case report	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); VEGF (P15692); IFNA; PDGFR (P16234); 	PD-1 ;  VEGF ;  IFNA	INFA plus sunitinib plus axitinib followed by Nivolumab	N/A	Immune cytokine plus Target therapy followed by Immune checkpoint therapy	Nivolumab (DB09035); axitinib (DB06626); sunitinib (DB01268); 	1	N/A	Case	A 66-year-old Japanese man with metastatic renal cell carcinoma became refractory to interferon A and sunitinib therapies. He started treatment with axitinib at 10 mg/day, and the dose was gradually tapered down to 4 mg/day because of intolerable adverse events. His metastatic lesions shrank; however, he could not continue due to the adverse events. He started fourth-line therapy with nivolumab; however, the metastatic lesions increased. Rechallenge with axitinib 4 mg/day was started, and the dose was reduced to 2 mg/day because of adverse events. Subsequently, the adverse events became controllable, and the metastatic lesions were maintained at reduced size.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Apr 22	Low-dose axitinib rechallenge with positive outcomes in a patient with metastatic renal cell carcinoma refractory to interferon a, sunitinib, axitinib, and nivolumab therapies: a case report.	 J Med Case Rep	BACKGROUND: There is no established treatment after failure of proven therapies for patients with metastatic renal cell carcinoma.CASE PRESENTATION: A 66-year-old Japanese man with metastatic renal cell carcinoma became refractory to interferon a and sunitinib therapies. He started treatment with axitinib at 10 mg/day, and the dose was gradually tapered down to 4 mg/day because of intolerable adverse events. His metastatic lesions shrank; however, he could not continue due to the adverse events. He started fourth-line therapy with nivolumab; however, the metastatic lesions increased. Rechallenge with axitinib 4 mg/day was started, and the dose was reduced to 2 mg/day because of adverse events. Subsequently, the adverse events became controllable, and the metastatic lesions were maintained at reduced size.CONCLUSION: Therapeutic drug monitoring of axitinib could play an important role in the development of safe and effective therapeutic treatment and individualization of these medications.
CANIT0002425	31012356	Clinical research	206 patients	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	206	N/A	Phase II KEYNOTE-087	Patients with relapsed/refractory classical Hodgkin lymphoma (rrHL) treated with pembrolizumab experienced overall improvement and/or maintenance in their health status, function, and symptoms over time. Clinically meaningful improvements were particularly noted among patients who responded to treatment with pembrolizumab	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Patient-reported outcomes in KEYNOTE-087, a phase 2 study of pembrolizumab in patients with classical Hodgkin lymphoma.	 Leuk Lymphoma	In KEYNOTE-087, pembrolizumab had a 69% overall response rate and acceptable safety in patients with relapsed/refractory classical Hodgkin lymphoma (rrHL). We assessed health-related quality of life (HRQoL) in KEYNOTE-087. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and the EuroQoL Five Dimensions Questionnaire 3-level version (EQ-5D) were administered to 206 patients across three cohorts defined by lymphoma progression after: (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV) (n = 69); (2) salvage chemotherapy and BV (n = 79); and (3) ASCT without post-transplantation BV (n = 58). Compliance/completion rates were >=90% at week 12 and >=70% at week 24. QLQ-C30 global health status/QoL and EQ-5D visual analog scale scores showed mean increases from baseline in overall health at all assessed timepoints. With few exceptions, mean improvements from baseline to weeks 12 and 24 in QLQ-C30 functional and symptom scores occurred in all cohorts.Clinicaltrials.gov identifier: NCT02453594.
CANIT0002426	31012765	Clinical research	High-risk stage III melanoma	The adjuvant treatment of completely resected stage III melanoma in the US	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	N/A	N/A	N/A	Based on common willingness-to-pay benchmarks, pembrolizumab is highly cost-effective compared with observation alone for the adjuvant treatment of completely resected stage III melanoma in the US	Diarrhea	N/A	N/A	N/A	N/A	N/A	 2019 Oct	Cost-effectiveness of pembrolizumab for the adjuvant treatment of resected high-risk stage III melanoma in the United States.	 J Med Econ	Aims: To evaluate the cost-effectiveness of adjuvant pembrolizumab relative to observation alone following complete resection of high-risk stage III melanoma with lymph node involvement, from a US health system perspective. Materials and methods: A Markov cohort model with four health states (recurrence-free, locoregional recurrence, distant metastases, and death) was developed to estimate costs, life-years, and quality-adjusted life-years (QALYs) associated with pembrolizumab vs observation over a lifetime (46-year) horizon. Using a parametric multi-state modeling approach, transition probabilities starting from recurrence-free were estimated based on patient-level data from KEYNOTE-054 (NCT02362594), a direct head-to-head phase 3 trial. Post-recurrence transition probabilities were informed by real-world retrospective data and clinical trials in advanced melanoma. Health state utilities and adverse event-related disutility were derived from KEYNOTE-054 trial data and published literature. Costs of drug acquisition and administration, adverse events, disease management, and terminal care were estimated in 2018 US dollars. Deterministic and probabilistic sensitivity analyses were conducted to assess robustness. Results: Over a lifetime horizon, adjuvant pembrolizumab and observation were associated with total QALYs of 9.24 and 5.95, total life-years of 10.54 and 7.15, and total costs of $489,820 and $440,431, respectively. The resulting incremental cost-effectiveness ratios (ICERs) for pembrolizumab vs observation were $15,009/QALY and $14,550/life-year. Across the range of input values and assumptions tested in deterministic sensitivity analyses, pembrolizumab ranged from being a dominant strategy to having an ICER of $57,449/QALY vs observation. The ICER was below a willingness-to-pay threshold of $100,000/QALY in 90.2% of probabilistic simulations. Limitations: Long-term extrapolation of outcomes was based on interim results from KEYNOTE-054, with a median follow-up of 15 months. Conclusions: Based on common willingness-to-pay benchmarks, pembrolizumab is highly cost-effective compared with observation alone for the adjuvant treatment of completely resected stage III melanoma in the US.
CANIT0002427	31015235	Case report	Renal cell carcinoma inferior vena cava tumour thrombus	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab plus target therapy	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); 	1	N/A	Case	A 47-year-old previously healthy man presented with acute moderate flank pain. Evaluation revealed left renal cell carcinoma, with inferior vena cava tumour thrombus invasion. Patient had no significant history or risk factors to pre-dispose him to genitourinary cancers. Surgery was deemed to not be appropriate due to distant metastases, but patient received targeted molecular therapy and immunotherapy with striking regression of the thrombus.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Apr 23	Robust response to nivolumab in patient with renal cell carcinoma inferior vena cava tumour thrombus.	 BMJ Case Rep	A 47-year-old previously healthy man presented with acute moderate flank pain. Evaluation revealed left renal cell carcinoma, with inferior vena cava tumour thrombus invasion. Patient had no significant history or risk factors to pre-dispose him to genitourinary cancers. Surgery was deemed to not be appropriate due to distant metastases, but patient received targeted molecular therapy and immunotherapy with striking regression of the thrombus.
CANIT0002428	31015314	Clinical research	Stage IV melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	N/A	Immunotherapy is viewed as a symbol of hope, with high-profile anecdotes reinforcing this perception. Only a minority of patients expressed a good understanding of the likely efficacy and potential treatment side effects. Patients are reliant on their clinicians' recommendation regarding immunotherapy treatment decisions.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Balancing the Hype with Reality: What Do Patients with Advanced Melanoma Consider When Making the Decision to Have Immunotherapy 	 Oncologist	BACKGROUND: Immunotherapy has resulted in unprecedented improvements in survival and maintained quality of life for many patients with advanced melanoma. However, durable responses are observed in only a minority of patients, and severe treatment side effects are experienced by 5%-30%. There are no reliable tests that can differentiate between patients who are likely to respond to immunotherapy and those who will not. Hence, new challenges have arisen as clinicians try to facilitate patients in their decision-making regarding immunotherapy. Furthermore, little is known about the real-world patients' experience and understanding of immunotherapy outside the clinical trial setting. Here, we explore the perspectives of patients undergoing immunotherapy for melanoma and focus on factors that influenced their treatment decision-making.MATERIALS AND METHODS: Twenty-three in-depth semistructured interviews were conducted with patients receiving pembrolizumab for stage IV melanoma at an Australian public cancer hospital. Patients were recruited at a range of time points after commencing therapy, and their experience of treatment was explored. Interviews were audio recorded, transcribed verbatim, coded, and analyzed thematically.RESULTS: Immunotherapy is viewed as a symbol of hope, with high-profile anecdotes reinforcing this perception. Only a minority of patients expressed a good understanding of the likely efficacy and potential treatment side effects. Patients are reliant on their clinicians' recommendation regarding immunotherapy treatment decisions.CONCLUSION: Novel treatments such as immunotherapy provide significant hope for patients. This may influence their preference for immunotherapy over and above the usual considerations of the trade-off between efficacy and toxicity. Careful counsel and individualized patient resources may further facilitate treatment decision-making.IMPLICATIONS FOR PRACTICE: This study highlighted some of the misconceptions held by patients that need to be addressed when discussing the possibility of receiving treatment with immunotherapy for advanced melanoma. Patients placed a lot of importance on high-profile anecdotes rather than truly understanding likely outcomes of treatment based on personal circumstances. The majority of patients had a poor understanding of the potential side effects and long-term implications of treatment with immunotherapy. Careful counsel is required in order to facilitate informed decision-making about treatment and to ensure possible side effects are known and appreciated. Further research is needed to develop tools to aid decision-making in everyday clinical practice.
CANIT0002429	31017739	Clinical research	Advanced esophageal squamous cell carcinoma	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Camrelizumab	N/A	Immune checkpoint therapy	Camrelizumab (DB14776); 	43	N/A	Retrospective analysis	After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Multivariate Cox analysis identified serum c-reactive protein levels (HR 0.27) independent prognostic factor.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Jun	Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody.	 Thorac Cancer	BACKGROUND: A small proportion of patients with advanced esophageal squamous cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors; however, reliable peripheral blood biomarkers for outcomes of anti-PD-1 immunotherapy in ESCC have not been identified.METHODS: The data of 43 patients in the ESCC cohort of a phase I trial at our center were retrospectively reviewed. All patients were administered intravenous camrelizumab (SHR-1210), a novel anti-PD-1 antibody, at doses of 60 mg, 200 mg, or 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. Associations between lactate dehydrogenase (LDH) and other peripheral blood biomarkers at baseline and the efficacy of camrelizumab were also investigated.RESULTS: After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Patients with an elevated baseline LDH had lower tumor response rates (P = 0.02) and shorter progression-free (P = 0.002) and overall (P < 0.0001) survival than patients with normal LDH levels. An increase in LDH levels during treatment was significantly associated with disease progression. Multivariate Cox analysis identified LDH (hazard ratio [HR] 0.18), CRP (HR 0.27), the number of organs involved (HR 0.31), absolute monocyte count (HR 0.33), and Eastern Cooperative Oncology Group performance status (HR 0.36) as independent prognostic factors.CONCLUSIONS: Serum LDH, which is readily available in routine clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients treated with anti-PD-1 therapy.
CANIT0002430	31017739	Clinical research	Advanced esophageal squamous cell carcinoma	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Camrelizumab	N/A	Immune checkpoint therapy	Camrelizumab (DB14776); 	43	N/A	Retrospective analysis	After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Patients with an elevated baseline serum lactate dehydrogenase levels (LDH) had lower tumor response rates (P = 0.02) and shorter progression-free (P = 0.002) and overall (P < 0.0001) survival than patients with normal LDH levels. An increase in LDH levels during treatment was significantly associated with disease progression. Multivariate Cox analysis identified LDH (hazard ratio [HR] 0.18) as independent prognostic factor. Serum LDH, which is readily available in routine clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients treated with anti-PD-1 therapy.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Jun	Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody.	 Thorac Cancer	BACKGROUND: A small proportion of patients with advanced esophageal squamous cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors; however, reliable peripheral blood biomarkers for outcomes of anti-PD-1 immunotherapy in ESCC have not been identified.METHODS: The data of 43 patients in the ESCC cohort of a phase I trial at our center were retrospectively reviewed. All patients were administered intravenous camrelizumab (SHR-1210), a novel anti-PD-1 antibody, at doses of 60 mg, 200 mg, or 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. Associations between lactate dehydrogenase (LDH) and other peripheral blood biomarkers at baseline and the efficacy of camrelizumab were also investigated.RESULTS: After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Patients with an elevated baseline LDH had lower tumor response rates (P = 0.02) and shorter progression-free (P = 0.002) and overall (P < 0.0001) survival than patients with normal LDH levels. An increase in LDH levels during treatment was significantly associated with disease progression. Multivariate Cox analysis identified LDH (hazard ratio [HR] 0.18), CRP (HR 0.27), the number of organs involved (HR 0.31), absolute monocyte count (HR 0.33), and Eastern Cooperative Oncology Group performance status (HR 0.36) as independent prognostic factors.CONCLUSIONS: Serum LDH, which is readily available in routine clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients treated with anti-PD-1 therapy.
CANIT0002431	31017739	Clinical research	Advanced esophageal squamous cell carcinoma	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Camrelizumab	N/A	Immune checkpoint therapy	Camrelizumab (DB14776); 	43	N/A	Retrospective analysis	After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Multivariate Cox analysis identified the number of organs involved (HR 0.31) as independent prognostic factor.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	The number of organs involved	Disease status	 2019 Jun	Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody.	 Thorac Cancer	BACKGROUND: A small proportion of patients with advanced esophageal squamous cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors; however, reliable peripheral blood biomarkers for outcomes of anti-PD-1 immunotherapy in ESCC have not been identified.METHODS: The data of 43 patients in the ESCC cohort of a phase I trial at our center were retrospectively reviewed. All patients were administered intravenous camrelizumab (SHR-1210), a novel anti-PD-1 antibody, at doses of 60 mg, 200 mg, or 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. Associations between lactate dehydrogenase (LDH) and other peripheral blood biomarkers at baseline and the efficacy of camrelizumab were also investigated.RESULTS: After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Patients with an elevated baseline LDH had lower tumor response rates (P = 0.02) and shorter progression-free (P = 0.002) and overall (P < 0.0001) survival than patients with normal LDH levels. An increase in LDH levels during treatment was significantly associated with disease progression. Multivariate Cox analysis identified LDH (hazard ratio [HR] 0.18), CRP (HR 0.27), the number of organs involved (HR 0.31), absolute monocyte count (HR 0.33), and Eastern Cooperative Oncology Group performance status (HR 0.36) as independent prognostic factors.CONCLUSIONS: Serum LDH, which is readily available in routine clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients treated with anti-PD-1 therapy.
CANIT0002432	31017739	Clinical research	Advanced esophageal squamous cell carcinoma	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Camrelizumab	N/A	Immune checkpoint therapy	Camrelizumab (DB14776); 	43	N/A	Retrospective analysis	After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Multivariate Cox analysis identified absolute monocyte count (HR 0.33) as independent prognostic factor.	N/A	N/A	N/A	Monocyte counts (NCIT:C12547); 	Absolute monocyte counts	Cell percentage/counts in blood	 2019 Jun	Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody.	 Thorac Cancer	BACKGROUND: A small proportion of patients with advanced esophageal squamous cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors; however, reliable peripheral blood biomarkers for outcomes of anti-PD-1 immunotherapy in ESCC have not been identified.METHODS: The data of 43 patients in the ESCC cohort of a phase I trial at our center were retrospectively reviewed. All patients were administered intravenous camrelizumab (SHR-1210), a novel anti-PD-1 antibody, at doses of 60 mg, 200 mg, or 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. Associations between lactate dehydrogenase (LDH) and other peripheral blood biomarkers at baseline and the efficacy of camrelizumab were also investigated.RESULTS: After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Patients with an elevated baseline LDH had lower tumor response rates (P = 0.02) and shorter progression-free (P = 0.002) and overall (P < 0.0001) survival than patients with normal LDH levels. An increase in LDH levels during treatment was significantly associated with disease progression. Multivariate Cox analysis identified LDH (hazard ratio [HR] 0.18), CRP (HR 0.27), the number of organs involved (HR 0.31), absolute monocyte count (HR 0.33), and Eastern Cooperative Oncology Group performance status (HR 0.36) as independent prognostic factors.CONCLUSIONS: Serum LDH, which is readily available in routine clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients treated with anti-PD-1 therapy.
CANIT0002433	31017739	Clinical research	Advanced esophageal squamous cell carcinoma	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Camrelizumab	N/A	Immune checkpoint therapy	Camrelizumab (DB14776); 	43	N/A	Retrospective analysis	After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Multivariate Cox analysis identified Eastern Cooperative Oncology Group performance status (HR 0.36) as independent prognostic factor.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Jun	Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody.	 Thorac Cancer	BACKGROUND: A small proportion of patients with advanced esophageal squamous cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors; however, reliable peripheral blood biomarkers for outcomes of anti-PD-1 immunotherapy in ESCC have not been identified.METHODS: The data of 43 patients in the ESCC cohort of a phase I trial at our center were retrospectively reviewed. All patients were administered intravenous camrelizumab (SHR-1210), a novel anti-PD-1 antibody, at doses of 60 mg, 200 mg, or 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. Associations between lactate dehydrogenase (LDH) and other peripheral blood biomarkers at baseline and the efficacy of camrelizumab were also investigated.RESULTS: After median follow-up of 19.6 months, the overall response rate was 25.6% (11/43), including one complete response. Median progression-free and overall survival rates were 2.0 and 8.0 months, respectively. Patients with an elevated baseline LDH had lower tumor response rates (P = 0.02) and shorter progression-free (P = 0.002) and overall (P < 0.0001) survival than patients with normal LDH levels. An increase in LDH levels during treatment was significantly associated with disease progression. Multivariate Cox analysis identified LDH (hazard ratio [HR] 0.18), CRP (HR 0.27), the number of organs involved (HR 0.31), absolute monocyte count (HR 0.33), and Eastern Cooperative Oncology Group performance status (HR 0.36) as independent prognostic factors.CONCLUSIONS: Serum LDH, which is readily available in routine clinical practice, is a potential marker for response and a powerful independent factor for survival in advanced ESCC patients treated with anti-PD-1 therapy.
CANIT0002434	31020849	Clinical research	Melanoma or non-small-cell lung cancer	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	15	N/A	N/A	Images of nivolumab-induced pneumonitis showed previously unobserved radiological patterns. Among 144 cases analyzed, 91 (63.2%) had radiological patterns considered typical for drug-induced pneumonitis and 53 (36.8%) patients had previously unobserved patterns with one or more atypical features, including 23 cases (16.0%) with ground glass opacity confined to the area around the tumor (peritumoral infiltration). A higher proportion of patients with (vs without) peritumoral infiltration had an antitumor response to nivolumab.	Pneumonitis	N/A	N/A	Tumor infiltrate (NCIT:C12546); Immune responses (NCIT:C17930); 	Peritumoral infiltration	Tumor-infiltrating immune cell	 2019 Jun	Radiologic features of pneumonitis associated with nivolumab in non-small-cell lung cancer and malignant melanoma.	 Future Oncol	Aim: To assess the clinical features/imaging characteristics of pneumonitis reported during nationwide nivolumab postmarketing surveillance in Japan. Patients & methods: Clinical and radiological data were collected from pneumonitis cases reported during/after nivolumab treatment for melanoma or non-small-cell lung cancer. The expert central review committee evaluated each case. Results: Among 144 cases analyzed, 91 (63.2%) had radiological patterns considered typical for drug-induced pneumonitis and 53 (36.8%) patients had previously unobserved patterns with one or more atypical features, including 23 cases (16.0%) with ground glass opacity confined to the area around the tumor (peritumoral infiltration). A higher proportion of patients with (vs without) peritumoral infiltration had an antitumor response to nivolumab. Conclusion: Images of nivolumab-induced pneumonitis showed previously unobserved radiological patterns.
CANIT0002435	31020849	Clinical research	Melanoma or non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	129	N/A	N/A	Images of nivolumab-induced pneumonitis showed previously unobserved radiological patterns. Among 144 cases analyzed, 91 (63.2%) had radiological patterns considered typical for drug-induced pneumonitis and 53 (36.8%) patients had previously unobserved patterns with one or more atypical features, including 23 cases (16.0%) with ground glass opacity confined to the area around the tumor (peritumoral infiltration). A higher proportion of patients with (vs without) peritumoral infiltration had an antitumor response to nivolumab.	Pneumonitis	N/A	N/A	Tumor infiltrate (NCIT:C12546); Immune responses (NCIT:C17930); 	Peritumoral infiltration	Tumor-infiltrating immune cell	 2019 Jun	Radiologic features of pneumonitis associated with nivolumab in non-small-cell lung cancer and malignant melanoma.	 Future Oncol	Aim: To assess the clinical features/imaging characteristics of pneumonitis reported during nationwide nivolumab postmarketing surveillance in Japan. Patients & methods: Clinical and radiological data were collected from pneumonitis cases reported during/after nivolumab treatment for melanoma or non-small-cell lung cancer. The expert central review committee evaluated each case. Results: Among 144 cases analyzed, 91 (63.2%) had radiological patterns considered typical for drug-induced pneumonitis and 53 (36.8%) patients had previously unobserved patterns with one or more atypical features, including 23 cases (16.0%) with ground glass opacity confined to the area around the tumor (peritumoral infiltration). A higher proportion of patients with (vs without) peritumoral infiltration had an antitumor response to nivolumab. Conclusion: Images of nivolumab-induced pneumonitis showed previously unobserved radiological patterns.
CANIT0002436	31021376	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	20 128	N/A	Meta-analysis	Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.	This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54).	N/A	N/A	N/A	N/A	N/A	 2019 Jul 1	Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis.	 JAMA Oncol	IMPORTANCE: Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice.OBJECTIVE: To evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types.DATA SOURCES: PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018.STUDY SELECTION: Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included.DATA EXTRACTION AND SYNTHESIS: Trial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis.MAIN OUTCOMES AND MEASURES: Incidences of treatment-related adverse events and differences between different drugs and cancer types.RESULTS: This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54).CONCLUSIONS AND RELEVANCE: Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.
CANIT0002437	31025831	Clinical research	Non-small cell lung carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	265	N/A	N/A	The data indicate that cytologic specimens are comparable to surgical specimens for PD-L1 evaluation. The association of PD-L1 expression with KRAS mutations may have clinical relevance in selecting patients with NSCLC for immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	KRAS (P01116); 	KRAS mutational status	Mutational status	 2019 Jul	Programmed cell death ligand 1 expression in cytologic and surgical non-small cell lung carcinoma specimens from a single institution: Association with clinicopathologic features and molecular alterations.	 Cancer Cytopathol	BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression by the 22C3 pharmDx companion assay has been validated in surgical specimens to support pembrolizumab treatment decisions for patients with non-small cell lung carcinoma (NSCLC). The aims of this study were 1) to assess the adequacy of cytologic specimens for PD-L1 evaluation and 2) to explore correlations of PD-L1 expression with clinicopathologic and molecular features.METHODS: The study cohort included 100 cytology specimens (fluid [n = 28] and fine-needle aspiration [n = 72]) and 165 surgical specimens (biopsy [n = 138] and resection [n = 27]). The PD-L1 immunohistochemistry 22C3 assay and staining assessment were performed according to the manufacturer's instructions. PD-L1 expression was correlated with patients' demographics, pathologic characteristics, and molecular alterations.RESULTS: One hundred forty-two specimens (53.6%) were positive for PD-L1 expression (>=1%). No statistically significant difference in PD-L1 expression was identified between cytologic (56.0%) and surgical specimens (52.1%). Seventy-four of 190 tested cases (38.9%) had genetic alterations. PD-L1 positivity was significantly more prevalent in cases with genetic alterations than in cases without genetic alterations. Furthermore, both PD-L1 positivity and high PD-L1 expression (>=50%) had statistically significant associations with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. PD-L1 expression had no significant association with histologic phenotypes or other clinicopathologic features.CONCLUSIONS: The data indicate that cytologic specimens are comparable to surgical specimens for PD-L1 evaluation. The association of PD-L1 expression with KRAS mutations may have clinical relevance in selecting patients with NSCLC for immunotherapy.
CANIT0002438	31025831	Clinical research	Non-small cell lung carcinoma	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	265	N/A	N/A	The data indicate that cytologic specimens are comparable to surgical specimens for PD-L1 evaluation. The association of PD-L1 expression with KRAS mutations may have clinical relevance in selecting patients with NSCLC for immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Jul	Programmed cell death ligand 1 expression in cytologic and surgical non-small cell lung carcinoma specimens from a single institution: Association with clinicopathologic features and molecular alterations.	 Cancer Cytopathol	BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression by the 22C3 pharmDx companion assay has been validated in surgical specimens to support pembrolizumab treatment decisions for patients with non-small cell lung carcinoma (NSCLC). The aims of this study were 1) to assess the adequacy of cytologic specimens for PD-L1 evaluation and 2) to explore correlations of PD-L1 expression with clinicopathologic and molecular features.METHODS: The study cohort included 100 cytology specimens (fluid [n = 28] and fine-needle aspiration [n = 72]) and 165 surgical specimens (biopsy [n = 138] and resection [n = 27]). The PD-L1 immunohistochemistry 22C3 assay and staining assessment were performed according to the manufacturer's instructions. PD-L1 expression was correlated with patients' demographics, pathologic characteristics, and molecular alterations.RESULTS: One hundred forty-two specimens (53.6%) were positive for PD-L1 expression (>=1%). No statistically significant difference in PD-L1 expression was identified between cytologic (56.0%) and surgical specimens (52.1%). Seventy-four of 190 tested cases (38.9%) had genetic alterations. PD-L1 positivity was significantly more prevalent in cases with genetic alterations than in cases without genetic alterations. Furthermore, both PD-L1 positivity and high PD-L1 expression (>=50%) had statistically significant associations with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. PD-L1 expression had no significant association with histologic phenotypes or other clinicopathologic features.CONCLUSIONS: The data indicate that cytologic specimens are comparable to surgical specimens for PD-L1 evaluation. The association of PD-L1 expression with KRAS mutations may have clinical relevance in selecting patients with NSCLC for immunotherapy.
CANIT0002439	31026247	Case report	Multiple nevi and melanoma metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	1	N/A	Case	A major regression of multiple nevi on ipilimumab might be associated with immunotherapy response	Halo nevi reaction£¬vitiligo	N/A	N/A	A major regression of multiple nevi (); 	A major regression of multiple nevi on ipilimumab	Disease status	 2019 Jun	Simultaneous long-lasting regression of multiple nevi and melanoma metastases after ipilimumab therapy.	 Melanoma Res	We report a case of major regression of multiple atypical melanocytic nevi with a vitiligoid reaction in a patient with metastatic melanoma who achieved long-lasting complete remission after ipilimumab therapy. In 2008, a 54-year-old man presented with a dysplastic nevus syndrome. The patient was diagnosed with a scalp ulcerated melanoma (Breslow index 5.1 mm and Clark level IV), which was removed surgically. Four years later in April 2012, the patient was diagnosed with a right parietal skin metastasis, brain, lymph nodes, and bilateral lung metastases. The patient was first treated with vemurafenib, which had to be stopped because of renal toxicity. Disease stabilization was achieved after the second line of treatment with immunotherapy (ipilimumab, four infusions). However, 6 months later, the lung metastases had progressed. The patient was treated with pulmonary stereotactic radiotherapy associated with a second cycle of ipilimumab. After 6 months, he achieved complete remission. Simultaneously, the patient presented a generalized regression of his nevi with a vitiligoid reaction, or halo nevus, associated with a vitiligo located on the hands and inguinal areas. Vitiligo is a frequent immune-related adverse event of immunotherapy. Immunotherapy-induced halo nevus reaction is much less frequent than vitiligo. It was associated in the two case reports from the literature and in our patient with a quick and long-lasting complete remission of nodes and visceral metastases. Therefore, it might correspond to a stronger antimelanocyte immune reaction, associated with a favorable prognosis. The generalized halo nevi reaction in our patient could be more important because of the two cycles of ipilimumab compared with a single one. In conclusion, this case report suggests that a major regression of multiple nevi on ipilimumab might be associated with immunotherapy response.
CANIT0002440	31026576	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	Retrospective analysis	When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Microbiota modification (NCIT:C128320); 	Diversity of Gut Microbiome	Microbiota	 2019 Aug	The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti-Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC.	 J Thorac Oncol	INTRODUCTION: Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade.METHODS: Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.RESULTS: When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.CONCLUSIONS: Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.
CANIT0002441	31026576	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	Retrospective analysis	Compositional difference was observed between the the responder and non-responder groups as well with the enrichment of Alistipes putredinisresponder (R) . 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Alistipes putredinis (NCIT:C86871); 	Alistipes putredinis	Microbiota	 2019 Aug	The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti-Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC.	 J Thorac Oncol	INTRODUCTION: Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade.METHODS: Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.RESULTS: When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.CONCLUSIONS: Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.
CANIT0002442	31026576	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	Retrospective analysis	Compositional difference was observed between the the responder and non-responder groups as well with the enrichment of Bifidobacterium longum in responder (R). 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Bifidobacterium longum (NCIT:C86199); 	Bifidobacterium longum	Microbiota	 2019 Aug	The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti-Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC.	 J Thorac Oncol	INTRODUCTION: Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade.METHODS: Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.RESULTS: When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.CONCLUSIONS: Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.
CANIT0002443	31026576	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	Retrospective analysis	Compositional difference was observed between the the responder and non-responder groups as well with the enrichment of Prevotella copri in responder (R). 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Prevotella copri (NCBITaxon:537011 ); 	Prevotella copr	Microbiota	 2019 Aug	The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti-Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC.	 J Thorac Oncol	INTRODUCTION: Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade.METHODS: Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.RESULTS: When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.CONCLUSIONS: Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.
CANIT0002444	31026576	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	Retrospective analysis	Compositional difference was observed between the the responder and non-responder groups as well with Ruminococcus_unclassified enriched in nonresponding patients. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Ruminococcus (NCIT:C86729 ); 	Ruminococcus_unclassified	Microbiota	 2019 Aug	The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti-Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC.	 J Thorac Oncol	INTRODUCTION: Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade.METHODS: Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.RESULTS: When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.CONCLUSIONS: Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.
CANIT0002445	31026576	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	Retrospective analysis	When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8(+) T-cells	Gene expression signature on/in immune cell	 2019 Aug	The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti-Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC.	 J Thorac Oncol	INTRODUCTION: Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade.METHODS: Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.RESULTS: When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.CONCLUSIONS: Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.
CANIT0002446	31026576	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	Retrospective analysis	When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Natural killer-cells (NCIT:C98762); 	Natural killer cell subsets	Cell percentage/counts in blood	 2019 Aug	The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti-Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC.	 J Thorac Oncol	INTRODUCTION: Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade.METHODS: Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel.RESULTS: When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy.CONCLUSIONS: Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.
CANIT0002447	31027701	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-1 ;  PD-L1 ;  VEGF 	Pembrolizumab or nivolumab or bevacizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); bevacizumab (DB00112); 	1547	N/A	Retrospective analysis	The introduction of new classes of drugs has significantly improved the survival of patients with stage IV NSCLC. However, the approval of similar types of drugs may not be associated with further improvement in survival.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 May	Improvement in the survival of patients with stage IV non-small-cell lung cancer: Experience in a single institutional 1995-2017.	 Lung Cancer	OBJECTIVES: In the past two decades several antineoplastic agents have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC), and the management of these patients has drastically changed. However, there is limited information regarding the impact of these advances on patient survival in clinical practice.MATERIALS AND METHODS: We analyzed the survival of patients with stage IV NSCLC who received any treatment in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) between January 1, 1995 and March 1, 2017. A total of 1,547 consecutive patients were included in this case series. In this analysis, five diagnostic periods were evaluated: 1995-1999 (period A), 2000-2004 (period B), 2005-2009 (period C), 2010-2014 (period D), and 2015-2017 (period E). We compared overall survival (OS) between the periods before and after propensity score matching (PSM) and in patients with EGFR mutation, with ALK fusion gene, or without driver mutation.RESULTS: In the past two decades the OS of patients with stage IV NSCLC improved. The median OSs for periods A, B, C, D, and E were 9.0, 11.0, 13.7, 17.9 months, and not reached, respectively. After PSM with known baseline characteristics, the trend of improvement in OS was similar. However, the OS of patients with EGFR mutation or ALK fusion gene did not improve between periods, despite the availability of several tyrosine kinase inhibitors in Japan. The OS of patients without a driver mutation was slightly longer in the period E.CONCLUSION: The introduction of new classes of drugs has significantly improved the survival of patients with stage IV NSCLC. However, the approval of similar types of drugs may not be associated with further improvement in survival.
CANIT0002448	31029646	Clinical research	T-cell lymphomas	T-cell lymphoma	MONDO:0019474	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	18	N/A	Phase II single-arm multicenter trial	The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4+ T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74).Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma.	Rash was the most common adverse event (17%; n = 3). The most common >= grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each).	N/A	N/A	AKT (P31749); 	P-Akt expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jun	Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma.	 Clin Lymphoma Myeloma Leuk	BACKGROUND: Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are frequently expressed in T-cell lymphomas. This provides a rationale for exploration of immune checkpoint inhibitors in the management of T-cell lymphomas.PATIENTS AND METHODS: In this phase II single-arm multicenter trial, patients with relapsed or refractory systemic T-cell lymphoma were treated with 200 mg pembrolizumab intravenously every 21 days. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, response duration, and safety. We assessed PD-L1, p-AKT expression, and peripheral blood immune cells as potential predictive biomarkers.RESULTS: Of 18 enrolled patients, 13 were evaluable for the primary endpoint. The trial was halted early after a preplanned interim futility analysis. The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Rash was the most common adverse event (17%; n = 3). The most common >= grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each). Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4+ T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74).CONCLUSION: Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma.
CANIT0002449	31029646	Clinical research	T-cell lymphomas	T-cell lymphoma	MONDO:0019474	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	18	N/A	Phase II single-arm multicenter trial	The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4+ T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74).Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma.	Rash was the most common adverse event (17%; n = 3). The most common >= grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each).	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	Relative frequency of CD4(+) T lymphocytes pre-treatment	Gene expression signature on/in immune cell	 2019 Jun	Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma.	 Clin Lymphoma Myeloma Leuk	BACKGROUND: Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are frequently expressed in T-cell lymphomas. This provides a rationale for exploration of immune checkpoint inhibitors in the management of T-cell lymphomas.PATIENTS AND METHODS: In this phase II single-arm multicenter trial, patients with relapsed or refractory systemic T-cell lymphoma were treated with 200 mg pembrolizumab intravenously every 21 days. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, response duration, and safety. We assessed PD-L1, p-AKT expression, and peripheral blood immune cells as potential predictive biomarkers.RESULTS: Of 18 enrolled patients, 13 were evaluable for the primary endpoint. The trial was halted early after a preplanned interim futility analysis. The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Rash was the most common adverse event (17%; n = 3). The most common >= grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each). Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4+ T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74).CONCLUSION: Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma.
CANIT0002450	31029646	Clinical research	T-cell lymphomas	T-cell lymphoma	MONDO:0019474	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	18	N/A	Phase II single-arm multicenter trial	The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4+ T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74).Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma.	Rash was the most common adverse event (17%; n = 3). The most common >= grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Jun	Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma.	 Clin Lymphoma Myeloma Leuk	BACKGROUND: Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are frequently expressed in T-cell lymphomas. This provides a rationale for exploration of immune checkpoint inhibitors in the management of T-cell lymphomas.PATIENTS AND METHODS: In this phase II single-arm multicenter trial, patients with relapsed or refractory systemic T-cell lymphoma were treated with 200 mg pembrolizumab intravenously every 21 days. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, response duration, and safety. We assessed PD-L1, p-AKT expression, and peripheral blood immune cells as potential predictive biomarkers.RESULTS: Of 18 enrolled patients, 13 were evaluable for the primary endpoint. The trial was halted early after a preplanned interim futility analysis. The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Rash was the most common adverse event (17%; n = 3). The most common >= grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each). Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4+ T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74).CONCLUSION: Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma.
CANIT0002451	31031204	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy plus radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	N/A	188	N/A	Retrospective analysis	Patients received anti-PD-1/PD-L1 monotherapy (n = 127, 68%) or PD-1/PD-L1-based combinations (n = 61, 32%). In the entire cohort, 70% (132/188) received any radiotherapy (RT), 53% (100/188) chest RT, and 37% (70/188) curative-intent chest RT. Any grade IR pneumonitis occurred in 19% (36/188; 95% confidence interval, 13.8-25.6). Of those who developed IR pneumonitis and received chest RT (n = 19), patients were more likely to have received curative-intent versus palliative-intent chest RT (17/19, 89%, vs. 2/19, 11%; P = .051). Predominant IR pneumonitis appearances were ground-glass opacities outside high-dose chest RT regions. No RT parameter was significantly associated with IR pneumonitis. On subset analysis of patients who developed IR pneumonitis and who had received prior chest RT, IR pneumonitis was more common in patients who received curative-intent chest RT. Attention should be paid to NSCLC patients receiving curative-intent RT followed by anti-PD-1/PD-L1 agents.	Immune-related (IR) pneumonitis	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Relationship Between Prior Radiotherapy and Checkpoint-Inhibitor Pneumonitis in Patients With Advanced Non-Small-Cell Lung Cancer.	 Clin Lung Cancer	PURPOSE: To investigate the relationship between radiotherapy (RT), in particular chest RT, and development of immune-related (IR) pneumonitis in non-small-cell lung cancer (NSCLC) patients treated with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1).PATIENTS AND METHODS: Between June 2011 and July 2017, NSCLC patients treated with anti-PD-1/PD-L1 at a tertiary-care academic cancer center were identified. Patient, treatment, prior RT (intent, technique, timing, courses), and IR pneumonitis details were collected. Treating investigators diagnosed IR pneumonitis clinically. Diagnostic IR pneumonitis scans were overlaid with available chest RT plans to describe IR pneumonitis in relation to prior chest RT. We evaluated associations between patient, treatment, RT details, and development of IR pneumonitis by Fisher exact and Wilcoxon rank-sum tests.RESULTS: Of the 188 NSCLC patients we identified, median follow-up was 6.78 (range, 0.30-79.3) months and median age 66 (range, 39-91) years; 54% (n = 102) were male; and 42% (n = 79) had stage I-III NSCLC at initial diagnosis. Patients received anti-PD-1/PD-L1 monotherapy (n = 127, 68%) or PD-1/PD-L1-based combinations (n = 61, 32%). In the entire cohort, 70% (132/188) received any RT, 53% (100/188) chest RT, and 37% (70/188) curative-intent chest RT. Any grade IR pneumonitis occurred in 19% (36/188; 95% confidence interval, 13.8-25.6). Of those who developed IR pneumonitis and received chest RT (n = 19), patients were more likely to have received curative-intent versus palliative-intent chest RT (17/19, 89%, vs. 2/19, 11%; P = .051). Predominant IR pneumonitis appearances were ground-glass opacities outside high-dose chest RT regions.CONCLUSION: No RT parameter was significantly associated with IR pneumonitis. On subset analysis of patients who developed IR pneumonitis and who had received prior chest RT, IR pneumonitis was more common in patients who received curative-intent chest RT. Attention should be paid to NSCLC patients receiving curative-intent RT followed by anti-PD-1/PD-L1 agents.
CANIT0002452	31043740	Clinical research	Colon cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); PD-1 (Q15116); TNFA (P01375); 	CTLA-4 ;  PD-1 ;  TNFA 	Prophylactic TNF blockade plus ipilimumab plus nivolumab	Ipilimumab plus nivolumab	Immune checkpoint therapy plus Target therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	0	0	N/A	Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2-/-Il2rg-/- mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy.	Colitis and hepatitis	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 May	Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.	 Nature	Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer1-3. However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of ipilimumab that is given to patients4. In mice, co-treatment with surrogate anti-PD-1 and anti-CTLA-4 monoclonal antibodies is effective in transplantable cancer models, but also exacerbates autoimmune colitis. Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2-/-Il2rg-/- mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy.
CANIT0002453	31043744	Basic research	Fibrosarcoma or melanoma or ovarian cancer	Fibrosarcoma	MONDO:0019202	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNG) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNG expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNG and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 May	CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy.	 Nature	Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFN¦Ã) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFN¦Ã expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFN¦Ã and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.
CANIT0002454	31043744	Basic research	Fibrosarcoma or melanoma or ovarian cancer	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNG) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNG expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNG and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 May	CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy.	 Nature	Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFN¦Ã) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFN¦Ã expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFN¦Ã and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.
CANIT0002455	31043744	Basic research	Fibrosarcoma or melanoma or ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNG) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNG expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNG and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 May	CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy.	 Nature	Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFN¦Ã) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFN¦Ã expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFN¦Ã and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.
CANIT0002456	31043837	Case report	 2 cases of patients with a lung sarcomatoid carcinoma	Pulmonary sarcomatoid carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Case	Because PD-L1 was highly expressed in the tumour cells, we initiated therapy with nivolumab, which showed good efficacy, almost complete radiologic tumour remission, and a remarkable improvement in the condition of those patients. Immune checkpoint inhibitors targeting PD-1 might be a valuable therapy option for pulmonary sarcomatoid carcinoma.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Apr	Lazarus-type tumour response to therapy with nivolumab for sarcomatoid carcinomas of the lung.	 Curr Oncol	Pulmonary sarcomatoid carcinoma (psc) is a rare subtype of non-small-cell lung carcinoma with a poor prognosis and poor response to chemotherapy and radiotherapy. A previous study reported that psc expresses high levels of PD-L1, suggesting the potential efficacy of immune checkpoint inhibitors in these tumours. We report 2 cases of patients with a lung sarcomatoid carcinoma. Both patients initially underwent curative lung resection, but developed early recurrent disease. Because PD-L1 was highly expressed in the tumour cells, we initiated therapy with nivolumab, which showed good efficacy, almost complete radiologic tumour remission, and a remarkable improvement in the condition of those patients. Immune checkpoint inhibitors targeting PD-1 might be a valuable therapy option for pscs.
CANIT0002457	31045716	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Ipilimumab or nivolumab	Immune checkpoint therapy	N/A	11687	N/A	Meta-analysis	This meta-analysis shows that combination therapy with CTLA4 and PD-1 inhibitor have no difference in neurological toxicities compared to monotherapy with CTLA4 or PD-1 inhibitor.	Neurological Toxicities	N/A	N/A	N/A	N/A	N/A	 2019 May	Risk of Neurological Toxicities Following the Use of Different Immune Checkpoint Inhibitor Regimens in Solid Tumors: A Systematic Review and Meta-analysis.	 Neurologist	OBJECTIVES: The objective of this study was to assess risk of neurological toxicities following the use of different immune checkpoint inhibitor (ICI) regimens in solid tumors.METHODS: Pubmed, Embase, and ClinicalTrials.gov databases were searched for publications, and data were analyzed using Review Manager 5.3 software to compare the risk of immune-related and nonspecific neurological complications potentially triggered by ICIs to controls.RESULTS: In total 23 randomized clinical trials comprising 11,687 patients were included in this meta-analysis. Patients with PD-L1 (OR, 0.29; 95% confidence interval [CI], 0.18-0.48; P<0.01) or programmed cell-death protein 1 (PD-1) inhibitor (OR, 0.21; 95% CI, 0.14-0.31; P<0.01) were less likely to develop any-grade peripheral neuropathy than chemotherapy, while the risk of grade 3-5 was also smaller for PD-1 inhibitor (OR, 0.16; 95% CI, 0.05-0.54; P=0.003). Combination therapy with CTLA4 and PD-1 inhibitor did not significantly increase the risk of any-grade (OR, 0.83; 95% CI, 0.21-3.32; P>0.05) or grade 3-5 (OR, 1.4; 95% CI, 0.2-9.61; P>0.05) peripheral neuropathy compared to monotherapy with CTLA4 or PD-1 inhibitor. However, difference in risk of immune-related adverse events (irAEs) involving central nervous system did not reach statistical significance in patients with different ICI regimens compared those under chemotherapy. Additionally, risk of experiencing paresthesia was in line with that of peripheral neuropathy (OR, 0.42; 95% CI, 0.28-0.62; P<0.01).CONCLUSIONS: This meta-analysis shows that PD-L1/PD-1 and CTLA4 inhibitor have decreased risk of peripheral neuropathy compared to chemotherapy, while combination therapy with CTLA4 and PD-1 inhibitor have no difference in neurological toxicities compared to monotherapy with CTLA4 or PD-1 inhibitor.
CANIT0002458	31045716	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	Chemotherapy	Immune checkpoint therapy	N/A	11687	N/A	Meta-analysis	This meta-analysis shows that PD-L1/PD-1 inhibitor have decreased risk of peripheral neuropathy compared to chemotherapy.	Neurological Toxicities	N/A	N/A	N/A	N/A	N/A	 2019 May	Risk of Neurological Toxicities Following the Use of Different Immune Checkpoint Inhibitor Regimens in Solid Tumors: A Systematic Review and Meta-analysis.	 Neurologist	OBJECTIVES: The objective of this study was to assess risk of neurological toxicities following the use of different immune checkpoint inhibitor (ICI) regimens in solid tumors.METHODS: Pubmed, Embase, and ClinicalTrials.gov databases were searched for publications, and data were analyzed using Review Manager 5.3 software to compare the risk of immune-related and nonspecific neurological complications potentially triggered by ICIs to controls.RESULTS: In total 23 randomized clinical trials comprising 11,687 patients were included in this meta-analysis. Patients with PD-L1 (OR, 0.29; 95% confidence interval [CI], 0.18-0.48; P<0.01) or programmed cell-death protein 1 (PD-1) inhibitor (OR, 0.21; 95% CI, 0.14-0.31; P<0.01) were less likely to develop any-grade peripheral neuropathy than chemotherapy, while the risk of grade 3-5 was also smaller for PD-1 inhibitor (OR, 0.16; 95% CI, 0.05-0.54; P=0.003). Combination therapy with CTLA4 and PD-1 inhibitor did not significantly increase the risk of any-grade (OR, 0.83; 95% CI, 0.21-3.32; P>0.05) or grade 3-5 (OR, 1.4; 95% CI, 0.2-9.61; P>0.05) peripheral neuropathy compared to monotherapy with CTLA4 or PD-1 inhibitor. However, difference in risk of immune-related adverse events (irAEs) involving central nervous system did not reach statistical significance in patients with different ICI regimens compared those under chemotherapy. Additionally, risk of experiencing paresthesia was in line with that of peripheral neuropathy (OR, 0.42; 95% CI, 0.28-0.62; P<0.01).CONCLUSIONS: This meta-analysis shows that PD-L1/PD-1 and CTLA4 inhibitor have decreased risk of peripheral neuropathy compared to chemotherapy, while combination therapy with CTLA4 and PD-1 inhibitor have no difference in neurological toxicities compared to monotherapy with CTLA4 or PD-1 inhibitor.
CANIT0002459	31045716	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	Chemotherapy	Immune checkpoint therapy	N/A	11687	N/A	Meta-analysis	This meta-analysis shows that CTLA4 inhibitor have decreased risk of peripheral neuropathy compared to chemotherapy.	Neurological Toxicities	N/A	N/A	N/A	N/A	N/A	 2019 May	Risk of Neurological Toxicities Following the Use of Different Immune Checkpoint Inhibitor Regimens in Solid Tumors: A Systematic Review and Meta-analysis.	 Neurologist	OBJECTIVES: The objective of this study was to assess risk of neurological toxicities following the use of different immune checkpoint inhibitor (ICI) regimens in solid tumors.METHODS: Pubmed, Embase, and ClinicalTrials.gov databases were searched for publications, and data were analyzed using Review Manager 5.3 software to compare the risk of immune-related and nonspecific neurological complications potentially triggered by ICIs to controls.RESULTS: In total 23 randomized clinical trials comprising 11,687 patients were included in this meta-analysis. Patients with PD-L1 (OR, 0.29; 95% confidence interval [CI], 0.18-0.48; P<0.01) or programmed cell-death protein 1 (PD-1) inhibitor (OR, 0.21; 95% CI, 0.14-0.31; P<0.01) were less likely to develop any-grade peripheral neuropathy than chemotherapy, while the risk of grade 3-5 was also smaller for PD-1 inhibitor (OR, 0.16; 95% CI, 0.05-0.54; P=0.003). Combination therapy with CTLA4 and PD-1 inhibitor did not significantly increase the risk of any-grade (OR, 0.83; 95% CI, 0.21-3.32; P>0.05) or grade 3-5 (OR, 1.4; 95% CI, 0.2-9.61; P>0.05) peripheral neuropathy compared to monotherapy with CTLA4 or PD-1 inhibitor. However, difference in risk of immune-related adverse events (irAEs) involving central nervous system did not reach statistical significance in patients with different ICI regimens compared those under chemotherapy. Additionally, risk of experiencing paresthesia was in line with that of peripheral neuropathy (OR, 0.42; 95% CI, 0.28-0.62; P<0.01).CONCLUSIONS: This meta-analysis shows that PD-L1/PD-1 and CTLA4 inhibitor have decreased risk of peripheral neuropathy compared to chemotherapy, while combination therapy with CTLA4 and PD-1 inhibitor have no difference in neurological toxicities compared to monotherapy with CTLA4 or PD-1 inhibitor.
CANIT0002460	31045745	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	32	N/A	Retrospective analysis	The entire tumor burden evaluated by  fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) can be predictive of response to immunotherapy in patients with metastatic lung cancer. A large prospective multicenter trial is warranted to definitively assess the usefulness of F-FDG PET/CT as a predictive biomarker of response to immunotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Aug	18F-FDG PET/CT in non-small-cell lung cancer patients: a potential predictive biomarker of response to immunotherapy.	 Nucl Med Commun	AIM: The aim of this study was to assess the predictive role of fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in the evaluation of response to immunotherapy in patients affected by metastatic lung cancer.MATERIALS AND METHODS: From a single-center database, data for 32 patients (median age: 69 years; range: 37-78) with metastatic lung cancer were retrospectively retrieved. All patients were treated with nivolumab. PD-L1 expression was available in 19/32 patients. All patients underwent F-FDG PET/CT before immunotherapy. Whole-body maximum standardized uptake value (SUVmaxwb), metabolic tumor volume (MTVwb), and total lesion glycolysis (TLGwb) were obtained as the sum of SUVmax, metabolic tumor volume, and total lesion glycolysis in all metabolic lesions. The best response to therapy was considered in terms of partial response (PR), stable disease (SD), and progressive disease (PD) on the basis of clinical and radiological follow-up.RESULTS: F-FDG PET/CT was positive in 30/32 (94%) patients. The majority of them had a pathological F-FDG uptake in the lung, lymph nodes, and bones. SUVmaxwb, MTVwb, and TLGwb were higher in patients with a positive PD-L1 expression than those with negative expression. Twenty-one patients achieved disease control (PR+SD), whereas 11 did not (PD). SUVmaxwb was significantly higher in patients without a response to therapy than those with a response to immunotherapy (median: 48.97 vs. 20.85; Student t-test: P = 0.002). Similarly, TLGwb and MTVwb were also higher in nonresponders than responders, although not statistically significant. However, the difference was more evident in women than men (median SUVmaxwb in responders and nonresponders for women and men: 17.86 vs. 85.89 and 21.38 vs. 44.38, respectively).CONCLUSION: The entire tumor burden evaluated by F-FDG PET/CT can be predictive of response to immunotherapy in patients with metastatic lung cancer. A large prospective multicenter trial is warranted to definitively assess the usefulness of F-FDG PET/CT as a predictive biomarker of response to immunotherapy.
CANIT0002461	31053161	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus steroids	N/A	Immune checkpoint therapy	N/A	4253	N/A	Retrospective analysis	Immune checkpoint inhibitors (ICIs) treatment can result in a clinical condition similar to typical acute cholecystitis in a minority of patients. ICI-related cholecystitis should be managed in a similar fashion to typical cholecystitis. The efficacy of steroids for the treatment of ICI-related cholecystitis is unclear.	Acute cholecystitis	N/A	N/A	N/A	N/A	N/A	 2019 May 3	Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitors (ICIs) represent a promising novel class of cancer therapy, but immune-mediated adverse events can complicate ICI treatment. Acute cholecystitis in patients receiving ICI therapy has not been characterized. We aimed to describe the clinical features of patients who developed ICI-related cholecystitis.METHODS: We evaluated a case series of patients at a tertiary cancer center who received ICI therapy and developed cholecystitis, diagnosed by clinical presentation and diagnostic imaging, during 2010-2018. Patients with a history of chronic cholecystitis or other etiologies of acute cholecystitis, such as cholelithiasis, were excluded. A chi-square test was used to compare the frequency of cholecystitis between ICI regimens. Kaplan-Meier and log rank analyses were used to compare survival between subgroups.RESULTS: Of the 4253 patients who received ICIs in the study period, 25 (0.6%) patients developed suspected ICI-related cholecystitis. Alternatively, of the 31,426 cancer-matched patients who received non-ICI therapy, 72 (0.2%) developed acalculous cholecystitis (P < 0.001). Among the 25 included patients, the median time from ICI initiation to cholecystitis was 6 months (range, 0.1-31 months). Fifteen (60%) patients received an inhibitor of programmed death protein 1 (anti-PD-1) or of its ligand (anti-PD-L1) as a single agent, and 10 (40%) patients received an inhibitor of cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) therapy alone or combined with anti-PD-1/L1. Anti-CTLA-4 monotherapy was associated with a higher risk of cholecystitis (P = 0.006). ICI therapy was discontinued in 20 patients, in three (12%) as a result of acute cholecystitis. Two (8%) patients developed sepsis, and four (16%) had perforation of the gallbladder wall. Five (20%) patients underwent surgical cholecystectomy, and eight (32%) underwent percutaneous drainage. Five (20%) patients were treated with steroids; two of them required surgery. Ten (40%) patients were able to restart ICI therapy. Patients who received a combination of anti-CTLA-4 and anti-PD-1/L1 had more complications of cholecystitis than did patients who received either agent alone (P = 0.03).CONCLUSIONS: ICI treatment can result in a clinical condition similar to typical acute cholecystitis in a minority of patients. ICI-related cholecystitis should be managed in a similar fashion to typical cholecystitis. The efficacy of steroids for the treatment of ICI-related cholecystitis is unclear.
CANIT0002462	31062404	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A case of lichen planus pemphigoides (LPP) develop from a patient with non-small-cell lung cancer treated with nivolumab that was probably induced by vildagliptin. Our case showed a rapid response to systemic corticosteroids but, unlike previous reports, our case showed a rapid onset of LPP.	Lichen planus pemphigoides	N/A	N/A	N/A	N/A	N/A	 2019 Oct	Lichen planus pemphigoides developing from patient with non-small-cell lung cancer treated with nivolumab.	 J Dermatol	Unable to provide
CANIT0002463	31063862	Clinical research	20 patients with extensive-stage SCLC 	Small cell lung carcinoma	EFO:0000702	Lung	PD-L1 (Q9NZQ7); PARP1 (P09874); 	PD-L1; PARP1	Durvalumab plus olaparib	N/A	Immune checkpoint therapy plus Target therapy	Durvalumab (DB11714); olaparib (DB09074); 	20	N/A	Open-label, single-arm phase II study	The study combination did not meet the preset bar for efficacy. Pretreatment and during-treatment biopsy specimens suggested that tumor immune phenotypes may be relevant for SCLC responses to immune checkpoint blockade combinations. The predictive value of preexisting CD8-positive T-cell infiltrates observed in this study needs to be confirmed in larger cohorts.	Anemia,lymphopenia, leukopenia ,fatigue and thrombocytopenia	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Preexisting CD8-positive T-cell infiltrates	Tumor-infiltrating immune cell	 2019 Aug	Durvalumab in Combination with Olaparib in Patients with Relapsed SCLC: Results from a Phase II Study.	 J Thorac Oncol	PURPOSE: Despite high tumor mutationburden, immune checkpoint blockade has limited efficacy in SCLC. We hypothesized that poly (ADP-ribose) polymerase inhibition could render SCLC more susceptible to immune checkpoint blockade.METHODS: A single-arm, phase II trial (NCT02484404) enrolled patients with relapsed SCLC who received durvalumab, 1500 mg every 4 weeks, and olaparib, 300 mg twice a day. The primary outcome was objective response rate. Correlative studies included mandatory collection of pretreatment and during-treatment biopsy specimens, which were assessed to define SCLC immunephenotypes: desert (CD8-positive T-cell prevalence low), excluded (CD8-positive T cells in stroma immediately adjacent/within tumor), and inflamed (CD8-positive T cells in direct contact with tumor).RESULTS: A total of 20 patients were enrolled. Their median age was 64 years, and most patients (60%) had platinum-resistant/refractory disease. Of 19 evaluable patients, two were observed to have partial or complete responses (10.5%), including a patient with EGFR-transformed SCLC. Clinical benefit was observed in four patients (21.1% [95% confidence interval: 6.1%-45.6%]) with confirmed responses or prolonged stable disease (>=8 months). The most common treatment-related adverse events were anemia (80%), lymphopenia (60%), and leukopenia (50%). Nine of 14 tumors (64%) exhibited an excluded phenotype; 21% and 14% of tumors exhibited the inflamed and desert phenotypes, respectively. Tumor responses were observed in all instances in which pretreatment tumors showed an inflamed phenotype. Of the five tumors without an inflamed phenotype at baseline, no during-treatment increase in T-cell infiltration or programmed death ligand 1 expression on tumor-infiltrating immune cells was observed.CONCLUSIONS: The study combination did not meet the preset bar for efficacy. Pretreatment and during-treatment biopsy specimens suggested that tumor immune phenotypes may be relevant for SCLC responses to immune checkpoint blockade combinations. The predictive value of preexisting CD8-positive T-cell infiltrates observed in this study needs to be confirmed in larger cohorts.
CANIT0002464	31074244	Clinical research	Platinum resistant ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	18	N/A	N/A	The disease control rate was 44% (95% confidence interval [CI]=19-87) as 8 showed stable disease, 6 showed progressive disease and 4 died before the first radiological response evaluation. The median OS was 30 weeks (95% CI=14-42; range, 3-95), and PFS was 15 weeks (95% CI=13-17). The median follow-up time was 30 weeks (range, 3-123).This study shows few adverse events, and promising clinical efficacy when using nivolumab for ovarian cancer.	The rate of grade 2-5 adverse events was 28% (5 out of 18). Two patients (11%) developed grade 2 and 3 adverse events, respectively, while no grade 4 events were observed. One patient died from intestinal perforation, believed to be caused by concomitant bevacizumab rather than nivolumab.	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Early experiences with PD-1 inhibitor treatment of platinum resistant epithelial ovarian cancer.	 J Gynecol Oncol	OBJECTIVE: In this study, we evaluated the toxicity and clinical efficacy of nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, on patients with platinum resistant ovarian cancer.METHODS: Every second week, 18 patients with platinum resistance ovarian cancer received nivolumab until disease progression occurred. We assessed toxicity, disease control rate, progression free survival (PFS) and overall survival (OS). Radiological response evaluation according to irRECIST was performed every 12th week, while clinical evaluation was done every second week.RESULTS: The disease control rate was 44% (95% confidence interval [CI]=19-87) as 8 showed stable disease, 6 showed progressive disease and 4 died before the first radiological response evaluation. The median OS was 30 weeks (95% CI=14-42; range, 3-95), and PFS was 15 weeks (95% CI=13-17). The median follow-up time was 30 weeks (range, 3-123). The rate of grade 2-5 adverse events was 28% (5 out of 18). Two patients (11%) developed grade 2 and 3 adverse events, respectively, while no grade 4 events were observed. One patient died from intestinal perforation, believed to be caused by concomitant bevacizumab rather than nivolumab.CONCLUSION: This study shows few adverse events, and promising clinical efficacy when using nivolumab for ovarian cancer.
CANIT0002465	31075726	Clinical research	As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib.	Clear cell renal carcinoma	EFO:0000349	Kidney	CTLA-4 (P16410); PD-1 (Q15116); VEGF (P15692); 	CTLA-4 ;  PD-1 ;  VEGF 	Ipilimumab plus nivolumab followed by bevacizumab	N/A	Immune checkpoint therapy followed by Target therapy	Ipilimumab (DB06186); nivolumab (DB09035); bevacizumab (DB00112); 	25	N/A	Retrospective analysis	In this retrospective study of patients with metastatic clear-cell renal cell carcinoma (mccRCC) receiving second-line (2L) tyrosine kinase inhibitor(TKI) monotherapy after front-line (1L) immune checkpoint inhibitors (ICIs), we observed 2L antitumour activity and tolerance comparable to historical data for 3L TKI.	Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity.	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.	 Eur J Cancer	BACKGROUND: Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor-receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy.PATIENTS AND METHODS: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan-Meier method were used.RESULTS: Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity.CONCLUSIONS: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.
CANIT0002466	31075726	Clinical research	As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib.	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Nivolumab followed by bevacizumab	N/A	Immune checkpoint therapy followed by Target therapy	Nivolumab (DB09035); bevacizumab (DB00112); 	33	N/A	Retrospective analysis	In this retrospective study of patients with metastatic clear-cell renal cell carcinoma (mccRCC) receiving second-line (2L) tyrosine kinase inhibitor(TKI) monotherapy after front-line (1L) immune checkpoint inhibitors (ICIs), we observed 2L antitumour activity and tolerance comparable to historical data for 2L TKI.	Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity.	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.	 Eur J Cancer	BACKGROUND: Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor-receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy.PATIENTS AND METHODS: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan-Meier method were used.RESULTS: Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity.CONCLUSIONS: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.
CANIT0002467	31075726	Clinical research	As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib.	Clear cell renal carcinoma	EFO:0000349	Kidney	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab followed by bevacizumab	N/A	Immune checkpoint therapy followed by Target therapy	Atezolizumab (DB11595); bevacizumab (DB00112); 	12	N/A	Retrospective analysis	In this retrospective study of patients with metastatic clear-cell renal cell carcinoma (mccRCC) receiving second-line (2L) tyrosine kinase inhibitor(TKI) monotherapy after front-line (1L) immune checkpoint inhibitors (ICIs), we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.	Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity.	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.	 Eur J Cancer	BACKGROUND: Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor-receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy.PATIENTS AND METHODS: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan-Meier method were used.RESULTS: Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti-programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity.CONCLUSIONS: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.
CANIT0002468	31078463	Clinical research	36 participants were recruited and enrolled, of whom 33 (92%) were given study therapy and were evaluable for toxicity	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Pembrolizumab plus axitinib	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); axitinib (DB06626); 	33	N/A	Single-centre, single-arm, phase II	The combination of VEGF receptor and PD-1 blockade showed acceptable toxic effects and preliminary activity in alveolar soft-part sarcoma and other advanced sarcomas that warrant additional investigation through a randomised trial. Exploratory endpoints reported here include tumour PD-L1 expression, lymphocyte infiltration score, plasma angiogenic activity, and circulating neutrophil-tolymphocyte ratio, which were correlated with best response and progression- free survival. Other prespecified exploratory endpoints of immune phenotyping of tumour infiltrating and circulating lymphocytes, cytokine profiles, expression of immune-related genetic signatures, quantity of circulating tumour cells, and responses by MRI volumetrics will be reported elsewhere.	Anaemia,thrombocytopenia,neutropenic fever,acute kidney injury,proteinuria, transaminitis,nausea, vomiting, diarrhoea, constipation,oedema, and hypertension	N/A	ECO:0007120 - animal model system study evidence used in manual assertion	AGGF1 (Q8N302); 	Serum angiogenic activity	Gene expression signature in serum	 2019 Jun	Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial.	 Lancet Oncol	BACKGROUND: VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma.METHODS: This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual.FINDINGS: Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14.7 months (IQR 10.1-19.1), 3-month progression-free survival for all evaluable patients was 65.6% (95% CI 46.6-79.3). For patients with ASPS, 3-month progression-free survival was 72.7% (95% CI 37.1-90.3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths.INTERPRETATION: Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.FUNDING: Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.
CANIT0002469	31078463	Clinical research	36 participants were recruited and enrolled, of whom 33 (92%) were given study therapy and were evaluable for toxicity	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Pembrolizumab plus axitinib	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); axitinib (DB06626); 	33	N/A	Single-centre, single-arm, phase II	The combination of VEGF receptor and PD-1 blockade showed acceptable toxic effects and preliminary activity in alveolar soft-part sarcoma and other advanced sarcomas that warrant additional investigation through a randomised trial. Exploratory endpoints reported here include tumour PD-L1 expression, lymphocyte infiltration score, plasma angiogenic activity, and circulating neutrophil-tolymphocyte ratio, which were correlated with best response and progression- free survival. Other prespecified exploratory endpoints of immune phenotyping of tumour infiltrating and circulating lymphocytes, cytokine profiles, expression of immune-related genetic signatures, quantity of circulating tumour cells, and responses by MRI volumetrics will be reported elsewhere.	Anaemia,thrombocytopenia,neutropenic fever,acute kidney injury,proteinuria, transaminitis,nausea, vomiting, diarrhoea, constipation,oedema, and hypertension	N/A	ECO:0007120 - animal model system study evidence used in manual assertion	Lymphocyte (NCIT:C12535); 	Lymphocyte infiltration score	Tumor-infiltrating immune cell	 2019 Jun	Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial.	 Lancet Oncol	BACKGROUND: VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma.METHODS: This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual.FINDINGS: Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14.7 months (IQR 10.1-19.1), 3-month progression-free survival for all evaluable patients was 65.6% (95% CI 46.6-79.3). For patients with ASPS, 3-month progression-free survival was 72.7% (95% CI 37.1-90.3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths.INTERPRETATION: Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.FUNDING: Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.
CANIT0002470	31078463	Clinical research	36 participants were recruited and enrolled, of whom 33 (92%) were given study therapy and were evaluable for toxicity	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Pembrolizumab plus axitinib	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); axitinib (DB06626); 	33	N/A	Single-centre, single-arm, phase II	The combination of VEGF receptor and PD-1 blockade showed acceptable toxic effects and preliminary activity in alveolar soft-part sarcoma and other advanced sarcomas that warrant additional investigation through a randomised trial. Exploratory endpoints reported here include tumour PD-L1 expression, lymphocyte infiltration score, plasma angiogenic activity, and circulating neutrophil-tolymphocyte ratio, which were correlated with best response and progression- free survival. Other prespecified exploratory endpoints of immune phenotyping of tumour infiltrating and circulating lymphocytes, cytokine profiles, expression of immune-related genetic signatures, quantity of circulating tumour cells, and responses by MRI volumetrics will be reported elsewhere.	Anaemia,thrombocytopenia,neutropenic fever,acute kidney injury,proteinuria, transaminitis,nausea, vomiting, diarrhoea, constipation,oedema, and hypertension	N/A	ECO:0007120 - animal model system study evidence used in manual assertion	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Jun	Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial.	 Lancet Oncol	BACKGROUND: VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma.METHODS: This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual.FINDINGS: Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14.7 months (IQR 10.1-19.1), 3-month progression-free survival for all evaluable patients was 65.6% (95% CI 46.6-79.3). For patients with ASPS, 3-month progression-free survival was 72.7% (95% CI 37.1-90.3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths.INTERPRETATION: Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.FUNDING: Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.
CANIT0002471	31078463	Clinical research	36 participants were recruited and enrolled, of whom 33 (92%) were given study therapy and were evaluable for toxicity	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); VEGF (P15692); 	PD-1; VEGF	Pembrolizumab plus axitinib	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); axitinib (DB06626); 	33	N/A	Single-centre, single-arm, phase II	The combination of VEGF receptor and PD-1 blockade showed acceptable toxic effects and preliminary activity in alveolar soft-part sarcoma and other advanced sarcomas that warrant additional investigation through a randomised trial. Exploratory endpoints reported here include tumour PD-L1 expression, lymphocyte infiltration score, plasma angiogenic activity, and circulating neutrophil-tolymphocyte ratio, which were correlated with best response and progression- free survival. Other prespecified exploratory endpoints of immune phenotyping of tumour infiltrating and circulating lymphocytes, cytokine profiles, expression of immune-related genetic signatures, quantity of circulating tumour cells, and responses by MRI volumetrics will be reported elsewhere.	Anaemia,thrombocytopenia,neutropenic fever,acute kidney injury,proteinuria, transaminitis,nausea, vomiting, diarrhoea, constipation,oedema, and hypertension	N/A	ECO:0007120 - animal model system study evidence used in manual assertion	PD-1 (Q15116); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jun	Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial.	 Lancet Oncol	BACKGROUND: VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma.METHODS: This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual.FINDINGS: Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14.7 months (IQR 10.1-19.1), 3-month progression-free survival for all evaluable patients was 65.6% (95% CI 46.6-79.3). For patients with ASPS, 3-month progression-free survival was 72.7% (95% CI 37.1-90.3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths.INTERPRETATION: Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.FUNDING: Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.
CANIT0002472	31079556	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	60	N/A	Retrospective analysis	Sixty patients developed upper Gastrointestinal (GI) adverse events between immune checkpoint inhibitors (ICIs) initiation and 6 months after the last infusion. Among patients who had both esophagogastroduodenoscopy (EGD)D and colonoscopy (n = 38), 21 had endoscopic evidence of inflammation involving both the upper and lower GI tract. Overall, histological signs of inflammation of the stomach were evident in 83% of patients, but inflammation of the duodenum in 38%. Total of 42 patients had other risk factors of gastritis, i.e., chemotherapy, radiotherapy, and non-steroidal anti-inflammatory drugs. Only isolated gastric inflammation was seen on endoscopy in patients without these risk factors. The rates of ulceration were similar in the cohorts with and without other risk factors for gastritis. Isolated upper GI inflammation was related to anti-PD-1/L1 in 47% of patients. Immunosuppressive therapy in our cohort with upper GI toxicity consisted of steroids (42%) and infliximab or vedolizumab (23%). Most isolated upper GI symptoms were treated with proton pump inhibitors (65%) or H2 blockers (35%) The results shown a correlation between ICI use and onset of upper GI inflammation even when other risk factors were excluded. Gastric involvement was evident more often than duodenal involvement on endoscopic and histological level.	Upper gastrointestinal symptoms	N/A	N/A	N/A	N/A	N/A	 2019 May	Upper gastrointestinal symptoms and associated endoscopic and histological features in patients receiving immune checkpoint inhibitors.	 Scand J Gastroenterol	Background: Immune checkpoint inhibitors (ICIs) have demonstrated effectiveness in treating many malignancies. Gastrointestinal (GI) adverse events are commonly reported; however, few reports describe upper GI tract toxic effects. We aimed to describe clinical features of upper GI injury related to ICI. Methods: We studied consecutive patients who received ICIs between April 2011 and March 2018 and developed upper GI symptoms requiring esophagogastroduodenoscopy (EGD). Results: Sixty patients developed upper GI symptoms between ICI initiation and 6 months after the last infusion. Among patients who had both EGD and colonoscopy (n = 38), 21 had endoscopic evidence of inflammation involving both the upper and lower GI tract. Overall, histological signs of inflammation of the stomach were evident in 83% of patients, but inflammation of the duodenum in 38%. Total of 42 patients had other risk factors of gastritis, i.e., chemotherapy, radiotherapy, and non-steroidal anti-inflammatory drugs. Only isolated gastric inflammation was seen on endoscopy in patients without these risk factors. The rates of ulceration were similar in the cohorts with and without other risk factors for gastritis. Isolated upper GI inflammation was related to anti-PD-1/L1 in 47% of patients. Immunosuppressive therapy in our cohort with upper GI toxicity consisted of steroids (42%) and infliximab or vedolizumab (23%). Most isolated upper GI symptoms were treated with proton pump inhibitors (65%) or H2 blockers (35%). Conclusion: We observed a correlation between ICI use and onset of upper GI inflammation even when other risk factors were excluded. Gastric involvement was evident more often than duodenal involvement on endoscopic and histological level.
CANIT0002473	31082693	Clinical research	Relapsed/refractory (R/R) Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab plus allogenic haematopoietic stem cell transplantation	N/A	Immune checkpoint therapy plus Cell immunotherapy plus Radiotherapy	Nivolumab (DB09035); autologous stem cell transplantation (NCIT:C16039); 	78	N/A	Retrospective analysis	Most patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) treated with anti-PD1 monotherapy eventually progressed, notably those who did not achieve a complete responses (CR). Patients undergoing consolidation with allogenic haematopoietic stem cell transplantation (allo-HSCT)  after anti-PD1 therapy experienced prolonged disease-free survival compared with non-transplanted patients, but this difference did not translate into a benefit in overall survival (OS). This information should be considered when evaluating the risk/benefit ratio of allo-HSCT after anti-PD1 therapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Long-term efficacy of anti-PD1 therapy in Hodgkin lymphoma with and without allogenic stem cell transplantation.	 Eur J Cancer	INTRODUCTION: Long-term efficacy of anti-PD1 therapy and the need for a consolidation with allogenic haematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL).METHODS: We retrospectively analysed 78 patients with R/R HL treated with nivolumab in the French Early Access Program and compared their outcomes according to subsequent allo-HSCT.RESULTS: After a median follow-up of 34.3 months, the best overall response rate was 65.8%, including 38.2% complete responses (CRs). The median progression-free survival (PFS) was 12.1 months. Patients reaching a CR upon nivolumab had a significantly longer PFS than those reaching a partial response (PR) (median = not reached vs 9.3 months, p < 0.001). In our cohort, 13 patients who responded (i.e. in CR or PR) to nivolumab monotherapy underwent consolidation with allo-HSCT. Among responding patients, none of those who underwent subsequent allo-HSCT (N = 13) relapsed, whereas 62.2% of those who were not consolidated with allo-HSCT (N = 37) relapsed (p < 0.001). There was no difference in overall survival (OS) between the two groups. Five of 6 patients who were not in CR at the time of transplantation (4 PRs and 1 progressive disease) converted into a CR after allo-HSCT.CONCLUSION: Most patients with R/R HL treated with anti-PD1 monotherapy eventually progressed, notably those who did not achieve a CR. Patients undergoing consolidation with allo-HSCT after anti-PD1 therapy experienced prolonged disease-free survival compared with non-transplanted patients, but this difference did not translate into a benefit in OS. This information should be considered when evaluating the risk/benefit ratio of allo-HSCT after anti-PD1 therapy.
CANIT0002474	31086347	Clinical research	Metastatic triple-negative breast cancer ( TNBC ) 	Triple-negative breast cancer	EFO:0005537	Breast	PD-1 (Q15116); 	PD-1; 	Nivolumab plus (irradiation or cyclophosphamide or cisplatin or doxorubicin)	N/A	Immune checkpoint therapy plus Chemotherapy or Radiotherapy	Nivolumab (DB09035); cisplatin (DB00515); doxorubicin (DB00997); cyclophosphamide (DB00531); 	67	N/A	Adaptive, non-comparative phase 2 trial	Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in metastatic triple-negative breast cancer ( TNBC ) and exploration of induction treatments prior to PD-1 blockade in other cancer types.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.	 Nat Med	The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer ( TNBC ) is low1-5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6-13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 ¡Á 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-a signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.
CANIT0002475	31086392	Clinical research	Lung cancer etc.	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	200	N/A	Retrospective analysis	By thyroid uptake of FDG-PET, overt thyroid immune-related adverse events (irAEs) could be predicted before nivolumab therapy. Thyroid irAEs related to good prognosis in lung cancer but might be inconclusive in malignant melanoma.	Thyroid immune-related adverse events	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Thyroid immune-related adverse events	Adverse events	 2019 May 14	Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab.	 PLoS One	BACKGROUND: Blocking the PD-1 pathway induces immune-related adverse events (irAEs) which often involve the thyroid gland (thyroid irAEs). Clinical features of a thyroid irAE including its predictability and relationship to prognosis remain to be elucidated.METHODS: Two hundred consecutive patients treated with nivolumab at Kyoto University Hospital between September 1, 2014 and August 31, 2017 were included in a retrospective cohort study. We systematically determined and classified subclinical and overt thyroid irAEs based on data collected of serum free T4 and TSH levels. Baseline characteristics and detailed clinical data were analyzed, and analyses of overall survival (OS) excluded patients censored within 1 month from the first administration of nivolumab.RESULTS: Sixty-seven patients (33.5%) developed thyroid irAEs and these were divided into a subclinical thyroid irAE group (n = 40, 20.0%) and an overt thyroid irAE group (n = 27, 13.5%). Patients with thyroid uptake of FDG-PET before treatment showed high incidences of overt thyroid irAE (adjusted odds ratio 14.48; 95% confidence interval [CI] 3.12-67.19), while the same relationship was not seen with subclinical thyroid irAE. Regarding the total cohort, the thyroid irAE (+) group had a significantly longer median OS than the thyroid irAE (-) group (16.1 versus 13.6 months, hazard ratio [HR] 0.61; 95% CI 0.39-0.93). In 112 non-excluded patients with lung cancer, the thyroid irAE (+) group similarly had a longer median OS than the thyroid irAE (-) group (not reached versus 14.2 months, HR 0.51; 95% CI 0.27-0.92). However, this observation was not seen in 41 non-excluded patients with malignant melanoma (12.0 versus 18.3 months, HR 1.54; 95% CI 0.67-3.43).CONCLUSIONS: By thyroid uptake of FDG-PET, overt thyroid irAEs could be predicted before nivolumab therapy. Thyroid irAEs related to good prognosis in lung cancer but might be inconclusive in malignant melanoma.
CANIT0002476	31087200	Clinical research	493 enrolled patients, 81 (nivolumab, n = 59; placebo, n = 22) were Tmab+ and 412 (nivolumab, n = 271; placebo, n = 141) were Tmab-	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); EGFR (P00533); 	PD-1; EGFR	Trastuzumab followed by Nivolumab	Trastuzumab followed by  Placebo	Target therapy followed by Immune checkpoint therapy	Nivolumab (DB09035); 	330	163	A randomized, double-blind, placebo-controlled, phase III 	Nivolumab was efficacious and safe as third- or later-line therapy regardless of prior trastuzumab use in patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer.	 Gastric Cancer	BACKGROUND: Data on immune checkpoint inhibitor efficacy in patients with human epidermal growth factor receptor 2-positive (HER2+) advanced gastric/gastroesophageal junction (G/GEJ) cancer are lacking. Because HER2 status was not captured in the ATTRACTION-2 trial, we used patients with prior trastuzumab use (Tmab+) as surrogate for HER2 expression status to evaluate the efficacy and safety of nivolumab as third- or later-line therapy in these patients.METHODS: In ATTRACTION-2, a randomized, double-blind, placebo-controlled, phase 3 multicenter trial, patients were randomized (2:1) to receive nivolumab (3 mg/kg) or placebo every 2 weeks until disease progression or toxicity requiring study discontinuation. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were assessed.RESULTS: Of 493 enrolled patients, 81 (nivolumab, n = 59; placebo, n = 22) were Tmab+ and 412 (nivolumab, n = 271; placebo, n = 141) were Tmab-. In both groups, patients receiving nivolumab showed a longer median OS vs placebo (Tmab+, 8.3 [95% confidence interval, 5.3-12.9] vs 3.1 [1.9-5.3] months, hazard ratio, 0.38 [0.22-0.66]; P = 0.0006; Tmab-, 4.8 [4.1-6.0] vs 4.2 [3.6-4.9] months, 0.71 [0.57-0.88]; P = 0.0022). PFS was longer in both groups receiving nivolumab vs placebo (Tmab+, 1.6 [1.5-4.0] vs 1.5 [1.3-2.9] months, 0.49 [0.29-0.85]; P = 0.0111; Tmab-, 1.6 [1.5-2.4] vs 1.5 [1.5-1.5] months, 0.64 [0.51-0.80]; P = 0.0001).CONCLUSIONS: Nivolumab was efficacious and safe as third- or later-line therapy regardless of prior trastuzumab use in patients with advanced G/GEJ cancer.
CANIT0002477	31088651	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Case	It reports the first case of the successful treatment of grade 3 immune therapy-induced diarrhea (ITID) with steroids and an amino acid-based oral rehydration solution (AA-ORS), enterade. Research suggests that AA-ORS may be used to reduce diarrhea and adequately hydrate patients, in contrast to glucose-based oral rehydration solutions, which have been implicated as a contributing factor to diarrhea in cancer patients.	Immune therapy-induced diarrhea (ITID)	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Can an amino acid-based oral rehydration solution be effective in managing immune therapy-induced diarrhea 	 Med Hypotheses	Immune checkpoint inhibitor (ICPi) therapy has transformed the way we treat cancer. However, its immune related adverse events (irAEs) can be debilitating and life threatening. Immune therapy-induced diarrhea (ITID) is one of the most commonly encountered irAEs and can lead to expensive and prolonged hospitalizations. The current standard of care for grade 3 or 4 ITID involves ICPi discontinuation, the initiation of steroids, and infliximab for refractory disease. This treatment regimen reverses the desired anti-tumor effect of ICPis, can lead to side effects, and is cost-ineffective. We report the first case of the successful treatment of grade 3 ITID with steroids and an amino acid-based oral rehydration solution (AA-ORS), enterade. Research suggests that AA-ORS may be used to reduce diarrhea and adequately hydrate patients, in contrast to glucose-based oral rehydration solutions, which have been implicated as a contributing factor to diarrhea in cancer patients. We hypothesize that an AA-ORS may mitigate ITID via safer and more economically viable means than the current standard of care, but more controlled trials are needed to test this hypothesis.
CANIT0002478	31088979	Case report	Metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology.Patients with rheumatologic disorders have increased risk of reactivation with PD-(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment.Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.	Reactivation of granulomatosis with polyangiitis (GPA)-an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis	N/A	N/A	N/A	N/A	N/A	 2019 Aug	Anti-PD-1 Immunotherapy-Induced Flare of a Known Underlying Relapsing Vasculitis Mimicking Recurrent Cancer.	 Oncologist	Safe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)-an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD-1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T-cell infiltrate, correlating with increased CD4+ and CD8+ na ve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD-1 in GPA self-tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti-PD-1 blockade. KEY POINTS: Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology.Patients with rheumatologic disorders have increased risk of reactivation with PD-(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment.Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.
CANIT0002479	31090906	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); pembrolizumab (DB09037); nivolumab (DB09035); 	14	N/A	Retrospective analysis	A total of 317 patients discontinued the immune checkpoint inhibitors (ICIs) treatment, and 14 patients (4.4%) received ICI rechallenge. All 14 patients discontinued the first ICI due to disease progression. Eight patients received the same kind of ICIs, and six patients received different ICIs. Median progression-free survival and overall survival were 1.5 months [95% confidence interval (CI): 0.8-2.6] and 6.5 months [95% CI: 1.4-19.0], respectively. The objective response rate was 7.1%, and the disease control rate was 21.4%. Two of three patients who achieved at least a stable disease, received radiotherapy between the first and second ICIs.In this study, the effect of ICI rechallenge was limited. Careful consideration of the administration of ICI rechallenge is necessary. This report involved a small number of cases, so further large prospective studies are warranted to confirm the efficacy of ICI rechallenge and to investigate predictive markers to identify a patient population in which ICI rechallenge is effective.	Adverse events were not significantly different compared with the first ICIs.	N/A	N/A	N/A	N/A	N/A	 2019 Aug 1	The effect and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer.	 Jpn J Clin Oncol	INTRODUCTION: Immune checkpoint inhibitors (ICIs) have demonstrated long survival for the treatment of advanced non-small cell lung cancer (NSCLC). However, the effect and safety of ICI rechallenge have not been fully evaluated. The aim of this study was to investigate the efficacy and safety of ICI rechallenge in NSCLC patients.METHODS: We defined 'rechallenge' as re-administration of ICIs for patients who were previously treated with ICIs and discontinued treatment for any reason, and received subsequent chemotherapy. We retrospectively analyzed the histories of 434 patients with advanced NSCLC who received ICIs from December 2015 to December 2017 at seven centers.RESULTS: A total of 317 patients discontinued the ICI treatment, and 14 patients (4.4%) received ICI rechallenge. All 14 patients discontinued the first ICI due to disease progression. Eight patients received the same kind of ICIs, and six patients received different ICIs. Median progression-free survival and overall survival were 1.5 months [95% confidence interval (CI): 0.8-2.6] and 6.5 months [95% CI: 1.4-19.0], respectively. The objective response rate was 7.1%, and the disease control rate was 21.4%. Two of three patients who achieved at least a stable disease, received radiotherapy between the first and second ICIs. Adverse events were not significantly different compared with the first ICIs.CONCLUSIONS: In this study, the effect of ICI rechallenge was limited. Careful consideration of the administration of ICI rechallenge is necessary. This report involved a small number of cases, so further large prospective studies are warranted to confirm the efficacy of ICI rechallenge and to investigate predictive markers to identify a patient population in which ICI rechallenge is effective.
CANIT0002480	31092853	Clinical research	31 Melanoma patients (10 female, 21 male, age 29¨C89 y) suffering from stage IV malignant melanoma.	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	31	N/A	Retrospective analysis	The most robust and best performing model was a decision tree model based on relative densities of CD8+ tumor infiltrating lymphocytes in the intra-tumoral infiltration region.  The results are well in agreement with observations described in previously published studies regarding the predictive value of the immune contexture, and thus, provide predictive potential for future development of a companion diagnostic test	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8(+) tumor infiltrating lymphocytes in the intra-tumoral infiltration region	Tumor-infiltrating immune cell	 2019 May 15	Automatic discovery of image-based signatures for ipilimumab response prediction in malignant melanoma.	 Sci Rep	In the context of precision medicine with immunotherapies there is an increasing need for companion diagnostic tests to identify potential therapy responders and avoid treatment coming along with severe adverse events for non-responders. Here, we present a retrospective case study to discover image-based signatures for developing a potential companion diagnostic test for ipilimumab (IPI) in malignant melanoma. Signature discovery is based on digital pathology and fully automatic quantitative image analysis using virtual multiplexing as well as machine learning and deep learning on whole-slide images. We systematically correlated the patient outcome data with potentially relevant local image features using a Tissue Phenomics approach with a sound cross validation procedure for reliable performance evaluation. Besides uni-variate models we also studied combinations of signatures in several multi-variate models. The most robust and best performing model was a decision tree model based on relative densities of CD8+ tumor infiltrating lymphocytes in the intra-tumoral infiltration region. Our results are well in agreement with observations described in previously published studies regarding the predictive value of the immune contexture, and thus, provide predictive potential for future development of a companion diagnostic test.
CANIT0002481	31096532	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	11465	N/A	Meta-analysis	The meta-analysis concluded that anti PD-1/PD-L1 drugs have different dermatological and mucosal safety profile compared to conventional therapy, and differences of dermatological toxicity between PD-1 and PD-L1 inhibitor warrant further investigation.	Dermatologic and mucosal adverse events	N/A	N/A	N/A	N/A	N/A	 2019 May	Risk of dermatologic and mucosal adverse events associated with PD-1/PD-L1 inhibitors in cancer patients: A meta-analysis of randomized controlled trials.	 Medicine (Baltimore)	BACKGROUND: Programmed death 1 protein (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are promising cancer immunotherapy. Their dermatologic safety profiles are still poorly understood. The purpose of this article is to evaluate the incidence of selected dermatologic and mucosal adverse effects (AEs) and determine the risk of developing these adverse events associated with PD-1/PD-L1 inhibitors, compared with chemotherapy or ipilimumab.METHODS: PubMed was searched for eligible studies (up to February 21, 2019). Only phase II and phase III randomized controlled trials (RCTs) compared with chemotherapy or ipilimumab monotherapy were included in this meta-analysis.RESULTS: A total 11,465 patients from 18 clinical trials were included in this meta-analysis. Rash and pruritus were the most frequently reported dermatologic AE, with incidence 11.8% and 12.2% respectively. Compared with patients receiving chemotherapy, PD-1/PD-L1 inhibitor treated patients had higher risk of developing rash (RR = 1.84), pruritus (RR = 3.74) and vitiligo (RR = 9.54), and also lower risk in developing mucosal inflammation (RR = 0.26), stomatitis (RR = 0.26), and alopecia (RR = 0.03). Additionally, anti-PD1/PD-L1 drugs had similar risk of developing rash and lower risk of inducing pruritus compared to ipilimumab. In the subgroup analysis, PD-L1 inhibitor demonstrated better safety than PD-1 inhibitor in developing rash, with RR = 1.38 and RR = 2.11, respectively.CONCLUSION: Our meta-analysis concluded that anti PD-1/PD-L1 drugs have different dermatological and mucosal safety profile compared to conventional therapy, and differences of dermatological toxicity between PD-1 and PD-L1 inhibitor warrant further investigation.
CANIT0002482	31097082	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-A levels were significantly lower. In immune related adverse events (irAEs) patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE. Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.	N/A	N/A	N/A	BMP-9 (Q9UK05); 	Baseline serum BMP-9 levels	Gene expression signature in serum	 2019 Jun	Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab.	 Lung Cancer	BACKGROUND: Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.PATIENTS AND METHODS: Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.RESULTS: Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-a levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.CONCLUSION: Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.
CANIT0002483	31097082	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-A levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.	N/A	N/A	N/A	FSTL3 (O95633); 	Baseline serum follistatin levels	Gene expression signature in serum	 2019 Jun	Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab.	 Lung Cancer	BACKGROUND: Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.PATIENTS AND METHODS: Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.RESULTS: Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-a levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.CONCLUSION: Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.
CANIT0002484	31097082	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-A levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.	N/A	N/A	N/A	G-CSF (Q99062); 	Serum GM-CSF levels at week 4	Gene expression signature in serum	 2019 Jun	Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab.	 Lung Cancer	BACKGROUND: Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.PATIENTS AND METHODS: Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.RESULTS: Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-a levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.CONCLUSION: Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.
CANIT0002485	31097082	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-A levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.	N/A	N/A	N/A	IL8 (P10145); 	Serum IL8 expression levels	Gene expression signature in serum	 2019 Jun	Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab.	 Lung Cancer	BACKGROUND: Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.PATIENTS AND METHODS: Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.RESULTS: Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-a levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.CONCLUSION: Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.
CANIT0002486	31097082	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-A levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.	N/A	N/A	N/A	IP10 (P02778); 	Baseline serum IP10 levels	Gene expression signature in serum	 2019 Jun	Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab.	 Lung Cancer	BACKGROUND: Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.PATIENTS AND METHODS: Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.RESULTS: Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-a levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.CONCLUSION: Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.
CANIT0002487	31097082	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-A levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.	N/A	N/A	N/A	LEP (P41159); 	Serum leptin levels at week 4	Gene expression signature in serum	 2019 Jun	Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab.	 Lung Cancer	BACKGROUND: Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.PATIENTS AND METHODS: Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.RESULTS: Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-a levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.CONCLUSION: Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.
CANIT0002488	31097082	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-A levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.	N/A	N/A	N/A	RANTES (P13501); 	Serum RANTES levels at week 4	Gene expression signature in serum	 2019 Jun	Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab.	 Lung Cancer	BACKGROUND: Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.PATIENTS AND METHODS: Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.RESULTS: Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-a levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.CONCLUSION: Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.
CANIT0002489	31097082	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	38	N/A	N/A	In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-A levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.	N/A	N/A	N/A	TNFA (P01375); 	Baseline serum TNFA levels	Gene expression signature in serum	 2019 Jun	Predictive value of serum protein levels in patients with advanced non-small cell lung cancer treated with nivolumab.	 Lung Cancer	BACKGROUND: Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.PATIENTS AND METHODS: Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.RESULTS: Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-a levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.CONCLUSION: Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.
CANIT0002490	31098752	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); INAR1 (P17181); 	CTLA-4; INAR1	Ipilimumab or IFNA	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); IFNA (DB00018); 	161	N/A	Retrospective analysis	Cases of permanent visual loss were observed; yet, in the majority of side effects, they improved with topical therapy and/or holding the medication. Further research is needed to elucidate the incidence and the pathophysiology of these side effects and maximize patient quality of life.	Ocular toxicity	N/A	N/A	N/A	N/A	N/A	 2019 Aug	Known and novel ocular toxicities of biologics, targeted agents, and traditional chemotherapeutics.	 Graefes Arch Clin Exp Ophthalmol	PURPOSE: Increases in cancer with an aging population and the rapid development of new chemotherapeutics underscore the need for ophthalmologists to identify and manage potential ocular toxicities. This retrospective case series reports the ocular side effects of traditional and novel chemotherapeutic agents from a large center.METHODS: The medical records of 3537 adult patients 18 years and older who presented to an academic ophthalmology department on high-risk medications identified by ICD-9 search between January 2010 and February 2015 were reviewed. A cancer diagnosis, as well as a temporal association with chemotherapeutic use and ocular side effect, was deemed necessary for inclusion in the study. The main measures were ocular side effects in cancer patients taking chemotherapy, ocular imaging abnormalities, and the outcome of each side effect.RESULTS: Of the 161 oncology patients referred to the ophthalmology clinic for chemotherapeutic screening or ocular side effect, 31 (19.3%) were identified as having an ocular adverse reaction due to a novel or traditional chemotherapeutic medication. A novel flattening of the corneal curvature with hyperopic shift and corneal microcysts was identified in a patient taking the antibody-drug conjugate mirvetuximab soravtansine and was reversible with topical steroids. A bilateral medium-vessel choroidal vasculopathy with serous retinal detachment was seen with ipilimumab. The most frequent medication with ocular toxicity was interferon-a(2b) (IFN-a(2b)) (6/31, 19.4%); headache was typical in these patients (83.3%). Ibrutinib ocular toxicity was second most common (5/31, 16.1%), usually causing red or dry eye, while one patient developed branch retinal artery occlusion. Retinal abnormalities documented on OCT imaging occurred with IFN-a(2b), ipilimumab, binimetinib, and docetaxel, while rod-cone ERG abnormality was seen with cisplatin. Inflammatory conditions included anterior scleritis with zoledronic acid, focal eyelid inflammation with veliparib, bilateral chemosis with R-CHOP, iritis, and blepharospasm with IFN-a(2b). AION occurred with pemetrexed, and transient vision loss with hyperemic disc OS was seen with FOLFOX. Two patients (2/31, 6.5%) developed permanent vision loss. Six patients were lost to follow-up, and the clinical course was unknown (6/31, 19.4%).CONCLUSIONS AND RELEVANCE: Cases of permanent visual loss were observed; yet, in the majority of side effects, they improved with topical therapy and/or holding the medication. Further research is needed to elucidate the incidence and the pathophysiology of these side effects and maximize patient quality of life.
CANIT0002491	31098955	Basic research	Lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Pembrolizumab plus crizotinib	N/A	Immune cytokine plus Target therapy	Pembrolizumab (DB09037); crizotinib (DB08865); 	Cell lines	N/A	Basic research	ALK translocation can upregulate PD-L1 expression by activating ERK, STAT3 and AKT pathways. ALK inhibitor combined with a PD-L1-targeted therapy may be a potential strategy in ALK-translocated lung adenocarcinoma patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	ALK (Q9UM73); 	ALK translocation	Mutational status	 2019 Jun	PD-L1 Expression and Its Regulation in Lung Adenocarcinoma with ALK Translocation.	 Interdiscip Sci	BACKGROUND: The mechanism of regulation of PD-L1 expression by ALK translocation remains unclear. We detected PD-L1 protein expression and its regulation in lung adenocarcinoma patients with EML4-ALK fusion gene.METHODS: PD-L1 and ALK expression at protein level in human lung adenocarcinoma cell lines and tumor tissue specimens was evaluated by immunohistochemistry analysis and Western blotting. The expression at DNA level and RNA level was indicated by quantitative real-time PCR analysis. The signal pathway was indicated at protein level by western blotting.RESULTS: The PD-L1 protein expression was higher in human lung adenocarcinoma cell lines with EML4-ALK fusion gene than that without this fusion gene. Induced expression of EML4-ALK in A549 cells significantly increased PD-L1 protein expression, whereas PD-L1 protein expression was downregulated after crizotinib and pembrolizumab successively. Significant positive correlations between PD-L1 and p-ERK, p-STAT3 or p-AKT expression were observed in ALK-translocated tumors. PD-L1 overexpression was significantly associated with shorter progressive survival and overall survival after crizotinib in ALK-translocated patients.CONCLUSIONS: We demonstrate that ALK translocation can upregulate PD-L1 expression by activating ERK, STAT3 and AKT pathways. ALK inhibitor combined with a PD-L1-targeted therapy may be a potential strategy in ALK-translocated lung adenocarcinoma patients.
CANIT0002492	31100038	Clinical research	Unresectable locally advanced or metastatic urothelial carcinoma	Urothelial carcinoma	EFO:0008528	Bladder	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab followed by nivolumab	Nivolumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	196	78	An open-label, phase I/II multicenter study	Objective response rate was 25.6%, 26.9%, and 38.0% in the nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3) arms, respectively. Median duration of response was more than 22 months in all arms.	Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms.	N/A	N/A	N/A	N/A	N/A	 2019 Jul 1	Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results.	 J Clin Oncol	PURPOSE: CheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts.METHODS: Patients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response.RESULTS: Seventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms.CONCLUSION: With longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.
CANIT0002493	31101577	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Retrospective analysis	A total of 77 patients had Grade >=2 mucositis during therapy with sunitinib (n = 29), pazopanib (n = 24), everolimus (n = 10), axitinib (n = 4), temsirolimus (n = 3), interleukin-2/interferon-A (n = 3), cabozantinib (n = 2), bevacizumab (n = 1), and nivolumab (n = 1). Given in doses of 1 to 5 mg daily, folic acid significantly reduced mucositis, mean CTCAE grade 0.88 (95% confidence interval [CI], 0.74-1.03) versus 2.38 (95% CI, 2.26-2.54; P < .0001). Stratified according to treatment, folic acid significantly reduced mucositis grade for sunitinib (0.97 [95% CI, 0.75-1.18] vs. 2.45 [95% CI, 2.23-2.67], P < .0001), pazopanib (0.96 [95% CI, 0.67-1.25] vs. 2.20 [2.03-2.38], P < .0001), everolimus (0.60 [95% CI, 0.10-1.10] vs. 2.60 [95% CI, 2.23-2.97], P < .0001), and other treatments (0.79 [95% CI, 0.38-1.19] vs. 2.36 [95% CI, 2.07-2.64], P < .0001). Of the 77 patients, 8 (10%) patients received dose reduction. Overall progression-free survival was 14 months and overall survival was 31 months.Folic acid reduced mucositis in mRCC patients receiving systemic therapy. This finding needs prospective validation. A double-blind, placebo-controlled prospective evaluation of folic acid is ongoing (NCT03581773).	Mucositis	N/A	N/A	N/A	N/A	N/A	 2019 Aug	Folic Acid Reduces Mucositis in Metastatic Renal Cell Carcinoma Patients: A Retrospective Study.	 Clin Genitourin Cancer	BACKGROUND: Mucositis is often experienced in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies. This might impair daily quality of life and lead to dose reduction, discontinuation, or treatment shift. We assessed the effect of folic acid to reduce mucositis.PATIENTS AND METHODS: Patients treated with systemic therapy for mRCC who developed Grade >=2 mucositis according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) received oral folic acid to reduce mucositis. The medical charts were retrospectively reviewed.RESULTS: A total of 77 patients had Grade >=2 mucositis during therapy with sunitinib (n = 29), pazopanib (n = 24), everolimus (n = 10), axitinib (n = 4), temsirolimus (n = 3), interleukin-2/interferon-a (n = 3), cabozantinib (n = 2), bevacizumab (n = 1), and nivolumab (n = 1). Given in doses of 1 to 5 mg daily, folic acid significantly reduced mucositis, mean CTCAE grade 0.88 (95% confidence interval [CI], 0.74-1.03) versus 2.38 (95% CI, 2.26-2.54; P < .0001). Stratified according to treatment, folic acid significantly reduced mucositis grade for sunitinib (0.97 [95% CI, 0.75-1.18] vs. 2.45 [95% CI, 2.23-2.67], P < .0001), pazopanib (0.96 [95% CI, 0.67-1.25] vs. 2.20 [2.03-2.38], P < .0001), everolimus (0.60 [95% CI, 0.10-1.10] vs. 2.60 [95% CI, 2.23-2.97], P < .0001), and other treatments (0.79 [95% CI, 0.38-1.19] vs. 2.36 [95% CI, 2.07-2.64], P < .0001). Of the 77 patients, 8 (10%) patients received dose reduction. Overall progression-free survival was 14 months and overall survival was 31 months.CONCLUSION: Folic acid reduced mucositis in mRCC patients receiving systemic therapy. This finding needs prospective validation. A double-blind, placebo-controlled prospective evaluation of folic acid is ongoing (NCT03581773).
CANIT0002494	31104989	Clinical research	81 patients were identified. Of these, 73 were treated with platinum-based chemotherapy based on the PACIFIC study criteria.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Chemoradiotherapy followed by durvalumab	N/A	Chemoradiotherapy followed by Immune checkpoint therapy	Durvalumab (DB11714); Chemoradiotherapy (NCIT:C94626); 	73	N/A	Retrospective analysis	Approximately 70% of patients with unresectable stage III NSCLC would be eligible to receive consolidation therapy with durvalumab.	12 (16.4%) developed radiation pneumonitis of grade 2 or more within 42 days after chemoradiotherapy and were excluded from durvalumab treatment. Two patients (2.7%) developed other pneumonitis, seven patients (9.6%) showed poor performance status, and three patients (4.1%) displayed disease progression at the initial assessment	N/A	N/A	Radiation pneumonitis (EFO:1001411); 	Radiation pneumonitis	Disease status	 2019 Sep	Patients with unresectable stage III non-small cell lung cancer eligible to receive consolidation therapy with durvalumab in clinical practice based on PACIFIC study criteria.	 Respir Investig	BACKGROUND: Compared to a placebo, durvalumab has been reported to significantly prolong progression-free and overall survival in patients with stage III unresectable non-small cell lung cancer (NSCLC) after chemoradiotherapy. The aim of this retrospective study was to evaluate the eligibility of patients with unresectable stage III NSCLC able to receive consolidation therapy with durvalumab in clinical practice based on the PACIFIC study criteria.METHODS: From January 2011 to May 2018, electronic data were collected from patients diagnosed with unresectable stage III NSCLC treated with definitive chemoradiotherapy. A total of 81 patients were identified. Of these, 73 were treated with platinum-based chemotherapy based on the PACIFIC study criteria.RESULTS: Radiation pneumonitis of any grade occurred in 54 patients (73.9%) who received definitive chemoradiotherapy. Of these, 12 (16.4%) developed radiation pneumonitis of grade 2 or more within 42 days after chemoradiotherapy and were excluded from durvalumab treatment. Two patients (2.7%) developed other pneumonitis, seven patients (9.6%) showed poor performance status, and three patients (4.1%) displayed disease progression at the initial assessment. After considering overlapping cases mentioned above, 22 patients (30.1%) were ineligible to receive durvalumab by the criteria utilized in the PACIFIC study.CONCLUSION: In clinical practice, approximately 70% of patients with unresectable stage III NSCLC would be eligible to receive consolidation therapy with durvalumab.
CANIT0002495	31108244	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); IL2R (A2N4P8); INAR1 (P17181); 	CTLA-4 ;  IL2R ;  INAR1 	Ipilimumab plus IL2 plus IFNA	IL2 plus IFN	Immune checkpoint therapy plus Immune cytokine	Ipilimumab (DB06186); IFNA (DB00018); IL2 (NCIT:C24498); 	232	232	N/A	One hundred eighteen patients (25%) obtained an objective response rate (ORR) to treatment with a median progression-free survival (PFS) of 3.4 months and a median overall survival (OS) of 14.2 months. Furthermore, 2-, 3- and 5-year survival was 32.0%, 23.2% and 16.6%, respectively. Ipilimumab as second-line therapy has been used since July 2010. We divided patients in two subgroups before and after this date to evaluate the effects of new treatment strategies. Patient characteristics, ORR and PFS were comparable in the two subgroups. Survival was significantly improved after 2010, with an increase in median OS from 12.2 to 16.0 months and in 5-year OS from 12.5% to 20.7%.data confirm that HD IL-2/IFN as first-line therapy in metastatic melanoma leads to long-term survival in a subset of treated patients. Potentially, IL-2/IFN might represent a treatment option in patients with active melanoma after established initial treatment with checkpoint inhibitors and BRAF/MEK-targeted therapies.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	High-dose interleukin-2 and interferon as first-line immunotherapy for metastatic melanoma: long-term follow-up in a large unselected Danish patient cohort.	 Eur J Cancer	BACKGROUND AND PATIENTS: Between January 2007 and April 2014, 464 Danish patients received high-dose (HD) interleukin-2 (IL-2) and interferon (IFN) as first-line treatment for metastatic melanoma. Our data represent the largest cohort of patients with metastatic melanoma worldwide, with relevant data on all patients and no patients lost to follow-up. Data have been gathered in a national database on the treatment of metastatic melanoma established since 2011.RESULTS: One hundred eighteen patients (25%) obtained an objective response rate (ORR) to treatment with a median progression-free survival (PFS) of 3.4 months and a median overall survival (OS) of 14.2 months. Furthermore, 2-, 3- and 5-year survival was 32.0%, 23.2% and 16.6%, respectively. Ipilimumab as second-line therapy has been used since July 2010. We divided patients in two subgroups before and after this date to evaluate the effects of new treatment strategies. Patient characteristics, ORR and PFS were comparable in the two subgroups. Survival was significantly improved after 2010, with an increase in median OS from 12.2 to 16.0 months and in 5-year OS from 12.5% to 20.7%.CONCLUSIONS: Our data confirm that HD IL-2/IFN as first-line therapy in metastatic melanoma leads to long-term survival in a subset of treated patients. Potentially, IL-2/IFN might represent a treatment option in patients with active melanoma after established initial treatment with checkpoint inhibitors and BRAF/MEK-targeted therapies.
CANIT0002496	31112568	Basic research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); IDO1 (P14902); 	CTLA-4 ;  PD-1 ;  IDO1 	Ipilimumab or Nivolumab plus 9D9 plus epacadostat 	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); Nivolumab (DB09035); epacadostat (DB11717); 	Cell lines/ animal models	N/A	Basic research	Co-administration of CTLA-4 blocking antibody, 9D9, and/or an IDO1 inhibitor, epacadostat in wild-type and PD-1-/- mice (to simulate the effect of PD1 blockade) synergistically induced liver injury and immune cell infiltration. Infiltrated cells were primarily composed of CD8+ T cells and positively associated with hepatocyte necrosis. Strikingly, sites of hepatocyte necrosis were frequently surrounded by clusters of mononuclear immune cells. CPI treatments resulted in increased expression of genes associated with hepatocyte cell death, leukocyte migration and T cell activation in the liver. In conclusion, blockade of immune checkpoints PD-1, CTLA-4, and IDO1 act synergistically to enhance T cell infiltration and activity in the liver, leading to hepatocyte death.	Liver injury	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 May 21	Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice.	 PLoS One	Cancer cells harness immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase 1 (IDO1) to evade immune control. Checkpoint inhibitors have demonstrated durable anti-tumor efficacy in human and preclinical models. Liver toxicity is one of the common immune-related adverse events associated with checkpoint inhibitors (CPIs) and its frequency and severity often increase significantly during CPI combination therapies. We aim to develop a mouse model to elucidate the immune mechanisms of CPI-associated liver toxicity. Co-administration of CTLA-4 blocking antibody, 9D9, and/or an IDO1 inhibitor, epacadostat in wild-type and PD-1-/- mice (to simulate the effect of PD1 blockade) synergistically induced liver injury and immune cell infiltration. Infiltrated cells were primarily composed of CD8+ T cells and positively associated with hepatocyte necrosis. Strikingly, sites of hepatocyte necrosis were frequently surrounded by clusters of mononuclear immune cells. CPI treatments resulted in increased expression of genes associated with hepatocyte cell death, leukocyte migration and T cell activation in the liver. In conclusion, blockade of immune checkpoints PD-1, CTLA-4, and IDO1 act synergistically to enhance T cell infiltration and activity in the liver, leading to hepatocyte death.
CANIT0002497	31116807	Case report	An 87-year-old woman with stage IV non-small cell lung cancer 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We report an 87-year-old woman with stage IV non-small cell lung cancer who developed a bullous eruption on the trunk and extremities. Biopsy of the lesions revealed a subepidermal bullous lichenoid eruption with positive immunofluorescence in a linear pattern at the basement membrane zone, consistent with lichen planus pemphigoides (LPP). The patient improved with oral prednisone and cessation of nivolumab therapy.	Lichen planus pemphigoides	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Nivolumab-induced lichen planus pemphigoides.	 Cutis	Programmed cell death 1 (PD-1) receptor inhibitors, such as nivolumab, are used in the treatment of non-small cell lung cancers, melanoma, and other cancers. Cutaneous adverse events (AEs) associated with anti-PD-1 therapy have been widely documented. Although cutaneous AEs often are mild, some patients can develop notable morbidity. We report an 87-year-old woman with stage IV non-small cell lung cancer who developed a bullous eruption on the trunk and extremities. Biopsy of the lesions revealed a subepidermal bullous lichenoid eruption with positive immunofluorescence in a linear pattern at the basement membrane zone, consistent with lichen planus pemphigoides (LPP). The patient improved with oral prednisone and cessation of nivolumab therapy.
CANIT0002498	31120392	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	Retrospective analysis	Most single parameters failed to reflect treatment benefit. Three laboratory parameters (lactate dehydrogenase, C-reactive protein and the neutrophil/lymphocyte ratio) combined in a weighted score could predict benefit with a sensitivity of 92.3% and a hazard ratio of 0.31 (95% CI: 0.16-0.59) in an early phase of therapy. Sorting patients by score showed a 1-year survival of 36% in those predicted as not benefitting versus 68% in those predicted to benefit.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Jun	Monitoring efficacy of checkpoint inhibitor therapy in patients with non-small-cell lung cancer.	 Immunotherapy	Aim: Radiological criteria alone do not reflect the entire population benefitting from checkpoint inhibitor therapy (CIT). This study aimed to detect patterns to assess CIT efficacy in non-small-cell lung cancer (NSCLC) patients. Materials & methods: We evaluated clinical, radiological and laboratory parameters in a retrospective cohort of NSCLC patients treated with nivolumab. Results: A total of 51 patients were included in the analysis. Most single parameters failed to reflect treatment benefit. Three laboratory parameters (lactate dehydrogenase, C-reactive protein and the neutrophil/lymphocyte ratio) combined in a weighted score could predict benefit with a sensitivity of 92.3% and a hazard ratio of 0.31 (95% CI: 0.16-0.59) in an early phase of therapy. Sorting patients by score showed a 1-year survival of 36% in those predicted as not benefitting versus 68% in those predicted to benefit. Conclusion: A weighted score integrating common serum markers could help detect patients benefitting from checkpoint inhibitors during ongoing CIT.
CANIT0002499	31120392	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	Retrospective analysis	Most single parameters failed to reflect treatment benefit. Three laboratory parameters (lactate dehydrogenase, C-reactive protein and the neutrophil/lymphocyte ratio) combined in a weighted score could predict benefit with a sensitivity of 92.3% and a hazard ratio of 0.31 (95% CI: 0.16-0.59) in an early phase of therapy. Sorting patients by score showed a 1-year survival of 36% in those predicted as not benefitting versus 68% in those predicted to benefit.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Jun	Monitoring efficacy of checkpoint inhibitor therapy in patients with non-small-cell lung cancer.	 Immunotherapy	Aim: Radiological criteria alone do not reflect the entire population benefitting from checkpoint inhibitor therapy (CIT). This study aimed to detect patterns to assess CIT efficacy in non-small-cell lung cancer (NSCLC) patients. Materials & methods: We evaluated clinical, radiological and laboratory parameters in a retrospective cohort of NSCLC patients treated with nivolumab. Results: A total of 51 patients were included in the analysis. Most single parameters failed to reflect treatment benefit. Three laboratory parameters (lactate dehydrogenase, C-reactive protein and the neutrophil/lymphocyte ratio) combined in a weighted score could predict benefit with a sensitivity of 92.3% and a hazard ratio of 0.31 (95% CI: 0.16-0.59) in an early phase of therapy. Sorting patients by score showed a 1-year survival of 36% in those predicted as not benefitting versus 68% in those predicted to benefit. Conclusion: A weighted score integrating common serum markers could help detect patients benefitting from checkpoint inhibitors during ongoing CIT.
CANIT0002500	31120392	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	51	N/A	Retrospective analysis	Most single parameters failed to reflect treatment benefit. Three laboratory parameters (lactate dehydrogenase, C-reactive protein and the neutrophil/lymphocyte ratio) combined in a weighted score could predict benefit with a sensitivity of 92.3% and a hazard ratio of 0.31 (95% CI: 0.16-0.59) in an early phase of therapy. Sorting patients by score showed a 1-year survival of 36% in those predicted as not benefitting versus 68% in those predicted to benefit.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Jun	Monitoring efficacy of checkpoint inhibitor therapy in patients with non-small-cell lung cancer.	 Immunotherapy	Aim: Radiological criteria alone do not reflect the entire population benefitting from checkpoint inhibitor therapy (CIT). This study aimed to detect patterns to assess CIT efficacy in non-small-cell lung cancer (NSCLC) patients. Materials & methods: We evaluated clinical, radiological and laboratory parameters in a retrospective cohort of NSCLC patients treated with nivolumab. Results: A total of 51 patients were included in the analysis. Most single parameters failed to reflect treatment benefit. Three laboratory parameters (lactate dehydrogenase, C-reactive protein and the neutrophil/lymphocyte ratio) combined in a weighted score could predict benefit with a sensitivity of 92.3% and a hazard ratio of 0.31 (95% CI: 0.16-0.59) in an early phase of therapy. Sorting patients by score showed a 1-year survival of 36% in those predicted as not benefitting versus 68% in those predicted to benefit. Conclusion: A weighted score integrating common serum markers could help detect patients benefitting from checkpoint inhibitors during ongoing CIT.
CANIT0002501	31121324	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1426	N/A	Phase 3B/4 study	The median overall survival time was comparable in the overall population (9.1 months) and patients aged 70 years or older (10.3 months) but shorter in patients with an ECOG PS of 2 (4.0 months). Patient-reported outcomes generally improved. Data from this large predominantly community-based study, which included patients aged 70 years or older and with an ECOG PS of 2, are consistent with registrational studies. As expected, the median overall survival for patients with an ECOG PS of 2 was lower than for the overall population but comparable with historical data.	Across subgroups and the overall population, the incidences of select grade 3 to 5 TRAEs (6%-9%) and grade 3 or 4 TRAEs (12%-14%) were similar. One grade 5 TRAE was documented.	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Sep	Safety, Efficacy, and Patient-Reported Health-Related Quality of Life and Symptom Burden with Nivolumab in Patients with Advanced Non-Small Cell Lung Cancer, Including Patients Aged 70 Years or Older or with Poor Performance Status (CheckMate 153).	 J Thorac Oncol	INTRODUCTION: CheckMate 153 (NCT02066636) is a phase 3B/4 study assessing nivolumab in previously treated patients with advanced NSCLC. Eligibility criteria allowed enrollment of patients with poor prognostic features of advanced age or diminished Eastern Cooperative Oncology Group performance status (ECOG PS), which are typically underrepresented in or excluded from randomized controlled trials.METHODS: Patients with stage IIIB or IV NSCLC and an ECOG PS of 0 to 2 with disease progression after at least one systemic therapy received nivolumab (3 mg/kg every 2 weeks) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was the incidence of grade 3 to 5 select treatment-related adverse events (TRAEs).RESULTS: Among 1426 treated patients, 556 (39%) were aged 70 years or older and 128 (9%) had an ECOG PS of 2. The median treatment duration was 3.2 months. Across subgroups and the overall population, the incidences of select grade 3 to 5 TRAEs (6%-9%) and grade 3 or 4 TRAEs (12%-14%) were similar. One grade 5 TRAE was documented. The median overall survival time was comparable in the overall population (9.1 months) and patients aged 70 years or older (10.3 months) but shorter in patients with an ECOG PS of 2 (4.0 months). Patient-reported outcomes generally improved.CONCLUSIONS: Data from this large predominantly community-based study, which included patients aged 70 years or older and with an ECOG PS of 2, are consistent with registrational studies. As expected, the median overall survival for patients with an ECOG PS of 2 was lower than for the overall population but comparable with historical data.
CANIT0002502	31122866	Case report	A 58-year-old woman	Lung adenocarcinoma	EFO:0000571	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1	N/A	Case	The results provide the first evidence that immune checkpoint blockade may induce a comprehensive systemic alteration in the myeloid compartment in patients with lung cancer, probably through a progressive reduction of tumor burden and relief of tumor-induced immunosuppression. With this analysis, we demonstrated that tracking the immune environment is potentially feasible in daily clinical practice in order to characterize the dynamics of systemic immunologic factors during immunotherapy and evaluate their prognostic/predictive potential and applicability as surrogate markers for clinical response	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Jul	Characterization of Myeloid-derived Suppressor Cells in a Patient With Lung Adenocarcinoma Undergoing Durvalumab Treatment: A Case Report.	 Clin Lung Cancer	Unable to provide
CANIT0002503	31128053	Case report	A 67-year-old Caucasian Italian female	Adenocarcinoma	EFO:0000228	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The patient is still alive 41 months from the diagnosis of three cancers with good performance status (ECOG 0) and quality of lif.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar-Apr	Amazing result of Nivolumab in a patient with multiple carcinoma.	 J BUON	Unable to provide
CANIT0002504	31128053	Case report	A 67-year-old Caucasian Italian female	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The patient is still alive 41 months from the diagnosis of three cancers with good performance status (ECOG 0) and quality of lif.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar-Apr	Amazing result of Nivolumab in a patient with multiple carcinoma.	 J BUON	Unable to provide
CANIT0002505	31128053	Case report	A 67-year-old Caucasian Italian female	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The patient is still alive 41 months from the diagnosis of three cancers with good performance status (ECOG 0) and quality of lif.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar-Apr	Amazing result of Nivolumab in a patient with multiple carcinoma.	 J BUON	Unable to provide
CANIT0002506	31135622	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We present a patient who developed a severe and fatal relapse of postvaccination GBS after he was treated with nivolumab, a monoclonal antibody directed to programmed death-1 (PD-1), during a GBS treatment-related fluctuation.	Severe Relapse of Vaccine-Induced Guillain-Barr¨¦ Syndrome	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Severe Relapse of Vaccine-Induced Guillain-Barr¨¦ Syndrome After Treatment With Nivolumab.	 J Clin Neuromuscul Dis	Cancer immunotherapy with checkpoint inhibitors may result in neuromuscular immune-related adverse reactions, including Guillain-Barr¨¦ syndrome (GBS)-like disease. On the other hand, checkpoint inhibitor therapy may result in exacerbation of underlying autoimmune diseases such as myasthenia gravis and multiple sclerosis. We present a patient who developed a severe and fatal relapse of postvaccination GBS after he was treated with nivolumab, a monoclonal antibody directed to programmed death-1 (PD-1), during a GBS treatment-related fluctuation. We recommend that caution be exercised in starting treatment with PD-1 inhibitors in the acute stage or early in the recovery period of GBS.
CANIT0002507	31140644	Case report	Hodgkin's Lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Here, we report a patient with relapsed Hodgkin's Lymphoma who received nivolumab prior to autologous stem cell mobilization. She went on to develop cytokine storm shortly following transplantation, with marked T-cell proliferation coincident with myeloid engraftment. Non-cardiogenic pulmonary edema and alveolar hemorrhage developed despite corticosteroid therapy. There was rapid and complete resolution of these complications with parenteral ascorbic acid infusion.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Aug	Hematopoietic stem cell mobilization following PD-1 blockade: Cytokine release syndrome after transplantation managed with ascorbic acid.	 Eur J Haematol	Checkpoint inhibitor therapy is effective in the treatment of relapsed classical Hodgkin's Lymphoma. Here, we report a patient with relapsed Hodgkin's Lymphoma who received nivolumab prior to autologous stem cell mobilization. She went on to develop cytokine storm shortly following transplantation, with marked T-cell proliferation coincident with myeloid engraftment. Non-cardiogenic pulmonary edema and alveolar hemorrhage developed despite corticosteroid therapy. There was rapid and complete resolution of these complications with parenteral ascorbic acid infusion. Our case illustrates the risk of cytokine release syndrome following infusion of stem cells mobilized after checkpoint inhibitor therapy and the role of ascorbic acid in its management.
CANIT0002508	31142711	Case report	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	An 84-year-old woman developed blepharoptosis, diplopia, weakness of extremities, and dysphagia with elevation of serum CK levels after treatment with nivolumab against renal cell carcinoma. 3 Hz repetitive stimulation showed waning in the trapezius muscle, leading to the diagnosis of myasthenia gravis. Laboratory examination showed that anti-acetylcholine receptor antibody was negative. We performed IVIg and steroid therapy. However, her symptoms did not improve, and she died of respiratory failure, although serum CK levels ameliorated to the normal range. The results of autopsy showed atrophy of muscle fibers and massive infiltration of inflammatory cells in the endomysium of the iliopsoas muscle and diaphragm, indicating occurrence of myositis. Immunohistochemical analysis showed that CD8-positive T cells mainly infiltrates in the endomysium with a small number of CD4-potive T cells.	Nivolumab-induced myasthenia gravis and myositis	N/A	N/A	CD4 (P01730); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8-positive T-cells mainly infiltrates in the endomysium with a small number of CD4-potive T-cells	Gene expression signature on/in immune cell	 2019 Jun 22	[An autopsy case of nivolumab-induced myasthenia gravis and myositis].	 Rinsho Shinkeigaku	An 84-year-old woman developed blepharoptosis, diplopia, weakness of extremities, and dysphagia with elevation of serum CK levels after treatment with nivolumab against renal cell carcinoma. 3 Hz repetitive stimulation showed waning in the trapezius muscle, leading to the diagnosis of myasthenia gravis. Laboratory examination showed that anti-acetylcholine receptor antibody was negative. We performed IVIg and steroid therapy. However, her symptoms did not improve, and she died of respiratory failure, although serum CK levels ameliorated to the normal range. The results of autopsy showed atrophy of muscle fibers and massive infiltration of inflammatory cells in the endomysium of the iliopsoas muscle and diaphragm, indicating occurrence of myositis. Immunohistochemical analysis showed that CD8-positive T cells mainly infiltrates in the endomysium with a small number of CD4-potive T cells. Here, we report an autopsy case of nivolumab-induced myasthenia gravis and myositis.
CANIT0002509	31154669	Clinical research	18 patients were included, with 72% of them (13 of 18 patients) previously treated with sorafenib. 	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	18	N/A	Retrospective analysis	Patients with Child-Pugh class B (CPB) hepatocellular carcinoma experienced high rates of AEs, although the frequency of immune-related adverse events was similar to that of patients with Child-Pugh class A HCC in the CheckMate 040 trial. A subset of patients experienced prolonged tumor responses. Nivolumab warrants further study in patients with CPB HCC.	IrAEs were reported to occur in approximately 50% of patients (9 of 18 patients), and 28% (5 of 18 patients) required steroids. Treatment-related AEs required discontinuation in 4 patients (22%)	N/A	N/A	N/A	N/A	N/A	 2019 Sep 15	Nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis: Safety and clinical outcomes in a retrospective case series.	 Cancer	BACKGROUND: Nivolumab demonstrated durable responses and safety in patients with hepatocellular carcinoma (HCC) with Child-Pugh class A cirrhosis in the CheckMate 040 trial, with rates of hepatotoxicity that were similar to those of non-HCC populations. To the authors' knowledge, the safety and efficacy of nivolumab has not been established in patients with Child-Pugh class B (CPB) cirrhosis, a population with limited therapeutic options and a poor prognosis.METHODS: The authors conducted a retrospective case series of patients with advanced HCC and CPB cirrhosis who were treated with nivolumab and enrolled in the University of California at San Francisco Hepatobiliary Tissue Bank and Registry. Safety endpoints included rates of grade >=3 adverse events (AEs) (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) and serious AEs, immune-related AEs (irAE), steroid requirement, and discontinuation. Efficacy endpoints included time on treatment, the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, overall survival, and progression-free survival.RESULTS: A total of 18 patients were included, with 72% of them (13 of 18 patients) previously treated with sorafenib. The majority of patients (94%; 17 of 18 patients) experienced a grade >=3 AE, with treatment-related grade >=3 AEs reported in 28% of patients (5 of 18 patients). irAEs were reported to occur in approximately 50% of patients (9 of 18 patients), and 28% (5 of 18 patients) required steroids. Treatment-related AEs required discontinuation in 4 patients (22%). The median time on treatment was 2.3 months (95% CI, 1.9 months to upper bound not estimable). The objective response rate was 17% (3 of 18 patients), including 2 partial responses and 1 complete response. The median overall survival from the time of nivolumab initiation was 5.9 months (95% CI, 3 months to upper bound not estimable), with a median progression-free survival of 1.6 months (95% CI, 1.4-3.5 months).CONCLUSIONS: Patients with CPB HCC experienced high rates of AEs, although the frequency of irAEs was similar to that of patients with Child-Pugh class A HCC in the CheckMate 040 trial. A subset of patients experienced prolonged tumor responses. Nivolumab warrants further study in patients with CPB HCC.
CANIT0002510	31157737	Case report	A 39-year-old white male 	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); BRAF (P15056); 	PD-L1; BRAF	Atezolizumab plus cobimetinib and vemurafenib	N/A	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); cobimetinib (DB05239); vemurafenib (DB08881); 	1	N/A	Case	Through this case report, we aim to increase awareness about the diagnosis and management of patients with new primary melanomas (NPMs) and to express our concerns regarding further management of NPMs in patients under triple combination treatment	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Apr	New primary melanoma in a patient under triple therapy with vemurafenib, cobimetinib, and atezolizumab for metastatic melanoma.	 Melanoma Res	New primary melanomas (NPMs) in the era of combination treatments for melanoma constitute a challenge for physicians, especially due to the increased incidence of NPMs in patients treated with BRAF inhibitors. We present the unique case of a patient that developed an invasive NPM while under treatment with a combination of vemurafenib, cobimetinib, and atezolizumab. A 39-year-old white male was treated with vemurafenib, cobimetinib, and atezolizumab for a stage IV (T0, N3, M1) BRAF-V600E mutated malignant melanoma in the context of a clinical trial. Eight months from treatment initiation he was diagnosed with an NPM on his back that was found to be BRAF-wild type and neuroblastoma ras mutated, while he was in complete remission. Wide excision of the lesion followed, and the patient was not withdrawn from study treatment. Twenty-two months from treatment initiation, he is still in complete remission. NPMs are a well-known adverse effect of BRAF inhibitors and pose a challenge for the treating physician since these lesions are BRAF-wild type and usually have aggressive biologic behaviour. Invasive NPMs require an aggressive management strategy with clear guidelines to prevent the emergence of advanced or metastatic disease. The emergence of invasive NPMs in patients treated with triple regimens with BRAF/mitogen-activated protein kinase kinase inhibitors and PD1/PDL1 inhibitors is at least unexpected and constitutes a therapeutic stalemate for the physician. Through this case report, we aim to increase awareness about the diagnosis and management of patients with NPM and to express our concerns regarding further management of NPMs in patients under triple combination treatment.
CANIT0002511	31164319	Clinical research	2754 patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	Pembrolizumab	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	N/A	N/A	Meta-analysis	Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). For patients with NSCLC with PD-L1 tumor proportion score (TPS) >= 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Sep	First-line Pembrolizumab Versus Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone in Non-small-cell Lung Cancer: A Systematic Review and Network Meta-analysis.	 Clin Lung Cancer	BACKGROUND: This study aimed to comprehensively review the available evidence regarding the efficacy of first-line pembrolizumab for advanced/metastatic non-small-cell lung cancer (NSCLC), and to compare pembrolizumab monotherapy versus pembrolizumab plus chemotherapy versus chemotherapy alone.MATERIALS AND METHODS: A search of the PubMed, EMBASE, and Cochrane Library databases was performed in July 2018, and abstracts from the American Society of Clinical Oncology meetings (2015-2018) were reviewed. Summaries of the results were pooled using a random-effect model to determine the pooled hazard ratio (HR) for progression-free survival (PFS), overall survival (OS), and their 95% confidence intervals (CIs). A network meta-analysis was used to indirectly compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy.RESULTS: A total of 4 relevant phase III trials comprising 2754 patients were identified. Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). In particular, for the subgroup with PD-L1 TPS >= 50%, the HR of PFS was 0.49 (95% CI, 0.32-0.76; P = .001), and that of OS was 0.57 (95% CI, 0.45-0.73; P < .001). In terms of PFS, pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy with an HR of PFS 0.52 (95% CI, 0.27-0.99; P = .048) for the subgroup with PD-L1 TPS >= 50%.CONCLUSIONS: For patients with NSCLC with PD-L1 TPS >= 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy in this meta-analysis. To confirm this finding, a prospective phase III trial that directly compares the treatments is warranted.
CANIT0002512	31165561	Case report	Metastatic triple negative breast cancer	Triple-negative breast cancer	EFO:0005537	Breast	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumabl plus nab-paclitaxe	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); nab-paclitaxel (DB01229); 	1	N/A	Case	She was treated by nab-paclitaxel plus anti-PD-L1 in first line. After 2 months, a dramatic lung response was noticed but an involvement of mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epitheloid granulomas without caseating necrosis in favour of a sarcoidosis-like reaction. The patient remained free of symptom and in complete lung response on anti-PD-L1 treatment as a maintenance therapy.	Sarcoidosis-like reaction	N/A	N/A	N/A	N/A	N/A	 2019 Sep	Sarcoidosis-like reaction in metastatic triple negative breast cancer treated by anti-PD-L1.	 Breast J	We report the first case of sarcoidosis-like reaction in a patient treated by anti-PD-L1 for a breast cancer. A 69-year-old woman presented with a histologically confirmed lung metastasis of a triple negative breast cancer. She was treated by nab-paclitaxel plus anti-PD-L1 in first line. After 2 months, a dramatic lung response was noticed but an involvement of mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epitheloid granulomas without caseating necrosis in favour of a sarcoidosis-like reaction. The patient remained free of symptom and in complete lung response on anti-PD-L1 treatment as a maintenance therapy.
CANIT0002513	31171876	Clinical research	46 patients 	Melanoma	EFO:0000756	Skin	PD-L1 (Q9NZQ7); BRAF (P15056); 	PD-L1; BRAF	Atezolizumab plus cobimetinib and vemurafenib	Atezolizumab plus vemurafenib	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); cobimetinib (DB05239); vemurafenib (DB08881); 	39	17	Phase Ib	Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only runin period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1¨C85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6¨C25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up	Alanine aminotransferase (ALT) increase (23.5%), aspartate aminotransferase (AST) increase (17.6%) and rash (17.6%)	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	An increase in proliferating CD4(+) T-helper cells but not with an increase in T-regulatory cells	Gene expression signature on/in immune cell	 2019 Jun	Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.	 Nat Med	Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAFV600 mutations1-9. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors10-20. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAFV600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1-85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6-25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.
CANIT0002514	31171878	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); MEK (Q02750); 	PD-1 ;  BRAF ;  MEK 	Pembrolizumab plus dabrafenib plus trametinib	Dabrafenib plus trametinib	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); dabrafenib (DB08912); trametinib (DB08911); 	60	60	Randomized phase 2 trial ( NCT02130466 )	The primary end point of progression-free survival was numerically improved in the triplet group-16.0 months-compared with 10.3 months in the doublet group (hazard ratio, 0.66; P = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7 months (95% confidence interval, 10.1-22.1) and 12.5 months (95% confidence interval, 6.0-14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.	Grade 3-5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis.	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma.	 Nat Med	Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial ( NCT02130466 ), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60) or placebo (doublet; n = 60). The primary end point of progression-free survival was numerically improved in the triplet group-16.0 months-compared with 10.3 months in the doublet group (hazard ratio, 0.66; P = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7 months (95% confidence interval, 10.1-22.1) and 12.5 months (95% confidence interval, 6.0-14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 3-5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.
CANIT0002515	31171879	Clinical research	BRAFV600-mutated metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); MEK (Q02750); 	PD-1 ;  BRAF ;  MEK 	Pembrolizumab plus dabrafenib plus trametinib	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); dacarbazine (DB00851); trametinib (DB08911); 	15	N/A	N/A	Eleven patients (73%; 95% confidence interval = 45-92%) had an objective response, and six (40%; 95% confidence interval = 16-68%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.	Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination.	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2019 Jun	Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma.	 Nat Med	Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year1-3. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity4-6, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab ( NCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%; 95% confidence interval = 45-92%) had an objective response, and six (40%; 95% confidence interval = 16-68%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.
CANIT0002516	31176366	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	71	N/A	N/A	In patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiation (CD95+) and egression from tumor tissue (CD69-). In PR patients, the fraction of CD8 T cells that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) correlates significantly with the total numbers and differentiated phenotype of CD8 T cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	The fraction of CD8 T-cell that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) 	Gene expression signature on/in immune cell	 2019 Jun 8	CD45RA(+)CCR7(-) CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab.	 J Immunother Cancer	Unable to provide
CANIT0002517	31176366	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	71	N/A	N/A	In patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiation (CD95+) and egression from tumor tissue (CD69-). In PR patients, the fraction of CD8 T cells that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) correlates significantly with the total numbers and differentiated phenotype of CD8 T cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	The number of CD8 T-cell at baseline	Gene expression signature on/in immune cell	 2019 Jun 8	CD45RA(+)CCR7(-) CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab.	 J Immunother Cancer	Unable to provide
CANIT0002518	31176366	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	71	N/A	N/A	In patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiation (CD95+) and egression from tumor tissue (CD69-). In PR patients, the fraction of CD8 T cells that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) correlates significantly with the total numbers and differentiated phenotype of CD8 T cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	The number of CD8 T-cell during treatment	Gene expression signature on/in immune cell	 2019 Jun 8	CD45RA(+)CCR7(-) CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab.	 J Immunother Cancer	Unable to provide
CANIT0002519	31176366	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	71	N/A	N/A	In patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiation (CD95+) and egression from tumor tissue (CD69-). In PR patients, the fraction of CD8 T cells that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) correlates significantly with the total numbers and differentiated phenotype of CD8 T cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	T-cell that express markers of egression from tumor tissue (CD69-)	Gene expression signature on/in immune cell	 2019 Jun 8	CD45RA(+)CCR7(-) CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab.	 J Immunother Cancer	Unable to provide
CANIT0002520	31176366	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	71	N/A	N/A	In patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiation (CD95+) and egression from tumor tissue (CD69-). In PR patients, the fraction of CD8 T cells that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) correlates significantly with the total numbers and differentiated phenotype of CD8 T cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	T-cell that express markers of terminal differentiation (CD95(+))	Gene expression signature on/in immune cell	 2019 Jun 8	CD45RA(+)CCR7(-) CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab.	 J Immunother Cancer	Unable to provide
CANIT0002521	31176366	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	71	N/A	N/A	In patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiation (CD95+) and egression from tumor tissue (CD69-). In PR patients, the fraction of CD8 T cells that lacks co-stimulatory receptors (CD28, ICOS, CD40L, 4-1BB, OX40) correlates significantly with the total numbers and differentiated phenotype of CD8 T cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	T-Lymphocyte (NCIT:C12476); 	T effector memory re-expressing CD45RA (TEMRA) cells	Gene expression signature on/in immune cell	 2019 Jun 8	CD45RA(+)CCR7(-) CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab.	 J Immunother Cancer	Unable to provide
CANIT0002522	31182061	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	6208	N/A	Meta-analysis	The specificity of immune-related adverse events (irAEs) was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jun 10	Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis.	 BMC Cancer	BACKGROUND: Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC.METHODS: Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta.RESULTS: Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved.CONCLUSIONS: The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.
CANIT0002523	31194611	Clinical research	Brain Metastases From Renal Cell Carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	73	N/A	GETUG-AFU 26 NIVOREN phase II trial	Two cohorts were constituted: cohort A comprised patients with previously untreated brain metastases, and cohort B comprised patients whose brain metastases underwent prior therapy. Seventy-three patients with brain metastases were included: 39 in cohort A and 34 in cohort B. Intracranial response rate was 12% in cohort A; no objective response was reported in patients with brain lesions that were multiple or larger than 1 cm. Median intracranial progression-free survival was 2.7 months (95% CI, 2.3 to 4.6 months) in cohort A and 4.8 months (95% CI, 3.0 to 8.0 months) in cohort B, with adjusted hazard ratio of 2.04 (95% CI, 1.08 to 3.83). Overall survival rate at 12 months was 67% (95% CI, 49.6% to 79.1%) in cohort A and 59% (95% CI, 40.6% to 73.2%) in cohort B. Most patients in cohort A (72%) needed subsequent focal brain therapy. Nivolumab activity is limited in patients with untreated brain metastases from metastatic clear cell renal cell carcinoma (ccRCC). Brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC.	Nivolumab was well tolerated, with no unexpected toxicity.	N/A	N/A	N/A	N/A	N/A	 2019 Aug 10	Safety and Efficacy of Nivolumab in Brain Metastases From Renal Cell Carcinoma: Results of the GETUG-AFU 26 NIVOREN Multicenter Phase II Study.	 J Clin Oncol	PURPOSE: Nivolumab is standard of care for patients with metastatic clear cell renal cell carcinoma (ccRCC) after failure of antiangiogenic therapies, but its activity on brain metastases from ccRCC remains unknown, because these patients were excluded from pivotal studies. We aimed to assess the activity of nivolumab in this population.METHODS: The GETUG-AFU 26 NIVOREN phase II trial assessed the activity and safety of nivolumab in patients with metastatic ccRCC who failed vascular endothelial growth factor-directed therapies (ClinicalTrials.gov identifier: NCT03013335). Patients with asymptomatic brain metastases were prospectively identified and underwent dedicated brain evaluation. Two cohorts were constituted: cohort A comprised patients with previously untreated brain metastases, and cohort B comprised patients whose brain metastases underwent prior therapy. The primary end point was intracranial response rate in cohort A.RESULTS: Seventy-three patients with brain metastases were included: 39 in cohort A and 34 in cohort B. Intracranial response rate was 12% in cohort A; no objective response was reported in patients with brain lesions that were multiple or larger than 1 cm. Median intracranial progression-free survival was 2.7 months (95% CI, 2.3 to 4.6 months) in cohort A and 4.8 months (95% CI, 3.0 to 8.0 months) in cohort B, with adjusted hazard ratio of 2.04 (95% CI, 1.08 to 3.83). Overall survival rate at 12 months was 67% (95% CI, 49.6% to 79.1%) in cohort A and 59% (95% CI, 40.6% to 73.2%) in cohort B. Most patients in cohort A (72%) needed subsequent focal brain therapy. Nivolumab was well tolerated, with no unexpected toxicity.CONCLUSION: Nivolumab activity is limited in patients with untreated brain metastases from ccRCC. Brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC.
CANIT0002524	31195357	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Chemotherapy	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	583	583	Randomised, open-label, phase III study	First-line nivolumab + ipilimumab demonstrated early, sustained improvements in patient-reported outcomes versus chemotherapy in patients with advanced NSCLC and high tumour mutational burden (TMB; >=10 mutations/megabase).	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Jul	Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial.	 Eur J Cancer	BACKGROUND: In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; >=10 mutations/megabase).AIM: To evaluate patient-reported outcomes (PROs) in this population.METHODS: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses.RESULTS: In the high TMB population, PRO questionnaire completion rates were ¡«90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures.CONCLUSION: First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB.CLINICAL TRIAL REGISTRATION: NCT02477826.
CANIT0002525	31199005	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	71	N/A	Meta-analysis	Many people developed Type 1 diabetes within 3 months of initial PD-1/PD-L1 inhibitor exposure. People presenting with Type 1 diabetes-associated antibodies had a more rapid onset and higher incidence of ketoacidosis than those without antibodies. Healthcare providers caring for people receiving these state-of-the-art therapies need to be aware of this potential severe adverse event.	Immune checkpoint inhibitor-induced Type 1 diabetes	N/A	N/A	N/A	N/A	N/A	 2019 Sep	Immune checkpoint inhibitor-induced Type 1 diabetes: a systematic review and meta-analysis.	 Diabet Med	AIM: To conduct a systematic review and meta-analysis to understand the timing and factors associated with anti-programmed cell death protein-1 (PD-1)/anti-programmed cell death protein-1 ligand (PD-L1) inhibitor-induced Type 1 diabetes.METHODS: We searched MEDLINE, EMBASE, SCOPUS and Cochrane databases (August 2000-2018) for studies of any design on immune checkpoint inhibitors. A total of 71 cases were reviewed from 56 publications. Comparisons were made using Fisher's exact and Student's t-tests.RESULTS: The mean +/- sd age at Type 1 diabetes presentation was 61.7+/-12.2 years, 55% of cases were in men, and melanoma (53.5%) was the most frequent cancer. The median time to Type 1 diabetes onset was 49 (5-448) days with ketoacidosis in 76% of cases. The average +/- sd HbA1c concentration was 62 +/- 0.3 mmol/mol (7.84+/-1.0%) at presentation. All cases had insulin deficiency and required permanent exogenous insulin treatment. Half of the cases had Type 1 diabetes-associated antibodies at presentation, and those with antibodies had a more rapid onset (P=0.005) and higher incidence of diabetic ketoacidosis (P=0.02) compared to people without antibodies.CONCLUSIONS: Many people developed Type 1 diabetes within 3 months of initial PD-1/PD-L1 inhibitor exposure. People presenting with Type 1 diabetes-associated antibodies had a more rapid onset and higher incidence of ketoacidosis than those without antibodies. Healthcare providers caring for people receiving these state-of-the-art therapies need to be aware of this potential severe adverse event.
CANIT0002526	31199183	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	65	N/A	Retrospective analysis	No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2019 Aug	Nivolumab in disadvantaged subgroups of metastatic non-small-cell lung cancer patients: a single-institution experience.	 Immunotherapy	Aim: Immunotherapy opened new frontiers in metastatic non-small-cell lung cancer treatment, but not all patients benefit from it. Methods: We retrospectively evaluated 65 metastatic non-small-cell lung cancer patients, treated with nivolumab, considering as disadvantaged subgroups those with poor performance status, elderly, patients with brain metastases at baseline, with high disease burden and refractory to platinum. Results: No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor. Conclusion: Our study suggests that only refractoriness to platinum salts influence the efficacy of nivolumab.
CANIT0002527	31199183	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	65	N/A	Retrospective analysis	No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2019 Aug	Nivolumab in disadvantaged subgroups of metastatic non-small-cell lung cancer patients: a single-institution experience.	 Immunotherapy	Aim: Immunotherapy opened new frontiers in metastatic non-small-cell lung cancer treatment, but not all patients benefit from it. Methods: We retrospectively evaluated 65 metastatic non-small-cell lung cancer patients, treated with nivolumab, considering as disadvantaged subgroups those with poor performance status, elderly, patients with brain metastases at baseline, with high disease burden and refractory to platinum. Results: No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor. Conclusion: Our study suggests that only refractoriness to platinum salts influence the efficacy of nivolumab.
CANIT0002528	31199183	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	65	N/A	Retrospective analysis	No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance status	Disease status	 2019 Aug	Nivolumab in disadvantaged subgroups of metastatic non-small-cell lung cancer patients: a single-institution experience.	 Immunotherapy	Aim: Immunotherapy opened new frontiers in metastatic non-small-cell lung cancer treatment, but not all patients benefit from it. Methods: We retrospectively evaluated 65 metastatic non-small-cell lung cancer patients, treated with nivolumab, considering as disadvantaged subgroups those with poor performance status, elderly, patients with brain metastases at baseline, with high disease burden and refractory to platinum. Results: No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor. Conclusion: Our study suggests that only refractoriness to platinum salts influence the efficacy of nivolumab.
CANIT0002529	31199183	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	65	N/A	Retrospective analysis	No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor.	N/A	N/A	N/A	Platinum resistance (NCIT:C147558 ); 	Platinum resistance	Disease status	 2019 Aug	Nivolumab in disadvantaged subgroups of metastatic non-small-cell lung cancer patients: a single-institution experience.	 Immunotherapy	Aim: Immunotherapy opened new frontiers in metastatic non-small-cell lung cancer treatment, but not all patients benefit from it. Methods: We retrospectively evaluated 65 metastatic non-small-cell lung cancer patients, treated with nivolumab, considering as disadvantaged subgroups those with poor performance status, elderly, patients with brain metastases at baseline, with high disease burden and refractory to platinum. Results: No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor. Conclusion: Our study suggests that only refractoriness to platinum salts influence the efficacy of nivolumab.
CANIT0002530	31199183	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	65	N/A	Retrospective analysis	No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor.	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	High disease burden	Disease status	 2019 Aug	Nivolumab in disadvantaged subgroups of metastatic non-small-cell lung cancer patients: a single-institution experience.	 Immunotherapy	Aim: Immunotherapy opened new frontiers in metastatic non-small-cell lung cancer treatment, but not all patients benefit from it. Methods: We retrospectively evaluated 65 metastatic non-small-cell lung cancer patients, treated with nivolumab, considering as disadvantaged subgroups those with poor performance status, elderly, patients with brain metastases at baseline, with high disease burden and refractory to platinum. Results: No differences in overall survival or time to treatment failure were found according to performance status, age, presence of brain metastases at baseline or high disease burden. Conversely, patients refractory to platinum had a statistically significant shorter overall survival and time to treatment failure. At multivariate analysis only platinum resistance was confirmed as an independent predictive factor. Conclusion: Our study suggests that only refractoriness to platinum salts influence the efficacy of nivolumab.
CANIT0002531	31200359	Case report	Advanced intrahepatic cholangiocarcinoma	Intrahepatic cholangiocarcinoma	EFO:1001961 	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	This report presents a 66-year-old patient with chemotherapy-refractory intrahepatic cholangiocarcinoma (iCCA) who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Jun 1	Prolonged Response to Anti-PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden.	 J Natl Compr Canc Netw	Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.
CANIT0002532	31200747	Basic research	Colon cancer or melanoma	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	B-Lymphocyte (NCIT:C12474); 	Tumor infiltrating B cell content	Tumor-infiltrating immune cell	 2019 Jun 14	B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors.	 J Immunother Cancer	BACKGROUND: PD-1 inhibitors are approved for multiple malignancies and function by stimulating T cells. However, the role of B cells in the anti-tumor activity of these drugs is unknown, as is their activity in patients who have received B cell depleting drugs or with immunoglobulin deficiencies.METHODS: We studied B cell content in 40 melanomas from patients treated with pembrolizumab or nivolumab and assessed the association with response to therapy. Murine MC38 colon cancer and YUMMER1.7 melanoma models were used to determine whether concomitant anti-CD20 antibody injections diminish the anti-tumor effects of anti-PD-1. Results were validated in muMT mice, which lack B cells.RESULTS: B cells were sparse in most melanomas and B cell content was not associated with response to anti-PD-1 or overall survival. Employing MC38 and YUMMER1.7 models, we demonstrated that anti-CD20 antibodies reduce tumor-infiltrating B cells yet had no effect on tumor growth, response to PD-1 inhibition, or survival. In muMT mice, T-cell dependent tumor rejection and anti-PD-1 responses were no different than in wildtype C57BL/6 J mice.CONCLUSIONS: The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.
CANIT0002533	31200747	Basic research	Colon cancer or melanoma	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	Cell lines/ animal models	N/A	Basic research	The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	B-Lymphocyte (NCIT:C12474); 	Tumor infiltrating B cell content	Tumor-infiltrating immune cell	 2019 Jun 14	B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors.	 J Immunother Cancer	BACKGROUND: PD-1 inhibitors are approved for multiple malignancies and function by stimulating T cells. However, the role of B cells in the anti-tumor activity of these drugs is unknown, as is their activity in patients who have received B cell depleting drugs or with immunoglobulin deficiencies.METHODS: We studied B cell content in 40 melanomas from patients treated with pembrolizumab or nivolumab and assessed the association with response to therapy. Murine MC38 colon cancer and YUMMER1.7 melanoma models were used to determine whether concomitant anti-CD20 antibody injections diminish the anti-tumor effects of anti-PD-1. Results were validated in muMT mice, which lack B cells.RESULTS: B cells were sparse in most melanomas and B cell content was not associated with response to anti-PD-1 or overall survival. Employing MC38 and YUMMER1.7 models, we demonstrated that anti-CD20 antibodies reduce tumor-infiltrating B cells yet had no effect on tumor growth, response to PD-1 inhibition, or survival. In muMT mice, T-cell dependent tumor rejection and anti-PD-1 responses were no different than in wildtype C57BL/6 J mice.CONCLUSIONS: The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.
CANIT0002534	31200747	Basic research	Colon cancer or melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	B-Lymphocyte (NCIT:C12474); 	Tumor infiltrating B cell content	Tumor-infiltrating immune cell	 2019 Jun 14	B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors.	 J Immunother Cancer	BACKGROUND: PD-1 inhibitors are approved for multiple malignancies and function by stimulating T cells. However, the role of B cells in the anti-tumor activity of these drugs is unknown, as is their activity in patients who have received B cell depleting drugs or with immunoglobulin deficiencies.METHODS: We studied B cell content in 40 melanomas from patients treated with pembrolizumab or nivolumab and assessed the association with response to therapy. Murine MC38 colon cancer and YUMMER1.7 melanoma models were used to determine whether concomitant anti-CD20 antibody injections diminish the anti-tumor effects of anti-PD-1. Results were validated in muMT mice, which lack B cells.RESULTS: B cells were sparse in most melanomas and B cell content was not associated with response to anti-PD-1 or overall survival. Employing MC38 and YUMMER1.7 models, we demonstrated that anti-CD20 antibodies reduce tumor-infiltrating B cells yet had no effect on tumor growth, response to PD-1 inhibition, or survival. In muMT mice, T-cell dependent tumor rejection and anti-PD-1 responses were no different than in wildtype C57BL/6 J mice.CONCLUSIONS: The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.
CANIT0002535	31200747	Basic research	Colon cancer or melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	Cell lines/ animal models	N/A	Basic research	The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	B-Lymphocyte (NCIT:C12474); 	Tumor infiltrating B cell content	Tumor-infiltrating immune cell	 2019 Jun 14	B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors.	 J Immunother Cancer	BACKGROUND: PD-1 inhibitors are approved for multiple malignancies and function by stimulating T cells. However, the role of B cells in the anti-tumor activity of these drugs is unknown, as is their activity in patients who have received B cell depleting drugs or with immunoglobulin deficiencies.METHODS: We studied B cell content in 40 melanomas from patients treated with pembrolizumab or nivolumab and assessed the association with response to therapy. Murine MC38 colon cancer and YUMMER1.7 melanoma models were used to determine whether concomitant anti-CD20 antibody injections diminish the anti-tumor effects of anti-PD-1. Results were validated in muMT mice, which lack B cells.RESULTS: B cells were sparse in most melanomas and B cell content was not associated with response to anti-PD-1 or overall survival. Employing MC38 and YUMMER1.7 models, we demonstrated that anti-CD20 antibodies reduce tumor-infiltrating B cells yet had no effect on tumor growth, response to PD-1 inhibition, or survival. In muMT mice, T-cell dependent tumor rejection and anti-PD-1 responses were no different than in wildtype C57BL/6 J mice.CONCLUSIONS: The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.
CANIT0002536	31200826	Clinical research	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	50	N/A	N/A	Of the 50 patients, 20 were treated with chemotherapy and 30 were treated with anti-PD-1 therapy. Serum ADA decreased significantly between baseline and day 7 of the first cycle in patients undergoing chemotherapy, regardless of response (partial response [PR] or stable disease [SD]: -23% [-38 to +32; p = 0.002]; progressive disease [PD]: -12% [-42 to +6; p = 0.500]). Conversely, in patients undergoing anti-PD-1 therapy, serum ADA increased significantly between baseline and 7 days after the first dose and before subsequent doses in patients who had PR or SD. (day 7 of first cycle: +6% [-10 to +34; p = 0.034], day 0 of second cycle: 8% [-5 to +37; p = 0.002], day 0 of third cycle: 9% [-3 to +55; p = 0.002]). However, serum ADA did not significant change in PD patients undergoing anti-PD-1 therapy. Furthermore, early increases in serum ADA were associated with longer progression-free survival in patients receiving anti-PD-1 therapy (p = 0.006).Changes in serum ADA could be used to predict clinical benefit from anti-PD-1 therapy in patients with lung cancer. The association between changes in serum ADA and the efficacy of ant-PD-1 therapy thus remains inconclusive and requires further study.	N/A	N/A	N/A	ADAL (Q6DHV7); 	Serum ADAL levels	Gene expression signature in serum	 2019 Jul	Correlation between serum adenosine deaminase activity and efficacy of anti-programmed cell death-1 antibody.	 Lung Cancer	OBJECTIVE: Serum adenosine deaminase (ADA) activity is a marker of immune reaction to several diseases. We evaluated changes in serum ADA in patients with lung cancer undergoing chemotherapy or anti-programmed cell death-1 (PD-1) therapy to examine the correlation between serum ADA and the therapy efficacy.MATERIALS AND METHODS: We assessed 50 patients with advanced lung cancer receiving chemotherapy or anti-PD-1 therapy. Serum ADA was measured before and on day 7 of the first treatment cycle and day 0 of subsequent cycles. Correlations between ADA change and efficacy of treatment were evaluated.RESULTS: Of the 50 patients, 20 were treated with chemotherapy and 30 were treated with anti-PD-1 therapy. Serum ADA decreased significantly between baseline and day 7 of the first cycle in patients undergoing chemotherapy, regardless of response (partial response [PR] or stable disease [SD]: -23% [-38 to +32; p =  0.002]; progressive disease [PD]: -12% [-42 to +6; p =  0.500]). Conversely, in patients undergoing anti-PD-1 therapy, serum ADA increased significantly between baseline and 7 days after the first dose and before subsequent doses in patients who had PR or SD. (day 7 of first cycle: +6% [-10 to +34; p =  0.034], day 0 of second cycle: 8% [-5 to +37; p =  0.002], day 0 of third cycle: 9% [-3 to +55; p =  0.002]). However, serum ADA did not significant change in PD patients undergoing anti-PD-1 therapy. Furthermore, early increases in serum ADA were associated with longer progression-free survival in patients receiving anti-PD-1 therapy (p =  0.006).CONCLUSION: Changes in serum ADA could be used to predict clinical benefit from anti-PD-1 therapy in patients with lung cancer. The association between changes in serum ADA and the efficacy of ant-PD-1 therapy thus remains inconclusive and requires further study.
CANIT0002537	31200833	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Chemo-radiotherapy	N/A	Immune checkpoint therapy plus Radiotherapy	Nivolumab (DB09035); 	82	N/A	Phase-II trial	The early interim safety analysis (IA) provides evidence that the addition of nivolumab to concurrent Chemo-radiotherapy (CRT) is safe and tolerable regarding the 6-month rate of pneumonitis grade >=3 at the one-sided significance level of 5%. Following that, the 1-year progression-free survival will be evaluated in an expanded patient cohort. NICOLAS trial creates the opportunity for assessing the activity of the combination of checkpoint with concurrent CRT in larger prospective trials for locally advanced NSCLC.	The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed. For the first 21 patients, no grade->=3-pneumonitis was observed by the end of the 3-month post-RT follow-up period. 	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial.	 Lung Cancer	OBJECTIVES: Chemo-radiotherapy (CRT) and concurrent PD-1 inhibition has shown promising results in pre-clinical models. So far, the feasibility of delivering concurrent CRT and PD-1/PD-L1 inhibition has never been assessed in a clinical trial.MATERIAL AND METHODS: NICOLAS is a phase-II trial evaluating the safety and efficacy of nivolumab combined with CRT in stage III NSCLC. Patients received 3 cycles of platinum-based chemotherapy and concurrent RT (66 Gy/33fractions). Nivolumab started concurrently with RT. The primary endpoint was 6-month post-RT rate of grade->=3-pneumonitis. A formal interim safety analysis (IA) was scheduled when the first 21 patients reached 3 months follow-up post-RT. An early positive safety conclusion would be reached at IA if there were no grade >=3-pneumonitis in those patients. Efficacy evaluation was planned provided the safety conclusion was reached.RESULTS AND CONCLUSION: As of 13 December 2018, 82 patients were recruited with median follow-up of 13.4 months. The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed. For the first 21 patients, no grade->=3-pneumonitis was observed by the end of the 3-month post-RT follow-up period. The early safety IA provides evidence that the addition of nivolumab to concurrent CRT is safe and tolerable regarding the 6-month rate of pneumonitis grade >=3 at the one-sided significance level of 5%. Following that, the 1-year progression-free survival will be evaluated in an expanded patient cohort. NICOLAS trial creates the opportunity for assessing the activity of the combination of checkpoint with concurrent CRT in larger prospective trials for locally advanced NSCLC.
CANIT0002538	31204194	Case report	Choroidal melanoma	Choroidal melanoma	EFO:0009093	Nervous system	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	It reports a case of renal vasculitis or pauci-immune glomerulonephritis after checkpoint inhibitor therapy. Three patients had renal small- to medium-vessel vasculitis and 1 had focally crescentic pauci-immune glomerulonephritis. Three patients presented with acute kidney injury, and 1 presented with nephrotic syndrome and hematuria. Three patients were tested for antineutrophil cytoplasmic antibodies, which were negative. The time from checkpoint inhibitor initiation to immune-related adverse event presentation ranged from 2 weeks to 24 months. Three patients were treated with glucocorticoids, resulting in clinical resolution.	Checkpoint inhibitor-associated glomerulonephritis and renal vasculitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Renal Vasculitis and Pauci-immune Glomerulonephritis Associated With Immune Checkpoint Inhibitors.	 Am J Kidney Dis	Immune checkpoint inhibitors are increasingly used to treat a variety of solid-organ and hematologic cancers. However, overactivation of the immune system can lead to immune-related adverse events, which are increasingly recognized in the kidney. There have been only rare reported cases of checkpoint inhibitor-associated glomerulonephritis and renal vasculitis, although vasculitis in other organs has been well described. We report 4 cases of renal vasculitis or pauci-immune glomerulonephritis after checkpoint inhibitor therapy. Three patients had renal small- to medium-vessel vasculitis and 1 had focally crescentic pauci-immune glomerulonephritis. Three patients presented with acute kidney injury, and 1 presented with nephrotic syndrome and hematuria. Three patients were tested for antineutrophil cytoplasmic antibodies, which were negative. The time from checkpoint inhibitor initiation to immune-related adverse event presentation ranged from 2 weeks to 24 months. Three patients were treated with glucocorticoids, resulting in clinical resolution. Our series demonstrates that renal vasculitis and pauci-immune glomerulonephritis are important considerations in the differential diagnosis of checkpoint inhibitor-related reductions in kidney function.
CANIT0002539	31204194	Case report	Lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus carboplatin plus pemetrexed	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); carboplatin (DB00958); pemetrexed (DB00642); 	1	N/A	Case	It reports a case of renal vasculitis or pauci-immune glomerulonephritis after checkpoint inhibitor therapy. Three patients had renal small- to medium-vessel vasculitis and 1 had focally crescentic pauci-immune glomerulonephritis. Three patients presented with acute kidney injury, and 1 presented with nephrotic syndrome and hematuria. Three patients were tested for antineutrophil cytoplasmic antibodies, which were negative. The time from checkpoint inhibitor initiation to immune-related adverse event presentation ranged from 2 weeks to 24 months. Three patients were treated with glucocorticoids, resulting in clinical resolution.	Checkpoint inhibitor-associated glomerulonephritis and renal vasculitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Renal Vasculitis and Pauci-immune Glomerulonephritis Associated With Immune Checkpoint Inhibitors.	 Am J Kidney Dis	Immune checkpoint inhibitors are increasingly used to treat a variety of solid-organ and hematologic cancers. However, overactivation of the immune system can lead to immune-related adverse events, which are increasingly recognized in the kidney. There have been only rare reported cases of checkpoint inhibitor-associated glomerulonephritis and renal vasculitis, although vasculitis in other organs has been well described. We report 4 cases of renal vasculitis or pauci-immune glomerulonephritis after checkpoint inhibitor therapy. Three patients had renal small- to medium-vessel vasculitis and 1 had focally crescentic pauci-immune glomerulonephritis. Three patients presented with acute kidney injury, and 1 presented with nephrotic syndrome and hematuria. Three patients were tested for antineutrophil cytoplasmic antibodies, which were negative. The time from checkpoint inhibitor initiation to immune-related adverse event presentation ranged from 2 weeks to 24 months. Three patients were treated with glucocorticoids, resulting in clinical resolution. Our series demonstrates that renal vasculitis and pauci-immune glomerulonephritis are important considerations in the differential diagnosis of checkpoint inhibitor-related reductions in kidney function.
CANIT0002540	31204194	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	It reports a case of renal vasculitis or pauci-immune glomerulonephritis after checkpoint inhibitor therapy. Three patients had renal small- to medium-vessel vasculitis and 1 had focally crescentic pauci-immune glomerulonephritis. Three patients presented with acute kidney injury, and 1 presented with nephrotic syndrome and hematuria. Three patients were tested for antineutrophil cytoplasmic antibodies, which were negative. The time from checkpoint inhibitor initiation to immune-related adverse event presentation ranged from 2 weeks to 24 months. Three patients were treated with glucocorticoids, resulting in clinical resolution.	Checkpoint inhibitor-associated glomerulonephritis and renal vasculitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Renal Vasculitis and Pauci-immune Glomerulonephritis Associated With Immune Checkpoint Inhibitors.	 Am J Kidney Dis	Immune checkpoint inhibitors are increasingly used to treat a variety of solid-organ and hematologic cancers. However, overactivation of the immune system can lead to immune-related adverse events, which are increasingly recognized in the kidney. There have been only rare reported cases of checkpoint inhibitor-associated glomerulonephritis and renal vasculitis, although vasculitis in other organs has been well described. We report 4 cases of renal vasculitis or pauci-immune glomerulonephritis after checkpoint inhibitor therapy. Three patients had renal small- to medium-vessel vasculitis and 1 had focally crescentic pauci-immune glomerulonephritis. Three patients presented with acute kidney injury, and 1 presented with nephrotic syndrome and hematuria. Three patients were tested for antineutrophil cytoplasmic antibodies, which were negative. The time from checkpoint inhibitor initiation to immune-related adverse event presentation ranged from 2 weeks to 24 months. Three patients were treated with glucocorticoids, resulting in clinical resolution. Our series demonstrates that renal vasculitis and pauci-immune glomerulonephritis are important considerations in the differential diagnosis of checkpoint inhibitor-related reductions in kidney function.
CANIT0002541	31204194	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus systemic chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); 	1	N/A	Case	It reports a case of renal vasculitis or pauci-immune glomerulonephritis after checkpoint inhibitor therapy. Three patients had renal small- to medium-vessel vasculitis and 1 had focally crescentic pauci-immune glomerulonephritis. Three patients presented with acute kidney injury, and 1 presented with nephrotic syndrome and hematuria. Three patients were tested for antineutrophil cytoplasmic antibodies, which were negative. The time from checkpoint inhibitor initiation to immune-related adverse event presentation ranged from 2 weeks to 24 months. Three patients were treated with glucocorticoids, resulting in clinical resolution.	Checkpoint inhibitor-associated glomerulonephritis and renal vasculitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Renal Vasculitis and Pauci-immune Glomerulonephritis Associated With Immune Checkpoint Inhibitors.	 Am J Kidney Dis	Immune checkpoint inhibitors are increasingly used to treat a variety of solid-organ and hematologic cancers. However, overactivation of the immune system can lead to immune-related adverse events, which are increasingly recognized in the kidney. There have been only rare reported cases of checkpoint inhibitor-associated glomerulonephritis and renal vasculitis, although vasculitis in other organs has been well described. We report 4 cases of renal vasculitis or pauci-immune glomerulonephritis after checkpoint inhibitor therapy. Three patients had renal small- to medium-vessel vasculitis and 1 had focally crescentic pauci-immune glomerulonephritis. Three patients presented with acute kidney injury, and 1 presented with nephrotic syndrome and hematuria. Three patients were tested for antineutrophil cytoplasmic antibodies, which were negative. The time from checkpoint inhibitor initiation to immune-related adverse event presentation ranged from 2 weeks to 24 months. Three patients were treated with glucocorticoids, resulting in clinical resolution. Our series demonstrates that renal vasculitis and pauci-immune glomerulonephritis are important considerations in the differential diagnosis of checkpoint inhibitor-related reductions in kidney function.
CANIT0002542	31206316	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	650	N/A	N/A	Although patients with NSCLC treated with >= 10 mg of prednisone at the time of immunotherapy initiation have worse outcomes than patients who received 0 to < 10 mg of prednisone, this difference seems to be driven by a poor-prognosis subgroup of patients who receive corticosteroids for palliative indications.	N/A	N/A	N/A	Corticosteroids (NCIT:C211); 	Baseline use of corticosteroids	Exposure factors/status	 2019 Aug 1	Immune Checkpoint Inhibitor Outcomes for Patients With Non-Small-Cell Lung Cancer Receiving Baseline Corticosteroids for Palliative Versus Nonpalliative Indications.	 J Clin Oncol	PURPOSE: Baseline use of corticosteroids is associated with poor outcomes in patients with non-small-cell lung cancer (NSCLC) treated with programmed cell death-1 axis inhibition. To approach the question of causation versus correlation for this association, we examined outcomes in patients treated with immunotherapy depending on whether corticosteroids were administered for cancer-related palliative reasons or cancer-unrelated indications.PATIENTS AND METHODS: Clinical outcomes in patients with NSCLC treated with immunotherapy who received >= 10 mg prednisone were compared with outcomes in patients who received 0 to < 10 mg of prednisone.RESULTS: Of 650 patients, the 93 patients (14.3%) who received >= 10 mg of prednisone at the time of immunotherapy initiation had shorter median progression-free survival (mPFS) and median overall survival (mOS) times than patients who received 0 to < 10 mg of prednisone (mPFS, 2.0 v 3.4 months, respectively; P = .01; mOS, 4.9 v 11.2 months, respectively; P < .001). When analyzed by reason for corticosteroid administration, mPFS and mOS were significantly shorter only among patients who received >= 10 mg prednisone for palliative indications compared with patients who received >= 10 mg prednisone for cancer-unrelated reasons and with patients receiving 0 to < 10 mg of prednisone (mPFS, 1.4 v 4.6 v 3.4 months, respectively; log-rank P < .001 across the three groups; mOS, 2.2 v 10.7 v 11.2 months, respectively; log-rank P < .001 across the three groups). There was no significant difference in mPFS or mOS in patients receiving >= 10 mg of prednisone for cancer-unrelated indications compared with patients receiving 0 to < 10 mg of prednisone.CONCLUSION: Although patients with NSCLC treated with >= 10 mg of prednisone at the time of immunotherapy initiation have worse outcomes than patients who received 0 to < 10 mg of prednisone, this difference seems to be driven by a poor-prognosis subgroup of patients who receive corticosteroids for palliative indications.
CANIT0002543	31216228	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	285	N/A	Retrospective analysis	Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL6, IL10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.	Immune-related cutaneous adverse events	N/A	N/A	Eosinophil counts (NCIT:C12532); 	Eosinophil counts	Cell percentage/counts in blood	 2019 Oct 20	Treatment Outcomes of Immune-Related Cutaneous Adverse Events.	 J Clin Oncol	PURPOSE: The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics.METHODS: A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed.RESULTS: A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype (P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043).CONCLUSION: Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.
CANIT0002544	31216228	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	285	N/A	Retrospective analysis	Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL6, IL10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.	Immune-related cutaneous adverse events	N/A	N/A	IL6 (P05231); 	Serum IL6 expression levels	Gene expression signature in serum	 2019 Oct 20	Treatment Outcomes of Immune-Related Cutaneous Adverse Events.	 J Clin Oncol	PURPOSE: The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics.METHODS: A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed.RESULTS: A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype (P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043).CONCLUSION: Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.
CANIT0002545	31216228	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	285	N/A	Retrospective analysis	Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL6, IL10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.	Immune-related cutaneous adverse events	N/A	N/A	IL10 (P22301); 	Serum IL10 expression levels	Gene expression signature in serum	 2019 Oct 20	Treatment Outcomes of Immune-Related Cutaneous Adverse Events.	 J Clin Oncol	PURPOSE: The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics.METHODS: A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed.RESULTS: A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype (P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043).CONCLUSION: Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.
CANIT0002546	31216228	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	285	N/A	Retrospective analysis	Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL6, IL10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.	Immune-related cutaneous adverse events	N/A	N/A	Immunoglobulin E (P06734); 	Serum immunoglobulin E levels	Gene expression signature in serum	 2019 Oct 20	Treatment Outcomes of Immune-Related Cutaneous Adverse Events.	 J Clin Oncol	PURPOSE: The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics.METHODS: A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed.RESULTS: A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype (P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043).CONCLUSION: Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.
CANIT0002547	31216241	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus tyrosine kinase inhibitor	N/A	Immune checkpoint therapy plus Target therapy	N/A	15	N/A	Retrospective analysis	The median duration of combination therapy was 7.2 months (range: 0.2 to 39.8) with 126 incidences of toxicities. The most frequent toxicity was fatigue (n = 15), followed by diarrhea (n = 8), anorexia (n = 7) and palmar-plantar erythrodysesthesia (n = 7). Eight of 15 (53%) patients remained on therapy at the six-month mark and did not have progression confirmed by an oncologist. Of the 15 patients, 10 discontinued therapy due to progression, 2 due to intolerable side effects, 2 transitioned to end of life care, and 1 patient was still ongoing at the time of data collection.Based on this review, it appears that combination tyrosine kinase inhibitors/immune checkpoint inhibitors therapy in pre-treated patients with mRCC is tolerable and beneficial.	Overall, 9 (60%) patients experienced at least one grade 3 or 4 toxicity.	N/A	N/A	N/A	N/A	N/A	 2020 Apr	Outcomes of combination therapy with tyrosine kinase inhibitors and immune checkpoint inhibitors in metastatic renal cell carcinoma - A retrospective study.	 J Oncol Pharm Pract	INTRODUCTION: Renal cell carcinoma (RCC) is a highly vascularized and immunogenic tumor. At the time of this study, there was limited published data on the combination of tyrosine kinase inhibitors and immune checkpoint inhibitors in patients who were heavily pretreated. At our institution, providers have used these combinations in heavily pretreated patients.METHODS: We conducted a retrospective review of patients receiving this combination with the primary objectives of assessing duration of therapy and toxicities and a secondary objective of disease progression at six months. We included adult patients with confirmed mRCC receiving combination therapy (immune checkpoint inhibitors/tyrosine kinase inhibitors) any time after January 2015. Electronic medical records were reviewed for pertinent data and follow-up descriptive statistics were performed.RESULTS: Fifteen patients were on combination immune checkpoint inhibitors/tyrosine kinase inhibitors, with a median of three lines of previous therapy. The median duration of combination therapy was 7.2 months (range: 0.2 to 39.8) with 126 incidences of toxicities. The most frequent toxicity was fatigue (n = 15), followed by diarrhea (n = 8), anorexia (n = 7) and palmar-plantar erythrodysesthesia (n = 7). Overall, 9 (60%) patients experienced at least one grade 3 or 4 toxicity. Eight of 15 (53%) patients remained on therapy at the six-month mark and did not have progression confirmed by an oncologist. Of the 15 patients, 10 discontinued therapy due to progression, 2 due to intolerable side effects, 2 transitioned to end of life care, and 1 patient was still ongoing at the time of data collection.CONCLUSION: Based on this review, it appears that combination tyrosine kinase inhibitors/immune checkpoint inhibitors therapy in pre-treated patients with mRCC is tolerable and beneficial.
CANIT0002548	31221619	Clinical research	Unresectable stage III or IV melanoma	Melanoma	EFO:0000756	Skin	IDO1 (P14902); PD-1 (Q15116); 	IDO1; PD-1	Pembrolizumab plus epacadostat	Pembrolizumab plus placebo	Immune checkpoint therapy	Pembrolizumab (DB09037); epacadostat (DB11717); 	354	352	International, randomised, placebo-controlled, double-blind, parallel-group, phase 3 trial	No significant differences were found between the treatment groups for progression-free survival (median 4.7 months, 95% CI 2.9-6.8, for epacadostat plus pembrolizumab vs 4.9 months, 2.9-6.8, for placebo plus pembrolizumab; hazard ratio [HR] 1.00, 95% CI 0.83-1.21; one-sided p=0.52) or overall survival (median not reached in either group; epacadostat plus pembrolizumab vs placebo plus pembrolizumab: HR 1.13, 0.86-1.49; one-sided p=0.81). Epacadostat 100 mg twice daily plus pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus pembrolizumab in patients with unresectable or metastatic melanoma. The usefulness of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain.Epacadostat 100 mg twice daily plus pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus pembrolizumab in patients with unresectable or metastatic melanoma. The usefulness of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain.	The most common grade 3 or worse treatment-related adverse event was lipase increase, which occurred in 14 (4%) of 353 patients receiving epacadostat plus pembrolizumab and 11 (3%) of 352 patients receiving placebo plus pembrolizumab. Treatment-related serious adverse events were reported in 37 (10%) of 353 patients receiving epacadostat plus pembrolizumab and 32 (9%) of 352 patients receiving placebo plus pembrolizumab. There were no treatment-related deaths in either treatment group.	N/A	N/A	N/A	N/A	N/A	 2019 Aug	Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study.	 Lancet Oncol	BACKGROUND: Immunotherapy combination treatments can improve patient outcomes. Epacadostat, an IDO1 selective inhibitor, and pembrolizumab, a PD-1 inhibitor, showed promising antitumour activity in the phase 1-2 ECHO-202/KEYNOTE-037 study in advanced melanoma. In this trial, we aimed to compare progression-free survival and overall survival in patients with unresectable stage III or IV melanoma receiving epacadostat plus pembrolizumab versus placebo plus pembrolizumab.METHODS: In this international, randomised, placebo-controlled, double-blind, parallel-group, phase 3 trial, eligible participants were aged 18 years or older, with unresectable stage III or IV melanoma previously untreated with PD-1 or PD-L1 checkpoint inhibitors, an ECOG performance status of 0 or 1, and had a known BRAFV600 mutant status or consented to BRAFV600 mutation testing during screening. Patients were stratified by PD-L1 expression and BRAFV600 mutation status and randomly assigned (1:1) through a central interactive voice and integrated web response system to receive epacadostat 100 mg orally twice daily plus pembrolizumab 200 mg intravenously every 3 weeks or placebo plus pembrolizumab for up to 2 years. We used block randomisation with a block size of four in each stratum. Primary endpoints were progression-free survival and overall survival in the intention-to-treat population. The safety analysis population included randomly assigned patients who received at least one dose of study treatment. The study was stopped after the second interim analysis; follow-up for safety is ongoing. This study is registered with ClinicalTrials.gov, number NCT02752074.FINDINGS: Between June 21, 2016, and Aug 7, 2017, 928 patients were screened and 706 patients were randomly assigned to receive epacadostat plus pembrolizumab (n=354) or placebo plus pembrolizumab (n=352). Median follow-up was 12.4 months (IQR 10.3-14.5). No significant differences were found between the treatment groups for progression-free survival (median 4.7 months, 95% CI 2.9-6.8, for epacadostat plus pembrolizumab vs 4.9 months, 2.9-6.8, for placebo plus pembrolizumab; hazard ratio [HR] 1.00, 95% CI 0.83-1.21; one-sided p=0.52) or overall survival (median not reached in either group; epacadostat plus pembrolizumab vs placebo plus pembrolizumab: HR 1.13, 0.86-1.49; one-sided p=0.81). The most common grade 3 or worse treatment-related adverse event was lipase increase, which occurred in 14 (4%) of 353 patients receiving epacadostat plus pembrolizumab and 11 (3%) of 352 patients receiving placebo plus pembrolizumab. Treatment-related serious adverse events were reported in 37 (10%) of 353 patients receiving epacadostat plus pembrolizumab and 32 (9%) of 352 patients receiving placebo plus pembrolizumab. There were no treatment-related deaths in either treatment group.INTERPRETATION: Epacadostat 100 mg twice daily plus pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus pembrolizumab in patients with unresectable or metastatic melanoma. The usefulness of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain.FUNDING: Incyte Corporation, in collaboration with Merck Sharp & Dohme.
CANIT0002549	31237152	Clinical research	Pretreated advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Nivolumab	Atezolizumab	Immune checkpoint therapy	Atezolizumab (DB11595); nivolumab (DB09035); ipilimumab (DB06186); 	N/A	N/A	Meta-analysis	Considering the overall survival ICIs showed very robust efficacy over docetaxel, while in terms of progression-free survival the therapy with ICIs is slightly favored. Anti-PD-1 gives a more significant benefit than anti-PD-L1; however, excluding the KEYNOTE 010 trial that enrolled only PD-L1-positive patients, the subgroup difference remains only in terms of progression-free survival.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Anti-PD-1 versus anti-PD-L1 therapy in patients with pretreated advanced non-small-cell lung cancer: a meta-analysis.	 Future Oncol	Aim: At present three immune checkpoint inhibitors (ICIs), two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PD-L1 (atezolizumab) can be used in pretreated non-small-cell lung cancer patients. The aim of this meta-analysis is an indirect comparison between anti-PD-1 and anti-PD-L1 inhibitors. Methods: Seven studies (>4000 patients) were considered. Results: Considering the overall survival ICIs showed very robust efficacy over docetaxel, while in terms of progression-free survival the therapy with ICIs is slightly favored. Anti-PD-1 gives a more significant benefit than anti-PD-L1; however, excluding the KEYNOTE 010 trial that enrolled only PD-L1-positive patients, the subgroup difference remains only in terms of progression-free survival. Conclusion: This meta-analysis confirms the superiority of ICIs over docetaxel in pretreated non-small-cell lung cancer patients and would indicate a slight benefit from anti-PD-1 than from anti-PD-L1 inhibitors, always keeping in mind the possible biases of this indirect comparison.
CANIT0002550	31237152	Clinical research	Pretreated advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Pembrolizumab	Atezolizumab	Immune checkpoint therapy	Atezolizumab (DB11595); pembrolizumab (DB09037); 	N/A	N/A	Meta-analysis	Considering the overall survival ICIs showed very robust efficacy over docetaxel, while in terms of progression-free survival the therapy with ICIs is slightly favored. Anti-PD-1 gives a more significant benefit than anti-PD-L1; however, excluding the KEYNOTE 010 trial that enrolled only PD-L1-positive patients, the subgroup difference remains only in terms of progression-free survival.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Anti-PD-1 versus anti-PD-L1 therapy in patients with pretreated advanced non-small-cell lung cancer: a meta-analysis.	 Future Oncol	Aim: At present three immune checkpoint inhibitors (ICIs), two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PD-L1 (atezolizumab) can be used in pretreated non-small-cell lung cancer patients. The aim of this meta-analysis is an indirect comparison between anti-PD-1 and anti-PD-L1 inhibitors. Methods: Seven studies (>4000 patients) were considered. Results: Considering the overall survival ICIs showed very robust efficacy over docetaxel, while in terms of progression-free survival the therapy with ICIs is slightly favored. Anti-PD-1 gives a more significant benefit than anti-PD-L1; however, excluding the KEYNOTE 010 trial that enrolled only PD-L1-positive patients, the subgroup difference remains only in terms of progression-free survival. Conclusion: This meta-analysis confirms the superiority of ICIs over docetaxel in pretreated non-small-cell lung cancer patients and would indicate a slight benefit from anti-PD-1 than from anti-PD-L1 inhibitors, always keeping in mind the possible biases of this indirect comparison.
CANIT0002551	31238988	Clinical research	Recurrent/metastatic nasopharyngeal carcinoma	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Camrelizumab	Camrelizumab plus chemotherapy	Immune checkpoint therapy	Camrelizumab (DB14776); 	N/A	N/A	Meta-analysis	As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in recurrent/metastatic nasopharyngeal carcinoma. 	The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jun 25	Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials.	 J Immunother Cancer	Recent phase 1-2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC.
CANIT0002552	31238988	Clinical research	Recurrent/metastatic nasopharyngeal carcinoma	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Camrelizumab	Chemotherapy	Immune checkpoint therapy	Camrelizumab (DB14776); 	N/A	N/A	Meta-analysis	As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in recurrent/metastatic nasopharyngeal carcinoma. 	The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jun 25	Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials.	 J Immunother Cancer	Recent phase 1-2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC.
CANIT0002553	31238988	Clinical research	Recurrent/metastatic nasopharyngeal carcinoma	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Camrelizumab	Nivolumab	Immune checkpoint therapy	Camrelizumab (DB14776); nivolumab (DB09035); 	N/A	N/A	Meta-analysis	As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in recurrent/metastatic nasopharyngeal carcinoma. 	The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jun 25	Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials.	 J Immunother Cancer	Recent phase 1-2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC.
CANIT0002554	31238988	Clinical research	Recurrent/metastatic nasopharyngeal carcinoma	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Camrelizumab	Pembrolizumab	Immune checkpoint therapy	Camrelizumab (DB14776); pembrolizumab (DB09037); 	N/A	N/A	Meta-analysis	As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in recurrent/metastatic nasopharyngeal carcinoma. 	The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jun 25	Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials.	 J Immunother Cancer	Recent phase 1-2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC.
CANIT0002555	31238988	Clinical research	Recurrent/metastatic nasopharyngeal carcinoma	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Camrelizumab	Toripalimab	Immune checkpoint therapy	Camrelizumab (DB14776); Toripalimab (DB15043); 	N/A	N/A	Meta-analysis	As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in recurrent/metastatic nasopharyngeal carcinoma. 	The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jun 25	Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials.	 J Immunother Cancer	Recent phase 1-2 trials reported manageable safety profiles and promising antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), however head-to-head comparison among these regimens is lacking. We aimed to comprehensively compare the efficacy and safety of different anti-PD-1 drugs, standard chemotherapy, and their combination therapy in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed. The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4, 92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab, JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively, which suggested that nivolumab and pembrolizumab exhibited the optimal safety regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5 AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%), followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas ORR with first-line nivolumab reached 40%. Additionally, first-line camrelizumab+chemotherapy achieved a dramatically higher ORR than that with chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Here, we represent preliminary evidence for the comparative safety and efficacy of existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated that camrelizumab has the least toxicity profile and merits future investigation. Our findings might provide insights into the future design of immunotherapy trials in RM-NPC.
CANIT0002556	31243198	Case report	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A 77-year-old-man with renal cell carcinoma who was undergoing nivolumab treatment visited our department due to hyperglycemia; his plasma glucose level was 379 mg/dL. Although his serum C-peptide immunoreactivity (CPR) level was preserved (5.92 ng/mL), we suspected an onset of fulminant type 1 diabetes mellitus (FT1DM) and immediately started insulin therapy. His CPR levels gradually decreased and were depleted within 1 week. We later discovered that the patient's casual CPR level had been abnormally high (11.78 ng/mL) 2 weeks before his admission.	Nivolumab-related Fulminant Type 1 Diabetes Mellitus	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Oct 1	A Patient with Nivolumab-related Fulminant Type 1 Diabetes Mellitus whose Serum C-peptide Level Was Preserved at the Initial Detection of Hyperglycemia.	 Intern Med	A 77-year-old-man with renal cell carcinoma who was undergoing nivolumab treatment visited our department due to hyperglycemia; his plasma glucose level was 379 mg/dL. Although his serum C-peptide immunoreactivity (CPR) level was preserved (5.92 ng/mL), we suspected an onset of fulminant type 1 diabetes mellitus (FT1DM) and immediately started insulin therapy. His CPR levels gradually decreased and were depleted within 1 week. We later discovered that the patient's casual CPR level had been abnormally high (11.78 ng/mL) 2 weeks before his admission. Hence, the possibility of FT1DM in hyperglycemic patients undergoing nivolumab treatment should not be excluded, even with a preserved CPR level.
CANIT0002557	31246639	Case report	A 73-year-old male with advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We report the first case of gingival linear immunoglobulin A disease related to treatment with an antiprogrammed cell death protein 1 antibody.	 linear immunoglobulin A disease of the gingiva	N/A	N/A	N/A	N/A	N/A	 2019 Nov/Dec	Linear IgA Disease of the Gingiva Following Nivolumab Therapy.	 J Immunother	Immunotherapy has advanced the treatment of solid organ malignancies. Although generally well tolerated, treatment with immune checkpoint inhibitors can be complicated by immune-related adverse events, some of which are relatively uncommon. We report the first case of gingival linear immunoglobulin A disease related to treatment with an antiprogrammed cell death protein 1 antibody. A 73-year-old male with advanced non-small cell lung cancer achieved a durable response to nivolumab monotherapy. After 1 year of treatment, he developed gingival swelling and pain. Biopsy revealed linear immunoglobulin A disease of the gingiva which was effectively treated with systemic steroids. Ongoing vigilance for immune-mediated toxicity is paramount during and after treatment with immune checkpoint inhibitors.
CANIT0002558	31248832	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	83	N/A	Retrospective analysis	Among 83 enrolled patients, the incidence of  immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD) was 16.9% (14/83). All ICI-ILD cases developed by the third line of treatment. The incidence of ICI-ILD was significantly higher in patients with pre-existing ILA than that in those without (p = 0.007). Furthermore, patients with ground glass attenuation (GGA) in ILA had a higher incidence of ICI-ILD than that in those without (p < 0.001). In univariate logistic analysis, ILA were significant risk factors for ICI-ILD (p = 0.005). Multivariate logistic analysis revealed that only GGA in ILA was a significant risk factor for ICI-ILD (p < 0.001). Pre-existing ILA are risk factors for ICI-ILD and GGA in ILA is an independent risk factor for ICI-ILD. Therefore, we should be more aware of the development of ICI-ILD in patients with ILA, especially those with GGA.	Immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD)	N/A	N/A	Interstitial lung disease (NCIT:C27006); 	Ground glass attenuation in Interstitial lung abnormalities	Disease status	 2019 Sep	Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer.	 Respir Investig	BACKGROUND: Approximately 5% of non-small cell lung cancer (NSCLC) patients develop immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD), 10% of whom die. However, there are no established risk factors for its occurrence. Interstitial lung abnormalities (ILA) are areas of increased lung density on lung computed tomography (CT) in individuals with no known ILD. This study retrospectively investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with NSCLC.METHODS: NSCLC patients who received anti-programmed death (PD)-1 antibody treatment at our hospital between September 2015 and December 2017 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained.RESULTS: Among 83 enrolled patients, the incidence of ICI-ILD was 16.9% (14/83). All ICI-ILD cases developed by the third line of treatment. The incidence of ICI-ILD was significantly higher in patients with pre-existing ILA than that in those without (p = 0.007). Furthermore, patients with ground glass attenuation (GGA) in ILA had a higher incidence of ICI-ILD than that in those without (p < 0.001). In univariate logistic analysis, ILA were significant risk factors for ICI-ILD (p = 0.005). Multivariate logistic analysis revealed that only GGA in ILA was a significant risk factor for ICI-ILD (p < 0.001).CONCLUSIONS: Pre-existing ILA are risk factors for ICI-ILD and GGA in ILA is an independent risk factor for ICI-ILD. Therefore, we should be more aware of the development of ICI-ILD in patients with ILA, especially those with GGA.
CANIT0002559	31248832	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	83	N/A	Retrospective analysis	Among 83 enrolled patients, the incidence of  immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD) was 16.9% (14/83). All ICI-ILD cases developed by the third line of treatment. The incidence of ICI-ILD was significantly higher in patients with pre-existing ILA than that in those without (p = 0.007). Furthermore, patients with ground glass attenuation (GGA) in ILA had a higher incidence of ICI-ILD than that in those without (p < 0.001). In univariate logistic analysis, ILA were significant risk factors for ICI-ILD (p = 0.005). Multivariate logistic analysis revealed that only GGA in ILA was a significant risk factor for ICI-ILD (p < 0.001). Pre-existing ILA are risk factors for ICI-ILD and GGA in ILA is an independent risk factor for ICI-ILD. Therefore, we should be more aware of the development of ICI-ILD in patients with ILA, especially those with GGA.	Immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD)	N/A	N/A	Interstitial lung disease (NCIT:C27006); 	Pre-existing Interstitial lung abnormalities	Disease status	 2019 Sep	Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer.	 Respir Investig	BACKGROUND: Approximately 5% of non-small cell lung cancer (NSCLC) patients develop immune checkpoint inhibitor (ICI)-induced interstitial lung disease (ICI-ILD), 10% of whom die. However, there are no established risk factors for its occurrence. Interstitial lung abnormalities (ILA) are areas of increased lung density on lung computed tomography (CT) in individuals with no known ILD. This study retrospectively investigated whether any patient characteristics, including ILA, were risk factors for ICI-ILD in patients with NSCLC.METHODS: NSCLC patients who received anti-programmed death (PD)-1 antibody treatment at our hospital between September 2015 and December 2017 were enrolled. Information on patient characteristics before anti-PD-1 antibody administration, including chest CT findings and laboratory data, were obtained.RESULTS: Among 83 enrolled patients, the incidence of ICI-ILD was 16.9% (14/83). All ICI-ILD cases developed by the third line of treatment. The incidence of ICI-ILD was significantly higher in patients with pre-existing ILA than that in those without (p = 0.007). Furthermore, patients with ground glass attenuation (GGA) in ILA had a higher incidence of ICI-ILD than that in those without (p < 0.001). In univariate logistic analysis, ILA were significant risk factors for ICI-ILD (p = 0.005). Multivariate logistic analysis revealed that only GGA in ILA was a significant risk factor for ICI-ILD (p < 0.001).CONCLUSIONS: Pre-existing ILA are risk factors for ICI-ILD and GGA in ILA is an independent risk factor for ICI-ILD. Therefore, we should be more aware of the development of ICI-ILD in patients with ILA, especially those with GGA.
CANIT0002560	31260834	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	222	N/A	N/A	There was a mismatch in PD-L1 scores less than 1% and those of at least 1% between Max-TC and the total samples in one patient (1%) and between the largest number of TCs (Max-TC) and the smallest number of TCs (Min-TC) in six patients (8%). The optimal number of TCs to match PD-L1 expression less than 1% versus at least 1% between Max-TC and Min-TC was 100 (sensitivity = 0.676 and 1 - specificity = 0.333). PD-L1 expression of at least 1% in Min-TCs containing at least 100 TCs was associated with longer progression-free survival (median 7.6 versus 1.8 months [p < 0.01]) and overall survival (median not reached versus 9.9 months [p = 0.04]) compared with PD-L1 expression less than 1%. However, there were no differences in progression-free survival (median 3.9 versus 2.3 months [p = 0.37]) or overall survival (median 9.7 versus 7.6 months [p = 0.60]) between PD-L1 expression of at least 1% and PD-L1expression less than 1% in Min-TCs containing fewer than 100 TCs.Single biopsy samples containing at least 100 TCs are required to evaluate PD-L1 expression for predicting patient response to nivolumab.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Oct	A Minimum Of 100 Tumor Cells in a Single Biopsy Sample Is Required to Assess Programmed Cell Death Ligand 1 Expression in Predicting Patient Response to Nivolumab Treatment in Nonsquamous Non-Small Cell Lung Carcinoma.	 J Thorac Oncol	INTRODUCTION: Programmed death ligand 1 (PD-L1) expression is a predictive biomarker for patient response to nivolumab in nonsquamous NSCLC. However, the number of biopsy samples and tumor cells (TCs) required to assess PD-L1 expression remains unclear.METHODS: A total of 222 biopsy samples from 80 patients with nonsquamous NSCLC treated with nivolumab were collected. Number of TCs and PD-L1 score were compared among the sample containing the largest number of TCs (Max-TC), the sample containing the smallest number of TCs (Min-TC), and the total samples from each patient. The impact of the number of samples and TCs on the prediction of patient response to nivolumab with use of PD-L1 scores was evaluated.RESULTS: There was a mismatch in PD-L1 scores less than 1% and those of at least 1% between Max-TC and the total samples in one patient (1%) and between Max-TC and Min-TC in six patients (8%). The optimal number of TCs to match PD-L1 expression less than 1% versus at least 1% between Max-TC and Min-TC was 100 (sensitivity = 0.676 and 1 - specificity = 0.333). PD-L1 expression of at least 1% in Min-TCs containing at least 100 TCs was associated with longer progression-free survival (median 7.6 versus 1.8 months [p < 0.01]) and overall survival (median not reached versus 9.9 months [p = 0.04]) compared with PD-L1 expression less than 1%. However, there were no differences in progression-free survival (median 3.9 versus 2.3 months [p = 0.37]) or overall survival (median 9.7 versus 7.6 months [p = 0.60]) between PD-L1 expression of at least 1% and PD-L1expression less than 1% in Min-TCs containing fewer than 100 TCs.CONCLUSION: Single biopsy samples containing at least 100 TCs are required to evaluate PD-L1 expression for predicting patient response to nivolumab.
CANIT0002561	31260834	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	222	N/A	N/A	There was a mismatch in PD-L1 scores less than 1% and those of at least 1% between Max-TC and the total samples in one patient (1%) and between the largest number of TCs (Max-TC) and the smallest number of TCs (Min-TC) in six patients (8%). The optimal number of TCs to match PD-L1 expression less than 1% versus at least 1% between Max-TC and Min-TC was 100 (sensitivity = 0.676 and 1 - specificity = 0.333). PD-L1 expression of at least 1% in Min-TCs containing at least 100 TCs was associated with longer progression-free survival (median 7.6 versus 1.8 months [p < 0.01]) and overall survival (median not reached versus 9.9 months [p = 0.04]) compared with PD-L1 expression less than 1%. However, there were no differences in progression-free survival (median 3.9 versus 2.3 months [p = 0.37]) or overall survival (median 9.7 versus 7.6 months [p = 0.60]) between PD-L1 expression of at least 1% and PD-L1expression less than 1% in Min-TCs containing fewer than 100 TCs.Single biopsy samples containing at least 100 TCs are required to evaluate PD-L1 expression for predicting patient response to nivolumab.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Tumor burden (NCIT:C28384); 	Single biopsy samples containing at least 100 tumor cells	Disease status	 2019 Oct	A Minimum Of 100 Tumor Cells in a Single Biopsy Sample Is Required to Assess Programmed Cell Death Ligand 1 Expression in Predicting Patient Response to Nivolumab Treatment in Nonsquamous Non-Small Cell Lung Carcinoma.	 J Thorac Oncol	INTRODUCTION: Programmed death ligand 1 (PD-L1) expression is a predictive biomarker for patient response to nivolumab in nonsquamous NSCLC. However, the number of biopsy samples and tumor cells (TCs) required to assess PD-L1 expression remains unclear.METHODS: A total of 222 biopsy samples from 80 patients with nonsquamous NSCLC treated with nivolumab were collected. Number of TCs and PD-L1 score were compared among the sample containing the largest number of TCs (Max-TC), the sample containing the smallest number of TCs (Min-TC), and the total samples from each patient. The impact of the number of samples and TCs on the prediction of patient response to nivolumab with use of PD-L1 scores was evaluated.RESULTS: There was a mismatch in PD-L1 scores less than 1% and those of at least 1% between Max-TC and the total samples in one patient (1%) and between Max-TC and Min-TC in six patients (8%). The optimal number of TCs to match PD-L1 expression less than 1% versus at least 1% between Max-TC and Min-TC was 100 (sensitivity = 0.676 and 1 - specificity = 0.333). PD-L1 expression of at least 1% in Min-TCs containing at least 100 TCs was associated with longer progression-free survival (median 7.6 versus 1.8 months [p < 0.01]) and overall survival (median not reached versus 9.9 months [p = 0.04]) compared with PD-L1 expression less than 1%. However, there were no differences in progression-free survival (median 3.9 versus 2.3 months [p = 0.37]) or overall survival (median 9.7 versus 7.6 months [p = 0.60]) between PD-L1 expression of at least 1% and PD-L1expression less than 1% in Min-TCs containing fewer than 100 TCs.CONCLUSION: Single biopsy samples containing at least 100 TCs are required to evaluate PD-L1 expression for predicting patient response to nivolumab.
CANIT0002562	31262921	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Nivolumab followed by atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	8	N/A	Retrospective analysis	Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab. Nine patients a had high (>=50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9+/-1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response.	There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab.	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Retreatment With Anti-PD-L1 Antibody in Advanced Non-small Cell Lung Cancer Previously Treated With Anti-PD-1 Antibodies.	 Anticancer Res	AIM: To evaluate the efficacy and safety of re-treatment with anti-programmed death (PD)-L1 antibody (atezolizumab) after anti-PD-1 antibody (nivolumab/pembrolizumab) treatment in advanced non-small cell lung cancer (NSCLC) patients.PATIENTS AND METHODS: We retrospectively reviewed 18 NSCLC patients who received atezolizumab after anti-PD-1 antibody treatment. Data on patient characteristics, number of cycles of anti-PD-1 antibody and atezolizumab, regimens between anti-PD-1 antibody and atezolizumab, best response, and immune-related adverse events (irAEs) were collected and analyzed.RESULTS: Nine patients a had high (>=50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9+/-1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response. There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab.CONCLUSION: Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab.
CANIT0002563	31262921	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Pembrolizumab followed by atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); pembrolizumab (DB09037); 	7	N/A	Retrospective analysis	Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab. Nine patients a had high (>=50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9+/-1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response.	There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab.	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Retreatment With Anti-PD-L1 Antibody in Advanced Non-small Cell Lung Cancer Previously Treated With Anti-PD-1 Antibodies.	 Anticancer Res	AIM: To evaluate the efficacy and safety of re-treatment with anti-programmed death (PD)-L1 antibody (atezolizumab) after anti-PD-1 antibody (nivolumab/pembrolizumab) treatment in advanced non-small cell lung cancer (NSCLC) patients.PATIENTS AND METHODS: We retrospectively reviewed 18 NSCLC patients who received atezolizumab after anti-PD-1 antibody treatment. Data on patient characteristics, number of cycles of anti-PD-1 antibody and atezolizumab, regimens between anti-PD-1 antibody and atezolizumab, best response, and immune-related adverse events (irAEs) were collected and analyzed.RESULTS: Nine patients a had high (>=50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9+/-1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response. There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab.CONCLUSION: Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab.
CANIT0002564	31262921	Clinical research	Advanced non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Pembrolizumab plus Nivolumab followed by atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); pembrolizumab (DB09037); nivolumab (DB09035); 	3	N/A	Retrospective analysis	Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab. Nine patients a had high (>=50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9+/-1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response.	There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab.	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Retreatment With Anti-PD-L1 Antibody in Advanced Non-small Cell Lung Cancer Previously Treated With Anti-PD-1 Antibodies.	 Anticancer Res	AIM: To evaluate the efficacy and safety of re-treatment with anti-programmed death (PD)-L1 antibody (atezolizumab) after anti-PD-1 antibody (nivolumab/pembrolizumab) treatment in advanced non-small cell lung cancer (NSCLC) patients.PATIENTS AND METHODS: We retrospectively reviewed 18 NSCLC patients who received atezolizumab after anti-PD-1 antibody treatment. Data on patient characteristics, number of cycles of anti-PD-1 antibody and atezolizumab, regimens between anti-PD-1 antibody and atezolizumab, best response, and immune-related adverse events (irAEs) were collected and analyzed.RESULTS: Nine patients a had high (>=50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9+/-1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response. There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab.CONCLUSION: Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab.
CANIT0002565	31267017	Basic research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Basic research	Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors.The data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Aug	Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy.	 Cell Res	It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.
CANIT0002566	31272883	Clinical research	821 patients 	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	Everolimus	Immune checkpoint therapy	Nivolumab (DB09035); 	410	411	Post-hoc analysis	Nivolumab is associated with a statistically significant and clinically meaningful gain in quality-adjusted OS versus everolimus among previously treated patients with advanced renal cell carcinoma	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Oct	A Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) Analysis of Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma (aRCC).	 Clin Genitourin Cancer	BACKGROUND: This analysis compared quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) between nivolumab and everolimus among previously treated patients with advanced renal cell carcinoma enrolled in the phase III CheckMate 025 trial (NCT01668784).MATERIALS AND METHODS: At 45-month follow-up, overall survival (OS) was partitioned into 3 health states: TWiST, time with grade >= 3 toxicity (TOX), and time after progression (REL). Mean Q-TWiST was determined by multiplying each state's duration with its utility (TWiST, 1.0; TOX, 0.5; REL, 0.5). Relative Q-TWiST gains (calculated as Q-TWiST difference divided by everolimus OS) of >= 10% were predefined as clinically important. Immuno-oncology-specific sensitivity analyses considered 4 alternative progression definitions: Tumor size increase >= 25% from nadir; treatment discontinuation; >= 2-point reduction from baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index Disease-Related Symptoms scores; and a composite definition. A scenario incorporating grade >= 2 toxicities was tested.RESULTS: Compared with everolimus, nivolumab was associated with a significant Q-TWiST improvement of 3.3 months (P < .001). In all sensitivity analyses, nivolumab was associated with Q-TWiST gains (relative gain %) ranging from 3.3 months (14.4%) to 4.8 months (20.9%).CONCLUSIONS: Nivolumab is associated with a statistically significant and clinically meaningful gain in quality-adjusted OS versus everolimus among previously treated patients with advanced renal cell carcinoma.
CANIT0002567	31276163	Clinical research	Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy	Adrenocortical carcinoma	MONDO:0008734	Adrenal gland	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	Single-arm, multicenter, phase II	Nivolumab demonstrated modest antitumor activity in patients with advanced adrenocortical carcinoma. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec 1	Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial.	 J Clin Endocrinol Metab	CONTEXT: Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti-PD-1 nivolumab.OBJECTIVE: The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety.DESIGN: Single-arm, multicenter, phase 2 clinical trial with two-stage design.SETTING: Comprehensive cancer center.PATIENTS: Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy.INTERVENTION: Nivolumab (240 mg) IV every 2 weeks.RESULTS: Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment]. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia.CONCLUSION: Nivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population.
CANIT0002568	31277704	Case report	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	A 74 years old Caucasian male treated with single-agent pembrolizumab for metastatic non-small cell lung cancer presented with fevers, chills, and an isolated neutrophil count (ANC) of 0 2 weeks after the fourth dose. In addition to antibiotics, due to the strong suspicion of this neutropenia being immune-mediated, he was started on 1 mg/kg of steroids and also received filgrastim to accelerate neutrophil recovery. Serial trends in C-reactive protein and certain other inflammatory cytokines demonstrated a corresponding rise at the time of neutropenia. Post recovery, his pembrolizumab was kept on hold. Eight weeks later he had a second episode of neutropenia which was again managed similar to the first episode. Despite permanent discontinuation of ICI after the first neutropenia, his disease showed an ongoing complete metabolic response on imaging.Careful monitoring of these patients with the prompt initiation of immunosuppressive and supportive measures to promote rapid recovery as well as prevent and treat infectious complications should be part of the management algorithms. Serial monitoring of blood and plasma-based biomarkers from more extensive studies may help in identifying patients at risk for irAEs and thus guide patient selection for ICI.	Isolated neutropenia	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2019 Jul 5	Isolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: Compared to conventional chemotherapy, Immune checkpoint inhibitors (ICI) are known to have a distinct toxicity profile commonly identified as immune-related adverse events (irAEs). These irAEs that are believed to be related to immune dysregulations triggered by ICI can be serious and lead to treatment interruptions and in severe cases, precipitate permanent discontinuation. Isolated neutropenia secondary to ICI has been rarely documented in the literature and needs further description. We report a case of pembrolizumab related severe isolated neutropenia in a patient with metastatic non-small cell lung cancer. We were also able to obtain serial blood and plasma-based biomarkers for this patient during treatment and during neutropenia to understand trends that may correlate with the irAE. In addition we summarize important findings from other studies reporting on ICI related neutropenia.CASE PRESENTATION: A 74 years old Caucasian male treated with single-agent pembrolizumab for metastatic non-small cell lung cancer presented with fevers, chills, and an isolated neutrophil count (ANC) of 0 2 weeks after the fourth dose. In addition to antibiotics, due to the strong suspicion of this neutropenia being immune-mediated, he was started on 1 mg/kg of steroids and also received filgrastim to accelerate neutrophil recovery. Serial trends in C-reactive protein and certain other inflammatory cytokines demonstrated a corresponding rise at the time of neutropenia. Post recovery, his pembrolizumab was kept on hold. Eight weeks later he had a second episode of neutropenia which was again managed similar to the first episode. Despite permanent discontinuation of ICI after the first neutropenia, his disease showed an ongoing complete metabolic response on imaging. Our literature review reveals that hematological toxicities constitute < 1% irAEs with isolated neutropenia roughly accounting for one-fourth of the hematological irAEs. Based on the handful of ICI related neutropenia cases reported to date, we identified nivolumab to be the most common offender. The median number of ICI cycles administered before presenting with neutropenia was three, and the median time to recovery was approximately two weeks. All of these neutropenic episodes were >= grade 3 and led to permanent ICI discontinuation. Using immunosuppressive therapies in conjunction with granulocyte-colony stimulating factor was the most common strategy described to have favorable results.CONCLUSION: Neutropenia as an isolated irAE secondary to ICI is rare but represents a severe toxicity that needs early recognition and can often result in treatment discontinuations. Careful monitoring of these patients with the prompt initiation of immunosuppressive and supportive measures to promote rapid recovery as well as prevent and treat infectious complications should be part of the management algorithms. Serial monitoring of blood and plasma-based biomarkers from more extensive studies may help in identifying patients at risk for irAEs and thus guide patient selection for ICI.
CANIT0002569	31277704	Case report	Metastatic non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	A 74 years old Caucasian male treated with single-agent pembrolizumab for metastatic non-small cell lung cancer presented with fevers, chills, and an isolated neutrophil count (ANC) of 0 2 weeks after the fourth dose. In addition to antibiotics, due to the strong suspicion of this neutropenia being immune-mediated, he was started on 1 mg/kg of steroids and also received filgrastim to accelerate neutrophil recovery. Serial trends in C-reactive protein and certain other inflammatory cytokines demonstrated a corresponding rise at the time of neutropenia. Post recovery, his pembrolizumab was kept on hold. Eight weeks later he had a second episode of neutropenia which was again managed similar to the first episode. Despite permanent discontinuation of ICI after the first neutropenia, his disease showed an ongoing complete metabolic response on imaging.Careful monitoring of these patients with the prompt initiation of immunosuppressive and supportive measures to promote rapid recovery as well as prevent and treat infectious complications should be part of the management algorithms. Serial monitoring of blood and plasma-based biomarkers from more extensive studies may help in identifying patients at risk for irAEs and thus guide patient selection for ICI.	Isolated neutropenia	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Jul 5	Isolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition.	 J Immunother Cancer	BACKGROUND: Compared to conventional chemotherapy, Immune checkpoint inhibitors (ICI) are known to have a distinct toxicity profile commonly identified as immune-related adverse events (irAEs). These irAEs that are believed to be related to immune dysregulations triggered by ICI can be serious and lead to treatment interruptions and in severe cases, precipitate permanent discontinuation. Isolated neutropenia secondary to ICI has been rarely documented in the literature and needs further description. We report a case of pembrolizumab related severe isolated neutropenia in a patient with metastatic non-small cell lung cancer. We were also able to obtain serial blood and plasma-based biomarkers for this patient during treatment and during neutropenia to understand trends that may correlate with the irAE. In addition we summarize important findings from other studies reporting on ICI related neutropenia.CASE PRESENTATION: A 74 years old Caucasian male treated with single-agent pembrolizumab for metastatic non-small cell lung cancer presented with fevers, chills, and an isolated neutrophil count (ANC) of 0 2 weeks after the fourth dose. In addition to antibiotics, due to the strong suspicion of this neutropenia being immune-mediated, he was started on 1 mg/kg of steroids and also received filgrastim to accelerate neutrophil recovery. Serial trends in C-reactive protein and certain other inflammatory cytokines demonstrated a corresponding rise at the time of neutropenia. Post recovery, his pembrolizumab was kept on hold. Eight weeks later he had a second episode of neutropenia which was again managed similar to the first episode. Despite permanent discontinuation of ICI after the first neutropenia, his disease showed an ongoing complete metabolic response on imaging. Our literature review reveals that hematological toxicities constitute < 1% irAEs with isolated neutropenia roughly accounting for one-fourth of the hematological irAEs. Based on the handful of ICI related neutropenia cases reported to date, we identified nivolumab to be the most common offender. The median number of ICI cycles administered before presenting with neutropenia was three, and the median time to recovery was approximately two weeks. All of these neutropenic episodes were >= grade 3 and led to permanent ICI discontinuation. Using immunosuppressive therapies in conjunction with granulocyte-colony stimulating factor was the most common strategy described to have favorable results.CONCLUSION: Neutropenia as an isolated irAE secondary to ICI is rare but represents a severe toxicity that needs early recognition and can often result in treatment discontinuations. Careful monitoring of these patients with the prompt initiation of immunosuppressive and supportive measures to promote rapid recovery as well as prevent and treat infectious complications should be part of the management algorithms. Serial monitoring of blood and plasma-based biomarkers from more extensive studies may help in identifying patients at risk for irAEs and thus guide patient selection for ICI.
CANIT0002570	31277824	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines	N/A	Basic research	We identified drugs being studied in clinical trials at the time of ipilimumab's approval on clinicaltrials.gov and estimated their likelihood and timing of approval, potential efficacy, and cost. We accounted for increases in overall cancer treatment cost and unrelated medical cost in the option value scenario.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	How Does Option Value Affect the Potential Cost-Effectiveness of a Treatment  The Case of Ipilimumab for Metastatic Melanoma.	 Value Health	BACKGROUND: Innovations that extend life can generate option value and cost of experiencing future technologies.OBJECTIVES: To understand how consideration of option value may affect the potential cost-effectiveness of a treatment through a case study of ipilimumab for previously untreated metastatic melanoma.METHODS: We estimated the cost-effectiveness of ipilimumab in 2 scenarios: a conventional scenario, for which we constructed the model using the standard methods that rely on efficacy data directly from the phase III trial of ipilimumab, and an option value scenario, where we incorporated future hypothetical improvements in mortality for metastatic melanoma owing to innovations. We developed 2 approaches to incorporate option value. In the first approach, we forecasted mortality trends based on historical trends from the Surveillance, Epidemiology, and End Results (SEER) Program registry. Alternatively, we identified drugs being studied in clinical trials at the time of ipilimumab's approval on clinicaltrials.gov and estimated their likelihood and timing of approval, potential efficacy, and cost. We accounted for increases in overall cancer treatment cost and unrelated medical cost in the option value scenario.RESULTS: In the option value scenario, using the SEER approach, the incremental quality-adjusted life-years (QALYs) gained and the incremental cost increased by 6.2% and 3.8%, respectively, whereas the incremental cost-effectiveness ratio (ICER) decreased by 2.3% compared with the conventional scenario. Using the clinicaltrials.gov approach, the incremental QALY gained and the incremental cost increased by 7.5% and 7.1%, respectively, whereas the ICER decreased by 0.40%.CONCLUSIONS: We developed generalizable approaches to estimating option value in cost-effectiveness analysis.
CANIT0002571	31282096	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	44	N/A	N/A	The optimal cutoff value of systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) predicted PFS and OS was 603.5, 3.07, and 144. Low SII, NLR, and PLR were associated with longer PFS (HR for SII = 0.34, 95%CI 0.15-0.76, P = 0.006; HR for NLR = 0.46, 95%CI 0.22-0.99, P = 0.048; HR for PLR = 0.39, 95%CI 0.17-0.94, P = 0.025) and OS (HR for SII = 0.16, 95%CI 0.05-0.51, P = 0.005; HR for NLR = 0.20, 95%CI 0.06-0.62, P = 0.002; HR for PLR = 0.20, 95%CI 0.06-0.73, P = 0.008). NLR <= 3.07, PLR <= 144, SII <= 603.5 were independently associated with longer PFS and OS.The SII, NLR, and PLR are promising prognostic predictor for patients with metastatic NSCLC patients.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Oct	Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab.	 J Clin Lab Anal	BACKGROUND: Explore markers to predict the clinical outcomes of checkpoint inhibitors have high unmet needs. The following study investigates whether hematologic parameter such as systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) is associated with nivolumab efficacy in advanced non-small-cell lung cancer (NSCLC).METHODS: Advanced/metastatic NSCLC patients treated with nivolumab monotherapy for second-line or further-line treatment at Jilin Cancer Hospital between March 2016 and July 2018 were enrolled in this retrospective study. The optimal cutoff values of SII, NLR, and PLR for predicting efficacy and prognosis were determined according to receiver operating characteristic (ROC) curve and the areas under the ROC curve. Progression-free survival (PFS) and overall survival (OS) were calculated and compared using Kaplan-Meier method and log-rank test. Prognostic values of each variable were evaluated with univariate and multivariate Cox proportional hazard regression (PHR) analyses.RESULTS: A total of 44 patients with advanced NSCLC were included; the median age was 60 (range: 43-74). The optimal cutoff value of SII/NLR/PLR predicted PFS and OS was 603.5, 3.07, and 144. Low SII, NLR, and PLR were associated with longer PFS (HR for SII = 0.34, 95%CI 0.15-0.76, P = 0.006; HR for NLR = 0.46, 95%CI 0.22-0.99, P = 0.048; HR for PLR = 0.39, 95%CI 0.17-0.94, P = 0.025) and OS (HR for SII = 0.16, 95%CI 0.05-0.51, P = 0.005; HR for NLR = 0.20, 95%CI 0.06-0.62, P = 0.002; HR for PLR = 0.20, 95%CI 0.06-0.73, P = 0.008). NLR <= 3.07, PLR <= 144, SII <= 603.5 were independently associated with longer PFS and OS.CONCLUSION: The SII, NLR, and PLR are promising prognostic predictor for patients with metastatic NSCLC patients.
CANIT0002572	31282096	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	44	N/A	N/A	The optimal cutoff value of systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) predicted PFS and OS was 603.5, 3.07, and 144. Low SII, NLR, and PLR were associated with longer PFS (HR for SII = 0.34, 95%CI 0.15-0.76, P = 0.006; HR for NLR = 0.46, 95%CI 0.22-0.99, P = 0.048; HR for PLR = 0.39, 95%CI 0.17-0.94, P = 0.025) and OS (HR for SII = 0.16, 95%CI 0.05-0.51, P = 0.005; HR for NLR = 0.20, 95%CI 0.06-0.62, P = 0.002; HR for PLR = 0.20, 95%CI 0.06-0.73, P = 0.008). NLR <= 3.07, PLR <= 144, SII <= 603.5 were independently associated with longer PFS and OS.The SII, NLR, and PLR are promising prognostic predictor for patients with metastatic NSCLC patients.	N/A	N/A	N/A	Platelet-to-lymphocyte ratios (EFO:0008446); 	Platelet-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Oct	Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab.	 J Clin Lab Anal	BACKGROUND: Explore markers to predict the clinical outcomes of checkpoint inhibitors have high unmet needs. The following study investigates whether hematologic parameter such as systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) is associated with nivolumab efficacy in advanced non-small-cell lung cancer (NSCLC).METHODS: Advanced/metastatic NSCLC patients treated with nivolumab monotherapy for second-line or further-line treatment at Jilin Cancer Hospital between March 2016 and July 2018 were enrolled in this retrospective study. The optimal cutoff values of SII, NLR, and PLR for predicting efficacy and prognosis were determined according to receiver operating characteristic (ROC) curve and the areas under the ROC curve. Progression-free survival (PFS) and overall survival (OS) were calculated and compared using Kaplan-Meier method and log-rank test. Prognostic values of each variable were evaluated with univariate and multivariate Cox proportional hazard regression (PHR) analyses.RESULTS: A total of 44 patients with advanced NSCLC were included; the median age was 60 (range: 43-74). The optimal cutoff value of SII/NLR/PLR predicted PFS and OS was 603.5, 3.07, and 144. Low SII, NLR, and PLR were associated with longer PFS (HR for SII = 0.34, 95%CI 0.15-0.76, P = 0.006; HR for NLR = 0.46, 95%CI 0.22-0.99, P = 0.048; HR for PLR = 0.39, 95%CI 0.17-0.94, P = 0.025) and OS (HR for SII = 0.16, 95%CI 0.05-0.51, P = 0.005; HR for NLR = 0.20, 95%CI 0.06-0.62, P = 0.002; HR for PLR = 0.20, 95%CI 0.06-0.73, P = 0.008). NLR <= 3.07, PLR <= 144, SII <= 603.5 were independently associated with longer PFS and OS.CONCLUSION: The SII, NLR, and PLR are promising prognostic predictor for patients with metastatic NSCLC patients.
CANIT0002573	31282096	Clinical research	Advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	44	N/A	N/A	The optimal cutoff value of systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) predicted PFS and OS was 603.5, 3.07, and 144. Low SII, NLR, and PLR were associated with longer PFS (HR for SII = 0.34, 95%CI 0.15-0.76, P = 0.006; HR for NLR = 0.46, 95%CI 0.22-0.99, P = 0.048; HR for PLR = 0.39, 95%CI 0.17-0.94, P = 0.025) and OS (HR for SII = 0.16, 95%CI 0.05-0.51, P = 0.005; HR for NLR = 0.20, 95%CI 0.06-0.62, P = 0.002; HR for PLR = 0.20, 95%CI 0.06-0.73, P = 0.008). NLR <= 3.07, PLR <= 144, SII <= 603.5 were independently associated with longer PFS and OS.The SII, NLR, and PLR are promising prognostic predictor for patients with metastatic NSCLC patients.	N/A	N/A	N/A	Systemic immune-inflammation index ()	Systemic immune-inflammation index (SII)	Immune response	 2019 Oct	Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab.	 J Clin Lab Anal	BACKGROUND: Explore markers to predict the clinical outcomes of checkpoint inhibitors have high unmet needs. The following study investigates whether hematologic parameter such as systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) is associated with nivolumab efficacy in advanced non-small-cell lung cancer (NSCLC).METHODS: Advanced/metastatic NSCLC patients treated with nivolumab monotherapy for second-line or further-line treatment at Jilin Cancer Hospital between March 2016 and July 2018 were enrolled in this retrospective study. The optimal cutoff values of SII, NLR, and PLR for predicting efficacy and prognosis were determined according to receiver operating characteristic (ROC) curve and the areas under the ROC curve. Progression-free survival (PFS) and overall survival (OS) were calculated and compared using Kaplan-Meier method and log-rank test. Prognostic values of each variable were evaluated with univariate and multivariate Cox proportional hazard regression (PHR) analyses.RESULTS: A total of 44 patients with advanced NSCLC were included; the median age was 60 (range: 43-74). The optimal cutoff value of SII/NLR/PLR predicted PFS and OS was 603.5, 3.07, and 144. Low SII, NLR, and PLR were associated with longer PFS (HR for SII = 0.34, 95%CI 0.15-0.76, P = 0.006; HR for NLR = 0.46, 95%CI 0.22-0.99, P = 0.048; HR for PLR = 0.39, 95%CI 0.17-0.94, P = 0.025) and OS (HR for SII = 0.16, 95%CI 0.05-0.51, P = 0.005; HR for NLR = 0.20, 95%CI 0.06-0.62, P = 0.002; HR for PLR = 0.20, 95%CI 0.06-0.73, P = 0.008). NLR <= 3.07, PLR <= 144, SII <= 603.5 were independently associated with longer PFS and OS.CONCLUSION: The SII, NLR, and PLR are promising prognostic predictor for patients with metastatic NSCLC patients.
CANIT0002574	31290993	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus platinum-based chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	14395	N/A	Meta-analysis	Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001). Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); Immune responses (NCIT:C17930); 	CD8(+) T-cell tumor-infiltrating lymphocytes	Tumor-infiltrating immune cell	 2019 Jul 3	Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer: A Meta-analysis and Individual Patient-Level Analysis.	 JAMA Netw Open	IMPORTANCE: The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non-small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition.OBJECTIVES: To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors.DATA SOURCES: The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, including tumor vaccine, cellular immunotherapy, immune checkpoint inhibitor, cytotoxic T-lymphocyte-associated protein 4, programmed death-ligand 1, programmed death receptor 1, and non-small cell lung carcinoma. Systematic reviews, meta-analyses, references, and conference proceedings were manually searched.STUDY SELECTION: English-language randomized clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included. Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC.DATA EXTRACTION AND SYNTHESIS: Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS. Dichotomous data, such as object response rate data, were analyzed using the risk ratio. Mantel-Haenszel random-effects model was used. I2 was used to assess the heterogeneity between trials; an I2 value exceeding 50% indicated the existence of substantial heterogeneity. Analyses took place from February 1, 2018, to August 31, 2018.MAIN OUTCOMES AND MEASURES: Primary outcomes were OS and PFS.RESULTS: In total, 14 395 patients (9500 [66.0%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 65.2 [9.9] years; 1063 [58.0%] men) were included in the individual patient-level study. Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001).CONCLUSIONS AND RELEVANCE: Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.
CANIT0002575	31290993	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus platinum-based chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	14395	N/A	Meta-analysis	Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001). Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.	N/A	N/A	N/A	MGAM (O43451); 	MGAM mutation	Mutational status	 2019 Jul 3	Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer: A Meta-analysis and Individual Patient-Level Analysis.	 JAMA Netw Open	IMPORTANCE: The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non-small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition.OBJECTIVES: To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors.DATA SOURCES: The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, including tumor vaccine, cellular immunotherapy, immune checkpoint inhibitor, cytotoxic T-lymphocyte-associated protein 4, programmed death-ligand 1, programmed death receptor 1, and non-small cell lung carcinoma. Systematic reviews, meta-analyses, references, and conference proceedings were manually searched.STUDY SELECTION: English-language randomized clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included. Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC.DATA EXTRACTION AND SYNTHESIS: Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS. Dichotomous data, such as object response rate data, were analyzed using the risk ratio. Mantel-Haenszel random-effects model was used. I2 was used to assess the heterogeneity between trials; an I2 value exceeding 50% indicated the existence of substantial heterogeneity. Analyses took place from February 1, 2018, to August 31, 2018.MAIN OUTCOMES AND MEASURES: Primary outcomes were OS and PFS.RESULTS: In total, 14 395 patients (9500 [66.0%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 65.2 [9.9] years; 1063 [58.0%] men) were included in the individual patient-level study. Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001).CONCLUSIONS AND RELEVANCE: Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.
CANIT0002576	31290993	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus platinum-based chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	14395	N/A	Meta-analysis	Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001). Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jul 3	Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer: A Meta-analysis and Individual Patient-Level Analysis.	 JAMA Netw Open	IMPORTANCE: The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non-small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition.OBJECTIVES: To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors.DATA SOURCES: The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, including tumor vaccine, cellular immunotherapy, immune checkpoint inhibitor, cytotoxic T-lymphocyte-associated protein 4, programmed death-ligand 1, programmed death receptor 1, and non-small cell lung carcinoma. Systematic reviews, meta-analyses, references, and conference proceedings were manually searched.STUDY SELECTION: English-language randomized clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included. Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC.DATA EXTRACTION AND SYNTHESIS: Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS. Dichotomous data, such as object response rate data, were analyzed using the risk ratio. Mantel-Haenszel random-effects model was used. I2 was used to assess the heterogeneity between trials; an I2 value exceeding 50% indicated the existence of substantial heterogeneity. Analyses took place from February 1, 2018, to August 31, 2018.MAIN OUTCOMES AND MEASURES: Primary outcomes were OS and PFS.RESULTS: In total, 14 395 patients (9500 [66.0%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 65.2 [9.9] years; 1063 [58.0%] men) were included in the individual patient-level study. Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001).CONCLUSIONS AND RELEVANCE: Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.
CANIT0002577	31290993	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus platinum-based chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	14395	N/A	Meta-analysis	Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001). Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.	N/A	N/A	N/A	RYR1 (P21817); 	RYR1 mutation	Mutational status	 2019 Jul 3	Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer: A Meta-analysis and Individual Patient-Level Analysis.	 JAMA Netw Open	IMPORTANCE: The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non-small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition.OBJECTIVES: To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors.DATA SOURCES: The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, including tumor vaccine, cellular immunotherapy, immune checkpoint inhibitor, cytotoxic T-lymphocyte-associated protein 4, programmed death-ligand 1, programmed death receptor 1, and non-small cell lung carcinoma. Systematic reviews, meta-analyses, references, and conference proceedings were manually searched.STUDY SELECTION: English-language randomized clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included. Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC.DATA EXTRACTION AND SYNTHESIS: Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS. Dichotomous data, such as object response rate data, were analyzed using the risk ratio. Mantel-Haenszel random-effects model was used. I2 was used to assess the heterogeneity between trials; an I2 value exceeding 50% indicated the existence of substantial heterogeneity. Analyses took place from February 1, 2018, to August 31, 2018.MAIN OUTCOMES AND MEASURES: Primary outcomes were OS and PFS.RESULTS: In total, 14 395 patients (9500 [66.0%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 65.2 [9.9] years; 1063 [58.0%] men) were included in the individual patient-level study. Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001).CONCLUSIONS AND RELEVANCE: Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.
CANIT0002578	31290993	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus platinum-based chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	14395	N/A	Meta-analysis	Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001). Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Jul 3	Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer: A Meta-analysis and Individual Patient-Level Analysis.	 JAMA Netw Open	IMPORTANCE: The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non-small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition.OBJECTIVES: To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors.DATA SOURCES: The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, including tumor vaccine, cellular immunotherapy, immune checkpoint inhibitor, cytotoxic T-lymphocyte-associated protein 4, programmed death-ligand 1, programmed death receptor 1, and non-small cell lung carcinoma. Systematic reviews, meta-analyses, references, and conference proceedings were manually searched.STUDY SELECTION: English-language randomized clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included. Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC.DATA EXTRACTION AND SYNTHESIS: Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS. Dichotomous data, such as object response rate data, were analyzed using the risk ratio. Mantel-Haenszel random-effects model was used. I2 was used to assess the heterogeneity between trials; an I2 value exceeding 50% indicated the existence of substantial heterogeneity. Analyses took place from February 1, 2018, to August 31, 2018.MAIN OUTCOMES AND MEASURES: Primary outcomes were OS and PFS.RESULTS: In total, 14 395 patients (9500 [66.0%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 65.2 [9.9] years; 1063 [58.0%] men) were included in the individual patient-level study. Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001).CONCLUSIONS AND RELEVANCE: Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies.
CANIT0002579	31291995	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab plus nivolumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); nivolumab (DB09035); 	104	N/A	N/A	More tumor derived extracellular vesicles were associated with shorter survival but not with response rate.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Extracellular vesicles (OMIT:0001136); 	Tumor derived extracellular vesicles	Gene expression signature in serum	 2019 Jul 10	Circulating tumor cells in advanced non-small cell lung cancer patients are associated with worse tumor response to checkpoint inhibitors.	 J Immunother Cancer	BACKGROUND: Non-small cell lung cancer (NSCLC) patients treated with checkpoint inhibitors show long lasting responses, but it is hard to predict which patients will profit from this treatment with the currently used marker, programmed death ligand 1 (PD-L1). We hypothesized that circulating tumor cells (CTC) or tumor derived extracellular vesicles (tdEV) are markers of treatment efficacy.METHODS: Patients with advanced NSCLC treated with checkpoint inhibitors were included. Blood was drawn at baseline (T0) and at 4 weeks of treatment (T1) for analysis of CTC and tdEV using CellSearch . Tumor response was classified as partial or complete response based on the response evaluation criteria in solid tumors (RECISTv1.1) measured 4-6 weeks after start of treatment. Durable response was defined as stable disease, partial or complete response without disease progression at 6 months. Analyses were adjusted for covariables including PD-L1 expression.RESULTS: We included 104 patients (30 with a tumor response, 74 non-responders, 2 responses not evaluable due to early death); 63 patients provided T1 samples. All patients were treated with PD-L1 inhibitors. The majority of patients received second (85%) or third line (treatment with nivolumab monotherapy (89%). CTC were present in 33/104 patients at T0 (32%) and 17/63 at T1 (27%), 9/63 patients had CTC (14%) at both time points. The presence of CTC, both at T0 (OR = 0.28, p = 0.02,) and T1 (OR = 0.07, p < 0.01), was an independent predictive factor for a lack of durable response and was associated with worse progression free and overall survival. More tdEV were associated with shorter survival but not with response rate.CONCLUSION: CTC occur in one third of advanced NSCLC patients and their presence is a predictive factor for a worse durable response rate to checkpoint inhibitors. tdEV are associated with shorter survival but not with response.
CANIT0002580	31291995	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab plus nivolumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); nivolumab (DB09035); 	104	N/A	N/A	Circulating tumor cells (CTC) were present in 33/104 patients at baseline (T0) (32%) and 17/63 at 4 weeks of treatment (T1) (27%), 9/63 patients had CTC (14%) at both time points. The presence of CTC, both at T0 (OR = 0.28, p = 0.02,) and T1 (OR = 0.07, p < 0.01), was an independent predictive factor for a lack of durable response and was associated with worse progression free and overall survival. More tdEV were associated with shorter survival but not with response rate. CTC occur in one third of advanced NSCLC patients and their presence is a predictive factor for a worse durable response rate to checkpoint inhibitors. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Circulating tumour cells (NCIT:C96593); 	Circulating tumor cells	Cell percentage/counts in blood	 2019 Jul 10	Circulating tumor cells in advanced non-small cell lung cancer patients are associated with worse tumor response to checkpoint inhibitors.	 J Immunother Cancer	BACKGROUND: Non-small cell lung cancer (NSCLC) patients treated with checkpoint inhibitors show long lasting responses, but it is hard to predict which patients will profit from this treatment with the currently used marker, programmed death ligand 1 (PD-L1). We hypothesized that circulating tumor cells (CTC) or tumor derived extracellular vesicles (tdEV) are markers of treatment efficacy.METHODS: Patients with advanced NSCLC treated with checkpoint inhibitors were included. Blood was drawn at baseline (T0) and at 4 weeks of treatment (T1) for analysis of CTC and tdEV using CellSearch . Tumor response was classified as partial or complete response based on the response evaluation criteria in solid tumors (RECISTv1.1) measured 4-6 weeks after start of treatment. Durable response was defined as stable disease, partial or complete response without disease progression at 6 months. Analyses were adjusted for covariables including PD-L1 expression.RESULTS: We included 104 patients (30 with a tumor response, 74 non-responders, 2 responses not evaluable due to early death); 63 patients provided T1 samples. All patients were treated with PD-L1 inhibitors. The majority of patients received second (85%) or third line (treatment with nivolumab monotherapy (89%). CTC were present in 33/104 patients at T0 (32%) and 17/63 at T1 (27%), 9/63 patients had CTC (14%) at both time points. The presence of CTC, both at T0 (OR = 0.28, p = 0.02,) and T1 (OR = 0.07, p < 0.01), was an independent predictive factor for a lack of durable response and was associated with worse progression free and overall survival. More tdEV were associated with shorter survival but not with response rate.CONCLUSION: CTC occur in one third of advanced NSCLC patients and their presence is a predictive factor for a worse durable response rate to checkpoint inhibitors. tdEV are associated with shorter survival but not with response.
CANIT0002581	31292396	Case report	Non-small cell lung cancer, and granulomatosis with polyangiitis	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	An 83-year-old man with GPA that was well controlled with immunosuppressive therapy was diagnosed with a postoperative recurrence of non-small cell lung cancer (NSCLC). Because the programmed cell death ligand 1 (PD-L1) tumor proportion score was 90%, pembrolizumab was administered. After 10 cycles, immune-related adverse events or GPA flare was not observed, and the patient showed an antitumor response.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Nov 1	Non-small Cell Lung Cancer Treated by an Anti-programmed Cell Death-1 Antibody without a Flare-up of Preexisting Granulomatosis with Polyangiitis.	 Intern Med	The safety and efficacy of anti-programmed cell death-1 (PD-1) antibodies in patients with granulomatosis with polyangiitis (GPA) still remain unclear. An 83-year-old man with GPA that was well controlled with immunosuppressive therapy was diagnosed with a postoperative recurrence of non-small cell lung cancer (NSCLC). Because the programmed cell death ligand 1 (PD-L1) tumor proportion score was 90%, pembrolizumab was administered. After 10 cycles, immune-related adverse events or GPA flare was not observed, and the patient showed an antitumor response. Anti-PD-1 antibody should therefore be considered a treatment option for PD-L1-high-expressing NSCLC patients with well-controlled GPA.
CANIT0002582	31300602	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We report a case of a 74-year-old man who developed myocarditis complicated by atrioventricular (AV) block following two doses of nivolumab for the treatment of non-small cell lung cancer. A diagnosis of drug-induced acute myocarditis with complete AV block was considered on the basis of elevated troponin, new onset left ventricular (LV) systolic dysfunction, absence of acute myocardial infarction and some findings suggestive of myocarditis on cardiac magnetic resonance. The patient was commenced on glucocorticoids, perindopril and carvedilol. AV block and LV dysfunction persisted despite 2 weeks of treatment. He ultimately became hypotensive which prompted an implantation of a cardiac resynchronisation therapy pacemaker. Follow-up echocardiogram at 6 weeks showed resolution of LV systolic dysfunction. However, he continued to have AV block.	Myocarditis complicated by atrioventricular (AV) block	N/A	N/A	N/A	N/A	N/A	 2019 Jul 11	Nivolumab-induced myocarditis complicated by complete atrioventricular block in a patient with metastatic non-small cell lung cancer.	 BMJ Case Rep	We report a case of a 74-year-old man who developed myocarditis complicated by atrioventricular (AV) block following two doses of nivolumab for the treatment of non-small cell lung cancer. A diagnosis of drug-induced acute myocarditis with complete AV block was considered on the basis of elevated troponin, new onset left ventricular (LV) systolic dysfunction, absence of acute myocardial infarction and some findings suggestive of myocarditis on cardiac magnetic resonance. The patient was commenced on glucocorticoids, perindopril and carvedilol. AV block and LV dysfunction persisted despite 2 weeks of treatment. He ultimately became hypotensive which prompted an implantation of a cardiac resynchronisation therapy pacemaker. Follow-up echocardiogram at 6 weeks showed resolution of LV systolic dysfunction. However, he continued to have AV block.
CANIT0002583	31305421	Clinical research	484 patients(32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status ¡Ý2)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus Nivolumab	BRAF inhibition plus MEK inhibition	Immune checkpoint therapy	Nivolumab (DB09035); 	20	96	Retrospective analysis	The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Real-world treatment patterns and clinical outcomes among patients with advanced melanoma: A retrospective, community oncology-based cohort study (A STROBE-compliant article).	 Medicine (Baltimore)	Recently, the effectiveness of novel immune checkpoint inhibitors and BRAF-directed therapies has been demonstrated in advanced melanoma trial populations. Limited research, however, has evaluated the impact of these therapies in a real-world setting. The aim of this study was to evaluate treatment patterns and clinical outcomes among advanced melanoma patients treated with modern therapies within community oncology clinics. Adult patients with advanced melanoma who initiated treatment within the US Oncology Network between 1/1/14 and 12/31/16 were included. Data were sourced from electronic healthcare records. Patients were followed through 12/31/17. Descriptive analyses were performed to assess patient and treatment characteristics and Kaplan-Meier methods were used for time-to-event outcomes. In total, 484 patients met eligibility criteria (32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status >=2). In the first-line (1L) setting during the study period, 37.0% received anti-PD1 monotherapies, 26.4% ipilimumab monotherapy, 19.8% BRAF/MEK combination therapy, 6.4% BRAF or MEK monotherapy, 4.1% ipilimumab/nivolumab combination therapy and 6.2% other regimens. Differences in baseline demographic and clinical characteristics were observed across treatment groups. For the overall study population, the median (95% confidence interval) estimates for overall survival, time to next treatment and progression-free survival were 20.7 (16.0, 26.8), 5.8 (5.3, 6.5), and 4.9 (4.2, 5.7) months, respectively. The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy.
CANIT0002584	31305421	Clinical research	484 patients(32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status ¡Ý3)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); BRAF (P15056); MEK (Q02750); 	CTLA-4 ;  BRAF ;  MEK 	Ipilimumab	BRAF or MEK inhibition	Immune checkpoint therapy	Ipilimumab (DB06186); 	128	31	Retrospective analysis	The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Real-world treatment patterns and clinical outcomes among patients with advanced melanoma: A retrospective, community oncology-based cohort study (A STROBE-compliant article).	 Medicine (Baltimore)	Recently, the effectiveness of novel immune checkpoint inhibitors and BRAF-directed therapies has been demonstrated in advanced melanoma trial populations. Limited research, however, has evaluated the impact of these therapies in a real-world setting. The aim of this study was to evaluate treatment patterns and clinical outcomes among advanced melanoma patients treated with modern therapies within community oncology clinics. Adult patients with advanced melanoma who initiated treatment within the US Oncology Network between 1/1/14 and 12/31/16 were included. Data were sourced from electronic healthcare records. Patients were followed through 12/31/17. Descriptive analyses were performed to assess patient and treatment characteristics and Kaplan-Meier methods were used for time-to-event outcomes. In total, 484 patients met eligibility criteria (32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status >=2). In the first-line (1L) setting during the study period, 37.0% received anti-PD1 monotherapies, 26.4% ipilimumab monotherapy, 19.8% BRAF/MEK combination therapy, 6.4% BRAF or MEK monotherapy, 4.1% ipilimumab/nivolumab combination therapy and 6.2% other regimens. Differences in baseline demographic and clinical characteristics were observed across treatment groups. For the overall study population, the median (95% confidence interval) estimates for overall survival, time to next treatment and progression-free survival were 20.7 (16.0, 26.8), 5.8 (5.3, 6.5), and 4.9 (4.2, 5.7) months, respectively. The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy.
CANIT0002585	31305421	Clinical research	484 patients(32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status ¡Ý4)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); BRAF (P15056); MEK (Q02750); 	CTLA-4 ;  BRAF ;  MEK 	Ipilimumab	BRAF inhibition plus MEK inhibition	Immune checkpoint therapy	Ipilimumab (DB06186); 	128	96	Retrospective analysis	The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Real-world treatment patterns and clinical outcomes among patients with advanced melanoma: A retrospective, community oncology-based cohort study (A STROBE-compliant article).	 Medicine (Baltimore)	Recently, the effectiveness of novel immune checkpoint inhibitors and BRAF-directed therapies has been demonstrated in advanced melanoma trial populations. Limited research, however, has evaluated the impact of these therapies in a real-world setting. The aim of this study was to evaluate treatment patterns and clinical outcomes among advanced melanoma patients treated with modern therapies within community oncology clinics. Adult patients with advanced melanoma who initiated treatment within the US Oncology Network between 1/1/14 and 12/31/16 were included. Data were sourced from electronic healthcare records. Patients were followed through 12/31/17. Descriptive analyses were performed to assess patient and treatment characteristics and Kaplan-Meier methods were used for time-to-event outcomes. In total, 484 patients met eligibility criteria (32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status >=2). In the first-line (1L) setting during the study period, 37.0% received anti-PD1 monotherapies, 26.4% ipilimumab monotherapy, 19.8% BRAF/MEK combination therapy, 6.4% BRAF or MEK monotherapy, 4.1% ipilimumab/nivolumab combination therapy and 6.2% other regimens. Differences in baseline demographic and clinical characteristics were observed across treatment groups. For the overall study population, the median (95% confidence interval) estimates for overall survival, time to next treatment and progression-free survival were 20.7 (16.0, 26.8), 5.8 (5.3, 6.5), and 4.9 (4.2, 5.7) months, respectively. The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy.
CANIT0002586	31305421	Clinical research	484 patients(32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status ¡Ý5)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); MEK (Q02750); 	PD-1 ;  BRAF ;  MEK 	Nivolumab	BRAF or MEK inhibition	Immune checkpoint therapy	Nivolumab (DB09035); 	180	31	Retrospective analysis	The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Real-world treatment patterns and clinical outcomes among patients with advanced melanoma: A retrospective, community oncology-based cohort study (A STROBE-compliant article).	 Medicine (Baltimore)	Recently, the effectiveness of novel immune checkpoint inhibitors and BRAF-directed therapies has been demonstrated in advanced melanoma trial populations. Limited research, however, has evaluated the impact of these therapies in a real-world setting. The aim of this study was to evaluate treatment patterns and clinical outcomes among advanced melanoma patients treated with modern therapies within community oncology clinics. Adult patients with advanced melanoma who initiated treatment within the US Oncology Network between 1/1/14 and 12/31/16 were included. Data were sourced from electronic healthcare records. Patients were followed through 12/31/17. Descriptive analyses were performed to assess patient and treatment characteristics and Kaplan-Meier methods were used for time-to-event outcomes. In total, 484 patients met eligibility criteria (32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status >=2). In the first-line (1L) setting during the study period, 37.0% received anti-PD1 monotherapies, 26.4% ipilimumab monotherapy, 19.8% BRAF/MEK combination therapy, 6.4% BRAF or MEK monotherapy, 4.1% ipilimumab/nivolumab combination therapy and 6.2% other regimens. Differences in baseline demographic and clinical characteristics were observed across treatment groups. For the overall study population, the median (95% confidence interval) estimates for overall survival, time to next treatment and progression-free survival were 20.7 (16.0, 26.8), 5.8 (5.3, 6.5), and 4.9 (4.2, 5.7) months, respectively. The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy.
CANIT0002587	31305421	Clinical research	484 patients(32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status ¡Ý6)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); MEK (Q02750); 	PD-1 ;  BRAF ;  MEK 	Nivolumab	BRAF inhibition plus MEK inhibition	Immune checkpoint therapy	Nivolumab (DB09035); 	180	96	Retrospective analysis	The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Real-world treatment patterns and clinical outcomes among patients with advanced melanoma: A retrospective, community oncology-based cohort study (A STROBE-compliant article).	 Medicine (Baltimore)	Recently, the effectiveness of novel immune checkpoint inhibitors and BRAF-directed therapies has been demonstrated in advanced melanoma trial populations. Limited research, however, has evaluated the impact of these therapies in a real-world setting. The aim of this study was to evaluate treatment patterns and clinical outcomes among advanced melanoma patients treated with modern therapies within community oncology clinics. Adult patients with advanced melanoma who initiated treatment within the US Oncology Network between 1/1/14 and 12/31/16 were included. Data were sourced from electronic healthcare records. Patients were followed through 12/31/17. Descriptive analyses were performed to assess patient and treatment characteristics and Kaplan-Meier methods were used for time-to-event outcomes. In total, 484 patients met eligibility criteria (32.0% with brain metastasis, 12.6% with Eastern Cooperative Oncology Group performance status >=2). In the first-line (1L) setting during the study period, 37.0% received anti-PD1 monotherapies, 26.4% ipilimumab monotherapy, 19.8% BRAF/MEK combination therapy, 6.4% BRAF or MEK monotherapy, 4.1% ipilimumab/nivolumab combination therapy and 6.2% other regimens. Differences in baseline demographic and clinical characteristics were observed across treatment groups. For the overall study population, the median (95% confidence interval) estimates for overall survival, time to next treatment and progression-free survival were 20.7 (16.0, 26.8), 5.8 (5.3, 6.5), and 4.9 (4.2, 5.7) months, respectively. The results of this study provide real-world insight into advanced melanoma treatment trends and clinical outcomes, including high utilization of immunotherapies and BRAF/MEK combination therapy. Future research can explore underlying differences in patient subpopulations and the sequence of therapies across lines of therapy.
CANIT0002588	31314761	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	59	N/A	Retrospective analysis	Fifty-nine patients were included. The 29 early progressors had significantly more frequent neutrophil-to-lymphocyte ratio (NLR) > 1 (p = 0.0007), OR 18.08 [95% CI 2.96-246.24] with progressive disease as best response to prior treatment line (p = 0.0014). NLR < 1 prolonged OS (HR 0.001 [0.0007-0.18], p = 0.001); as did a partial response to prior line of systemic treatment (HR 0.14 [0.03--0.56], p = 0.005).Based on selected early progressors given second-line immunotherapy for advanced NSCLC, progression as best response to prior treatment and NLR > 1 characterized the early progressors and shortened OS after starting nivolumab. This phenomenon questions nivolumab utility in patients with a major host neutrophil inflammation.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Jul 17	Neutrophil-to-lymphocyte ratio evolution is an independent predictor of early progression of second-line nivolumab-treated patients with advanced non-small-cell lung cancers.	 PLoS One	INTRODUCTION: Although second-line immunotherapy obtained better outcomes than chemotherapy for patients with advanced non-small-cell lung cancers (NSCLCs), it is expensive and only a minority of patients seem to benefit, based on early tumor progression post-immunotherapy. Notable host inflammation, characterized by biomarkers (e.g. neutrophil-to-lymphocyte ratio (NLR])), prolongs overall survival (OS) of surgery-, chemotherapy- and immunotherapy-treated patients. To our knowledge, no previous studies used biomarker evolution to analyze the immunotherapy impact on host inflammation. Immunotherapy mainly exerts its activity by lymphocyte reactivation.METHODS: This retrospective study was conducted on patients, selected by their progression status just before their 4th nivolumab injection, and treated at Bordeaux and Limoges University Hospitals. A comparative group of at least 1-year responders was also selected. Clinical parameters and hematological data just before the 1st (baseline) and 4th nivolumab infusions were collected to calculate the NLR change (¦¤NLR) between those two infusions. The combined impact of the different known prognostic factors was also analyzed with multivariable analyses.RESULTS: Fifty-nine patients were included. The 29 early progressors had significantly more frequent ¦¤NLR > 1 (p = 0.0007), OR 18.08 [95% CI 2.96-246.24] with progressive disease as best response to prior treatment line (p = 0.0014). ¦¤NLR < 1 prolonged OS (HR 0.001 [0.0007-0.18], p = 0.001); as did a partial response to prior line of systemic treatment (HR 0.14 [0.03--0.56], p = 0.005).CONCLUSION: Based on selected early progressors given second-line immunotherapy for advanced NSCLC, progression as best response to prior treatment and ¦¤NLR > 1 characterized the early progressors and shortened OS after starting nivolumab. This phenomenon questions nivolumab utility in patients with a major host neutrophil inflammation.
CANIT0002589	31319996	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	Significant impact on OS was shown presence of cerebral metastases (p = 0.036).	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Cerebral metastasis	Disease status	 2019 Aug	Early serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC-A retrospective cohort study.	 Lung Cancer	OBJECTIVES: To evaluate serum tumor markers (STM) as biomarkers for treatment monitoring and prognosis in advanced non-small cell lung cancer (NSCLC) treated with single-agent PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy.MATERIALS AND METHODS: Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis, initially elevated markers were used for follow-up. Leading STM change between ICI initiation and first subsequent restaging as well as corresponding computed tomography evaluations according to response evaluation criteria in solid tumors (RECIST) were retrospectively analyzed regarding progression-free (PFS) and overall survival (OS). In uni- and multivariate stepwise Cox-regression analyses, STM and RECIST response were analyzed for their impact on PFS and OS together with other known prognostic patient and tumor characteristics.RESULTS: Among 84 patients (61% men, mean age 68 years), median PFS was significantly (p < 0.001) longer, when STM decreased (11 M (7,19) N = 37) than in case of increases (<2-fold: 6 M (3,8) N = 31; >=2-fold: 2 M (1,2) N = 16). Patients with initial STM decrease had longer (p < 0.001) median OS (not reached) than with STM increase (<2-fold: 14 M (12,26); >=2-fold: 4 M (3,7)). Patients with stable or progressive disease by RECIST and concomitant STM decrease had longer (p < 0.001) PFS and OS (8 M (4,14) and 18 M (10,n.e.) N = 24) than upon STM increase (PFS: 2 M (2,4); OS: 10 M (6,13) N = 42). Significant impact on PFS was shown for STM response (p < 0.001), RECIST response (p = 0.003) and PD-L1 status (p = 0.003). For OS, STM response (p < 0.001), presence of cerebral metastases (p = 0.036) and therapy line >=3 (p = 0.001) were identified.CONCLUSION: Decreasing leading STM at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.
CANIT0002590	31319996	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	Decreasing leading serum tumor markers at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.	N/A	N/A	N/A	Serum tumor markers (); 	Serum tumor markers	Gene expression signature in serum	 2019 Aug	Early serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC-A retrospective cohort study.	 Lung Cancer	OBJECTIVES: To evaluate serum tumor markers (STM) as biomarkers for treatment monitoring and prognosis in advanced non-small cell lung cancer (NSCLC) treated with single-agent PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy.MATERIALS AND METHODS: Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis, initially elevated markers were used for follow-up. Leading STM change between ICI initiation and first subsequent restaging as well as corresponding computed tomography evaluations according to response evaluation criteria in solid tumors (RECIST) were retrospectively analyzed regarding progression-free (PFS) and overall survival (OS). In uni- and multivariate stepwise Cox-regression analyses, STM and RECIST response were analyzed for their impact on PFS and OS together with other known prognostic patient and tumor characteristics.RESULTS: Among 84 patients (61% men, mean age 68 years), median PFS was significantly (p < 0.001) longer, when STM decreased (11 M (7,19) N = 37) than in case of increases (<2-fold: 6 M (3,8) N = 31; >=2-fold: 2 M (1,2) N = 16). Patients with initial STM decrease had longer (p < 0.001) median OS (not reached) than with STM increase (<2-fold: 14 M (12,26); >=2-fold: 4 M (3,7)). Patients with stable or progressive disease by RECIST and concomitant STM decrease had longer (p < 0.001) PFS and OS (8 M (4,14) and 18 M (10,n.e.) N = 24) than upon STM increase (PFS: 2 M (2,4); OS: 10 M (6,13) N = 42). Significant impact on PFS was shown for STM response (p < 0.001), RECIST response (p = 0.003) and PD-L1 status (p = 0.003). For OS, STM response (p < 0.001), presence of cerebral metastases (p = 0.036) and therapy line >=3 (p = 0.001) were identified.CONCLUSION: Decreasing leading STM at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.
CANIT0002591	31319996	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	Significant impact on PFS was shown PD-L1 status (p = 0.003). 	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Aug	Early serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC-A retrospective cohort study.	 Lung Cancer	OBJECTIVES: To evaluate serum tumor markers (STM) as biomarkers for treatment monitoring and prognosis in advanced non-small cell lung cancer (NSCLC) treated with single-agent PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy.MATERIALS AND METHODS: Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis, initially elevated markers were used for follow-up. Leading STM change between ICI initiation and first subsequent restaging as well as corresponding computed tomography evaluations according to response evaluation criteria in solid tumors (RECIST) were retrospectively analyzed regarding progression-free (PFS) and overall survival (OS). In uni- and multivariate stepwise Cox-regression analyses, STM and RECIST response were analyzed for their impact on PFS and OS together with other known prognostic patient and tumor characteristics.RESULTS: Among 84 patients (61% men, mean age 68 years), median PFS was significantly (p < 0.001) longer, when STM decreased (11 M (7,19) N = 37) than in case of increases (<2-fold: 6 M (3,8) N = 31; >=2-fold: 2 M (1,2) N = 16). Patients with initial STM decrease had longer (p < 0.001) median OS (not reached) than with STM increase (<2-fold: 14 M (12,26); >=2-fold: 4 M (3,7)). Patients with stable or progressive disease by RECIST and concomitant STM decrease had longer (p < 0.001) PFS and OS (8 M (4,14) and 18 M (10,n.e.) N = 24) than upon STM increase (PFS: 2 M (2,4); OS: 10 M (6,13) N = 42). Significant impact on PFS was shown for STM response (p < 0.001), RECIST response (p = 0.003) and PD-L1 status (p = 0.003). For OS, STM response (p < 0.001), presence of cerebral metastases (p = 0.036) and therapy line >=3 (p = 0.001) were identified.CONCLUSION: Decreasing leading STM at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.
CANIT0002592	31319996	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	Significant impact on PFS was shown response evaluation criteria in solid tumors response (p = 0.003).	N/A	N/A	N/A	RECIST response ()	RECIST response	Disease status	 2019 Aug	Early serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC-A retrospective cohort study.	 Lung Cancer	OBJECTIVES: To evaluate serum tumor markers (STM) as biomarkers for treatment monitoring and prognosis in advanced non-small cell lung cancer (NSCLC) treated with single-agent PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy.MATERIALS AND METHODS: Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis, initially elevated markers were used for follow-up. Leading STM change between ICI initiation and first subsequent restaging as well as corresponding computed tomography evaluations according to response evaluation criteria in solid tumors (RECIST) were retrospectively analyzed regarding progression-free (PFS) and overall survival (OS). In uni- and multivariate stepwise Cox-regression analyses, STM and RECIST response were analyzed for their impact on PFS and OS together with other known prognostic patient and tumor characteristics.RESULTS: Among 84 patients (61% men, mean age 68 years), median PFS was significantly (p < 0.001) longer, when STM decreased (11 M (7,19) N = 37) than in case of increases (<2-fold: 6 M (3,8) N = 31; >=2-fold: 2 M (1,2) N = 16). Patients with initial STM decrease had longer (p < 0.001) median OS (not reached) than with STM increase (<2-fold: 14 M (12,26); >=2-fold: 4 M (3,7)). Patients with stable or progressive disease by RECIST and concomitant STM decrease had longer (p < 0.001) PFS and OS (8 M (4,14) and 18 M (10,n.e.) N = 24) than upon STM increase (PFS: 2 M (2,4); OS: 10 M (6,13) N = 42). Significant impact on PFS was shown for STM response (p < 0.001), RECIST response (p = 0.003) and PD-L1 status (p = 0.003). For OS, STM response (p < 0.001), presence of cerebral metastases (p = 0.036) and therapy line >=3 (p = 0.001) were identified.CONCLUSION: Decreasing leading STM at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.
CANIT0002593	31319996	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	Significant impact on OS was shown therapy line >=3 (p = 0.001).	N/A	N/A	N/A	Therapy line (); 	Therapy line	Exposure factors/status	 2019 Aug	Early serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC-A retrospective cohort study.	 Lung Cancer	OBJECTIVES: To evaluate serum tumor markers (STM) as biomarkers for treatment monitoring and prognosis in advanced non-small cell lung cancer (NSCLC) treated with single-agent PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy.MATERIALS AND METHODS: Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis, initially elevated markers were used for follow-up. Leading STM change between ICI initiation and first subsequent restaging as well as corresponding computed tomography evaluations according to response evaluation criteria in solid tumors (RECIST) were retrospectively analyzed regarding progression-free (PFS) and overall survival (OS). In uni- and multivariate stepwise Cox-regression analyses, STM and RECIST response were analyzed for their impact on PFS and OS together with other known prognostic patient and tumor characteristics.RESULTS: Among 84 patients (61% men, mean age 68 years), median PFS was significantly (p < 0.001) longer, when STM decreased (11 M (7,19) N = 37) than in case of increases (<2-fold: 6 M (3,8) N = 31; >=2-fold: 2 M (1,2) N = 16). Patients with initial STM decrease had longer (p < 0.001) median OS (not reached) than with STM increase (<2-fold: 14 M (12,26); >=2-fold: 4 M (3,7)). Patients with stable or progressive disease by RECIST and concomitant STM decrease had longer (p < 0.001) PFS and OS (8 M (4,14) and 18 M (10,n.e.) N = 24) than upon STM increase (PFS: 2 M (2,4); OS: 10 M (6,13) N = 42). Significant impact on PFS was shown for STM response (p < 0.001), RECIST response (p = 0.003) and PD-L1 status (p = 0.003). For OS, STM response (p < 0.001), presence of cerebral metastases (p = 0.036) and therapy line >=3 (p = 0.001) were identified.CONCLUSION: Decreasing leading STM at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.
CANIT0002594	31320352	Clinical research	Fifteen subjects	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus BCG vaccine	N/A	Immune checkpoint therapy plus Tumor vaccine 	Pembrolizumab (DB09037); BCG vaccine (DB12768); 	15	N/A	Phase I	The current study to determine the safety and efficacy of administering pembrolizumab (a monoclonal antibody targeting the interaction between PD-1 and its ligand) in combination with BCG in high-risk non-muscle invasive bladder cancer	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul 17	Protocol for phase I study of pembrolizumab in combination with Bacillus Calmette-Gu¨¦rin for patients with high-risk non-muscle invasive bladder cancer.	 BMJ Open	INTRODUCTION: The initial treatment for high-risk non-muscle invasive bladder cancer (NMIBC) is endoscopic resection of the tumour followed by BCG therapy. In those who develop recurrence, the standard treatment is radical cystectomy. Despite the advancement in surgical technique and postoperative care, the degree of morbidity associated with radical cystectomy remains high, therefore less invasive treatment modalities are desirable. Therapies targeting the programmed death (PD) pathway have shown promise in urothelial carcinoma. We undertook the current study to determine the safety and efficacy of administering pembrolizumab (a monoclonal antibody targeting the interaction between PD-1 and its ligand) in combination with BCG in high-risk NMIBC.METHODS: This is a single-centre phase I safety and efficacy study of pembrolizumab used in combination with intravesicular BCG treatment for subjects with pathologically documented high-risk NMIBC despite having received two courses of induction therapy or BCG treatment followed by maintenance BCG. Fifteen subjects will be enrolled, patients will receive treatment with 200 mg of pembrolizumab every 21 days, starting 2 weeks from the initial endoscopic resection and continuing for 6 weeks after the final dose of BCG. The primary objective is to determine the safety of administering pembrolizumab at a fixed dose of 200 mg every 3 weeks in conjunction with intravesicular BCG treatment in patients with high-risk NMIBC who have failed previous treatment. Secondary objectives are to determine the 19 weeks and the 3, 12 and 24 months post-treatment completion complete response rate with combined pembrolizumab and intravesicular BCG therapy in the aforementioned patients.ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board of the Henry Ford Hospital. The results of this study will be published in a peer-reviewed journal and presented at a scientific conference.TRIAL REGISTRATION NUMBER: NCT02324582.
CANIT0002595	31327024	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	78	N/A	N/A	Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC.	N/A	N/A	N/A	PCSK9 (Q8NBP7); 	Serum PCSK9 levels at the second nivolumab cycle	Gene expression signature in serum	 2019 Aug	Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study.	 Cancer Immunol Immunother	Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results.
CANIT0002596	31330498	Case report	Lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.	Diabetic ketoacidosis (DKA) and autoimmune thyroiditis	N/A	N/A	HLA-DR4 (Q8WLQ7); 	HLA-DR4 genotype	Gene expression signature on/in immune cell	 2019 Sep	Immune checkpoint inhibitors and type 1 diabetes mellitus: a case report and systematic review.	 Eur J Endocrinol	OBJECTIVE: To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs).DESIGN AND METHODS: We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy.RESULTS: Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population.CONCLUSION: ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.
CANIT0002597	31332464	Basic research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	Cell lines	N/A	Basic research	The results indicate that the therapeutic CTLA-4 antibody ipilimumab can impair CD4+ effector T-cell responses and that this activity is mediated by its Fc part and CD16-expressing cells.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD4(+) effector T-cell responses	Gene expression signature on/in immune cell	 2019 Aug	CTLA-4 antibody ipilimumab negatively affects CD4(+) T-cell responses in vitro.	 Cancer Immunol Immunother	Immune checkpoint inhibitors targeting coinhibitory pathways in T cells possess efficacy in combating cancer. In addition to PD-1/PD-L1 and CTLA-4 antibodies which are already established in tumor immunotherapy, immune checkpoints such as LAG-3 or BTLA are emerging, which may have the potential to enhance T-cell responses alone or in combination with PD-1 blockers. CD4+ T cells play a central role in the immune system and contribute to productive immune responses in multiple ways. The effects of immune checkpoint inhibitors on this cell subset may thus critically influence therapeutic outcomes. Here, we have used in vitro responses to tetanus toxoid (TT) as a model system to study the effects of immune checkpoint inhibitors on CD4+ T-cell responses. CFSE-labeled PBMCs of 65 donors were stimulated with TT in the presence of blocking antibodies to PD-L1, CTLA-4, LAG-3, or BTLA for 7 days. We found that the PD-L1 antibody greatly enhanced cytokine production and antigen-specific CD4+ T-cell proliferation, whereas blocking antibodies to BTLA or LAG-3 did not augment responses to TT. Surprisingly, the presence of the therapeutic CTLA-4 antibody ipilimumab resulted in a significant reduction of CD4+ T-cell proliferation and cytokine production. Stimulation experiments with an IgG4 variant of ipilimumab indicated that the inhibitory effect of ipilimumab was dependent on its IgG1 isotype. Our results indicate that the therapeutic CTLA-4 antibody ipilimumab can impair CD4+ effector T-cell responses and that this activity is mediated by its Fc part and CD16-expressing cells.
CANIT0002598	31345627	Clinical research	Advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Ipilimumab	Immune checkpoint therapy	Pembrolizumab (DB09037); 	556	278	Open-label, multicentre, randomised, controlled, phase 3 study	After a median follow-up of 57.7 months (IQR 56.7-59.2) in surviving patients, median overall survival was 32.7 months (95% CI 24.5-41.6) in the combined pembrolizumab groups and 15.9 months (13.3-22.0) in the ipilimumab group (hazard ratio [HR] 0.73, 95% CI 0.61-0.88, p=0.00049). Median progression-free survival was 8.4 months (95% CI 6.6-11.3) in the combined pembrolizumab groups versus 3.4 months (2.9-4.2) in the ipilimumab group (HR 0.57, 95% CI 0.48-0.67, p<0.0001). Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma.	Grade 3-4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the combined pembrolizumab groups and in 45 (18%) patients in the ipilimumab group. One patient assigned to pembrolizumab died from treatment-related sepsis.	N/A	N/A	N/A	N/A	N/A	 2019 Sep	Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.	 Lancet Oncol	BACKGROUND: Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006.METHODS: KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319.FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57.7 months (IQR 56.7-59.2) in surviving patients, median overall survival was 32.7 months (95% CI 24.5-41.6) in the combined pembrolizumab groups and 15.9 months (13.3-22.0) in the ipilimumab group (hazard ratio [HR] 0.73, 95% CI 0.61-0.88, p=0.00049). Median progression-free survival was 8.4 months (95% CI 6.6-11.3) in the combined pembrolizumab groups versus 3.4 months (2.9-4.2) in the ipilimumab group (HR 0.57, 95% CI 0.48-0.67, p<0.0001). Grade 3-4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the combined pembrolizumab groups and in 45 (18%) patients in the ipilimumab group. One patient assigned to pembrolizumab died from treatment-related sepsis.INTERPRETATION: Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma.FUNDING: Merck Sharp & Dohme.
CANIT0002599	31348077	Case report	Pulmonary and Bone Sarcoidosis	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A 57-year-old man with stage IIIB malignant melanoma of unknown primary presented for pretherapy FDG PET/CT that demonstrated metastatic left cervical lymph node with no other site of involvement. Following left neck dissection, nivolumab was initiated. Follow-up FDG PET/CT 3 months after initiation of nivolumab demonstrated extensive radiotracer-avid chest lymphadenopathy and multiple bone lesions. Ultrasound-guided endobronchial biopsy of the mediastinal lymph nodes demonstrated sarcoidosis.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Sep	Nivolumab-Associated Pulmonary and Bone Sarcoidosis in a Patient With Melanoma of Unknown Primary.	 Clin Nucl Med	A 57-year-old man with stage IIIB malignant melanoma of unknown primary presented for pretherapy FDG PET/CT that demonstrated metastatic left cervical lymph node with no other site of involvement. Following left neck dissection, nivolumab was initiated. Follow-up FDG PET/CT 3 months after initiation of nivolumab demonstrated extensive radiotracer-avid chest lymphadenopathy and multiple bone lesions. Ultrasound-guided endobronchial biopsy of the mediastinal lymph nodes demonstrated sarcoidosis.
CANIT0002600	31351692	Basic research	Cell lines	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	Cell lines	N/A	Basic research	These results not only indicate the feasibility of targeting the PD-1/PD-L1 pathway with small molecules, but illustrate the applicability of the symmetry-based ligand design as an attractive methodology for targeting protein-protein interaction stabilizers.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Sep 1	Symmetry-based ligand design and evaluation of small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 interaction.	 Bioorg Med Chem Lett	The development of small molecule inhibitors of PD-1/PD-L1 is eagerly anticipated for treatment of cancer. We focused on the symmetry of the ternary complex structure of reported small molecule ligands and hPD-L1 homodimers, and designed partially- or fully-symmetric compounds for more potent inhibitors. The design of the new compounds was guided by our hypothesis that the designed symmetric compound would induce a flip of sidechain of ATyr56 protein residue to form a new cavity. The designed compound 4 exhibited substantially increased binding affinity to hPD-L1, as well as PD-1/PD-L1 inhibitory activity in physiological conditions. Compound 4 also showed a dose-dependent increase in IFN-¦Ã secretion levels in a mixed lymphocyte reaction assay. These results not only indicate the feasibility of targeting the PD-1/PD-L1 pathway with small molecules, but illustrate the applicability of the symmetry-based ligand design as an attractive methodology for targeting protein-protein interaction stabilizers.
CANIT0002601	31353840	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	111	N/A	Phase II	Treatment with nivolumab improved long-term survival and was well tolerated in patients with advanced squamous (SQ) and non-SQ NSCLC. In SQ NSCLC patients, the median overall survival (OS)  (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found.	N/A	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	 2019 Sep	Three-year follow-up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non-small cell lung cancer: Pooled analysis of ONO-4538-05 and ONO-4538-06 studies.	 Cancer Med	BACKGROUND: Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials.METHODS: SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed.RESULTS: In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found.CONCLUSION: Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC.TRIAL REGISTRATION: JapicCTI-132072; JapicCTI-132073.
CANIT0002602	31359231	Clinical research	 Fifty-eight patients	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	58	N/A	Retrospective analysis	Serum c-reactive protein levels are predictive factors in nivolumab therapy for metastatic renal cell carcinoma. These easily monitored factors can contribute to effective treatment and follow-up.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Aug	Predictive Impact of Peripheral Blood Markers and C-Reactive Protein in Nivolumab Therapy for Metastatic Renal Cell Carcinoma.	 Target Oncol	BACKGROUND: Predictive factors that can be routinely used in clinical practice are critically needed for immune checkpoint inhibitor therapy in metastatic renal cell carcinoma (mRCC).OBJECTIVE: To comprehensively analyze the predictive impact of peripheral blood markers and C-reactive protein (CRP) in nivolumab therapy for mRCC.METHODS: Fifty-eight patients were retrospectively evaluated. We evaluated neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), absolute eosinophil count (AEC), and absolute monocyte count (AMC) as peripheral blood markers as well as serum CRP levels. The primary endpoints were progression-free survival (PFS) and overall survival (OS) after nivolumab initiation.RESULTS: Median PFS was significantly shorter in patients with high NLR (>= 3) versus low NLR (p = 0.0356), high MLR (>= 0.3) versus low MLR (p = 0.0013), or high PLR (>= 160) versus low PLR (p = 0.0073), and median OS was significantly shorter in patients with high NLR versus low NLR (p = 0.0025), high MLR versus low MLR (p = 0.0025), high PLR versus low PLR (p = 0.0256), or high CRP (>= 1.0 mg/dl) versus low CRP (p = 0.0006). Multivariate analyses showed that MLR (HR 2.65, p = 0.0068) was an independent factor for PFS and that NLR (HR 3.34, p = 0.0218), MLR (HR 3.42, p = 0.0381), and CRP (HR 4.98, p = 0.0108) were independent factors for OS.CONCLUSIONS: The systemic inflammatory factors NLR, MLR, and CRP were predictive factors in nivolumab therapy for mRCC. These easily monitored factors can contribute to effective treatment and follow-up.
CANIT0002603	31359231	Clinical research	 Fifty-eight patients	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	58	N/A	Retrospective analysis	Lymphocyte-to-monocyte ratios are predictive factors in nivolumab therapy for metastatic renal cell carcinoma. These easily monitored factors can contribute to effective treatment and follow-up.	N/A	N/A	N/A	Lymphocyte-to-monocyte ratios (EFO:0004587); 	Lymphocyte-to-monocyte ratios	Cell percentage/counts in blood	 2019 Aug	Predictive Impact of Peripheral Blood Markers and C-Reactive Protein in Nivolumab Therapy for Metastatic Renal Cell Carcinoma.	 Target Oncol	BACKGROUND: Predictive factors that can be routinely used in clinical practice are critically needed for immune checkpoint inhibitor therapy in metastatic renal cell carcinoma (mRCC).OBJECTIVE: To comprehensively analyze the predictive impact of peripheral blood markers and C-reactive protein (CRP) in nivolumab therapy for mRCC.METHODS: Fifty-eight patients were retrospectively evaluated. We evaluated neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), absolute eosinophil count (AEC), and absolute monocyte count (AMC) as peripheral blood markers as well as serum CRP levels. The primary endpoints were progression-free survival (PFS) and overall survival (OS) after nivolumab initiation.RESULTS: Median PFS was significantly shorter in patients with high NLR (>= 3) versus low NLR (p = 0.0356), high MLR (>= 0.3) versus low MLR (p = 0.0013), or high PLR (>= 160) versus low PLR (p = 0.0073), and median OS was significantly shorter in patients with high NLR versus low NLR (p = 0.0025), high MLR versus low MLR (p = 0.0025), high PLR versus low PLR (p = 0.0256), or high CRP (>= 1.0 mg/dl) versus low CRP (p = 0.0006). Multivariate analyses showed that MLR (HR 2.65, p = 0.0068) was an independent factor for PFS and that NLR (HR 3.34, p = 0.0218), MLR (HR 3.42, p = 0.0381), and CRP (HR 4.98, p = 0.0108) were independent factors for OS.CONCLUSIONS: The systemic inflammatory factors NLR, MLR, and CRP were predictive factors in nivolumab therapy for mRCC. These easily monitored factors can contribute to effective treatment and follow-up.
CANIT0002604	31359231	Clinical research	 Fifty-eight patients	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	58	N/A	Retrospective analysis	The systemic inflammatory factors NLR, MLR, and CRP were predictive factors in nivolumab therapy for mRCC. These easily monitored factors can contribute to effective treatment and follow-up.	N/A	N/A	N/A	Monocyte counts (NCIT:C12547); 	Absolute monocyte counts	Cell percentage/counts in blood	 2019 Aug	Predictive Impact of Peripheral Blood Markers and C-Reactive Protein in Nivolumab Therapy for Metastatic Renal Cell Carcinoma.	 Target Oncol	BACKGROUND: Predictive factors that can be routinely used in clinical practice are critically needed for immune checkpoint inhibitor therapy in metastatic renal cell carcinoma (mRCC).OBJECTIVE: To comprehensively analyze the predictive impact of peripheral blood markers and C-reactive protein (CRP) in nivolumab therapy for mRCC.METHODS: Fifty-eight patients were retrospectively evaluated. We evaluated neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), absolute eosinophil count (AEC), and absolute monocyte count (AMC) as peripheral blood markers as well as serum CRP levels. The primary endpoints were progression-free survival (PFS) and overall survival (OS) after nivolumab initiation.RESULTS: Median PFS was significantly shorter in patients with high NLR (>= 3) versus low NLR (p = 0.0356), high MLR (>= 0.3) versus low MLR (p = 0.0013), or high PLR (>= 160) versus low PLR (p = 0.0073), and median OS was significantly shorter in patients with high NLR versus low NLR (p = 0.0025), high MLR versus low MLR (p = 0.0025), high PLR versus low PLR (p = 0.0256), or high CRP (>= 1.0 mg/dl) versus low CRP (p = 0.0006). Multivariate analyses showed that MLR (HR 2.65, p = 0.0068) was an independent factor for PFS and that NLR (HR 3.34, p = 0.0218), MLR (HR 3.42, p = 0.0381), and CRP (HR 4.98, p = 0.0108) were independent factors for OS.CONCLUSIONS: The systemic inflammatory factors NLR, MLR, and CRP were predictive factors in nivolumab therapy for mRCC. These easily monitored factors can contribute to effective treatment and follow-up.
CANIT0002605	31359231	Clinical research	 Fifty-eight patients	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	58	N/A	Retrospective analysis	Platelet-to-lymphocyte ratios are predictive factors in nivolumab therapy for metastatic renal cell carcinoma. These easily monitored factors can contribute to effective treatment and follow-up.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Aug	Predictive Impact of Peripheral Blood Markers and C-Reactive Protein in Nivolumab Therapy for Metastatic Renal Cell Carcinoma.	 Target Oncol	BACKGROUND: Predictive factors that can be routinely used in clinical practice are critically needed for immune checkpoint inhibitor therapy in metastatic renal cell carcinoma (mRCC).OBJECTIVE: To comprehensively analyze the predictive impact of peripheral blood markers and C-reactive protein (CRP) in nivolumab therapy for mRCC.METHODS: Fifty-eight patients were retrospectively evaluated. We evaluated neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), absolute eosinophil count (AEC), and absolute monocyte count (AMC) as peripheral blood markers as well as serum CRP levels. The primary endpoints were progression-free survival (PFS) and overall survival (OS) after nivolumab initiation.RESULTS: Median PFS was significantly shorter in patients with high NLR (>= 3) versus low NLR (p = 0.0356), high MLR (>= 0.3) versus low MLR (p = 0.0013), or high PLR (>= 160) versus low PLR (p = 0.0073), and median OS was significantly shorter in patients with high NLR versus low NLR (p = 0.0025), high MLR versus low MLR (p = 0.0025), high PLR versus low PLR (p = 0.0256), or high CRP (>= 1.0 mg/dl) versus low CRP (p = 0.0006). Multivariate analyses showed that MLR (HR 2.65, p = 0.0068) was an independent factor for PFS and that NLR (HR 3.34, p = 0.0218), MLR (HR 3.42, p = 0.0381), and CRP (HR 4.98, p = 0.0108) were independent factors for OS.CONCLUSIONS: The systemic inflammatory factors NLR, MLR, and CRP were predictive factors in nivolumab therapy for mRCC. These easily monitored factors can contribute to effective treatment and follow-up.
CANIT0002606	31359231	Clinical research	 Fifty-eight patients	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	58	N/A	Retrospective analysis	Neutrophil-to-lymphocyte ratios are predictive factors in nivolumab therapy for metastatic renal cell carcinoma. These easily monitored factors can contribute to effective treatment and follow-up.	N/A	N/A	N/A	Platelet-to-lymphocyte ratios (EFO:0008446); 	Platelet-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Aug	Predictive Impact of Peripheral Blood Markers and C-Reactive Protein in Nivolumab Therapy for Metastatic Renal Cell Carcinoma.	 Target Oncol	BACKGROUND: Predictive factors that can be routinely used in clinical practice are critically needed for immune checkpoint inhibitor therapy in metastatic renal cell carcinoma (mRCC).OBJECTIVE: To comprehensively analyze the predictive impact of peripheral blood markers and C-reactive protein (CRP) in nivolumab therapy for mRCC.METHODS: Fifty-eight patients were retrospectively evaluated. We evaluated neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), absolute eosinophil count (AEC), and absolute monocyte count (AMC) as peripheral blood markers as well as serum CRP levels. The primary endpoints were progression-free survival (PFS) and overall survival (OS) after nivolumab initiation.RESULTS: Median PFS was significantly shorter in patients with high NLR (>= 3) versus low NLR (p = 0.0356), high MLR (>= 0.3) versus low MLR (p = 0.0013), or high PLR (>= 160) versus low PLR (p = 0.0073), and median OS was significantly shorter in patients with high NLR versus low NLR (p = 0.0025), high MLR versus low MLR (p = 0.0025), high PLR versus low PLR (p = 0.0256), or high CRP (>= 1.0 mg/dl) versus low CRP (p = 0.0006). Multivariate analyses showed that MLR (HR 2.65, p = 0.0068) was an independent factor for PFS and that NLR (HR 3.34, p = 0.0218), MLR (HR 3.42, p = 0.0381), and CRP (HR 4.98, p = 0.0108) were independent factors for OS.CONCLUSIONS: The systemic inflammatory factors NLR, MLR, and CRP were predictive factors in nivolumab therapy for mRCC. These easily monitored factors can contribute to effective treatment and follow-up.
CANIT0002607	31365588	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	149	N/A	Retrospective analysis	The patients with an ultra-high PD-L1 expression continued pembrolizumab therapy longer, driven by a reduced risk of treatment failure in the late phase. PD-L1 expression levels might be a predictive biomarker of a first-line immunotherapy benefit in the late phase among NSCLC patients with PD-L1 tumor proportion score (TPS) >=50%. 149 patients were included: 99 (66.4%) and 50 (33.6%) patients were in the TPS 50-89% and TPS 90-100% cohorts, respectively. Baseline characteristics were similar between the TPS 90-100% and TPS 50-89% cohorts. The objective response rates (ORR) in the TPS 90-100% and TPS 50-89% cohorts were 58.0% and 46.5%, respectively (p = 0.23). Time to treatment failure (TTF) was longer in the TPS 90-100% cohort than in the TPS 50-89% cohort (hazard ratio [HR]: 0.67, 95% confidence interval (CI): 0.42-1.07; p = 0.09). Although TTF within 120 days after the initiation of pembrolizumab therapy was comparable between both cohorts (p = 0.54), TTF after 120 days was significantly longer in the TPS 90-100% cohort than in the TPS 50-89% cohort (HR: 0.22, 95% CI: 0.06-0.87; p = 0.031).	Immune related adverse events of grade 3 or more occurred in 16.0% and 19.2% of patients in the TPS 90-100% and TPS 50-89% cohorts, respectively.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jul 31	Clinical outcomes in non-small cell lung cancer patients with an ultra-high expression of programmed death ligand-1 treated using pembrolizumab as a first-line therapy: A retrospective multicenter cohort study in Japan.	 PLoS One	BACKGROUND: Pembrolizumab is currently approved as a first-line therapy for advanced non-small cell lung cancer (NSCLC) patients with a programed death ligand-1 (PD-L1) expression >=50%. However, the association between the efficacy of pembrolizumab and PD-L1 expression levels in patients with PD-L1 expression >=50% has not been fully elucidated.METHODS: We retrospectively analyzed patients with advanced NSCLC and a PD-L1 tumor proportion score (TPS) of >=50% who received pembrolizumab as a first-line therapy at 11 institutions in Japan between February 2017 and January 2018. Patients were divided into TPS 50-89% and TPS 90-100% (ultra-high PD-L1 expression) cohorts.RESULTS: In total, 149 patients were included: 99 (66.4%) and 50 (33.6%) patients were in the TPS 50-89% and TPS 90-100% cohorts, respectively. Baseline characteristics were similar between the TPS 90-100% and TPS 50-89% cohorts. The objective response rates (ORR) in the TPS 90-100% and TPS 50-89% cohorts were 58.0% and 46.5%, respectively (p = 0.23). Time to treatment failure (TTF) was longer in the TPS 90-100% cohort than in the TPS 50-89% cohort (hazard ratio [HR]: 0.67, 95% confidence interval (CI): 0.42-1.07; p = 0.09). Although TTF within 120 days after the initiation of pembrolizumab therapy was comparable between both cohorts (p = 0.54), TTF after 120 days was significantly longer in the TPS 90-100% cohort than in the TPS 50-89% cohort (HR: 0.22, 95% CI: 0.06-0.87; p = 0.031). Immune related adverse events of grade 3 or more occurred in 16.0% and 19.2% of patients in the TPS 90-100% and TPS 50-89% cohorts, respectively.CONCLUSIONS: The patients with an ultra-high PD-L1 expression continued pembrolizumab therapy longer, driven by a reduced risk of treatment failure in the late phase. PD-L1 expression levels might be a predictive biomarker of a first-line immunotherapy benefit in the late phase among NSCLC patients with TPS >=50%.
CANIT0002608	31366516	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	37	N/A	N/A	The safety and efficacy of nivolumab in patients with nervous system (CNS) metastases appear to be similar to those seen in the overall EAP cohort in Italy. The objective response rate was 19%. Median overall survival was 5.8 (95% confidence interval=1.9-9.8) months and median progression-free survival was 4.9 (95% confidence interval=2.7-7.1) months.	Three patients (8%) had grade 3-4 adverse events and one patient discontinued due to an adverse event.	N/A	N/A	Metastasis (NCIT:C19151); 	Nervous system metastases	Disease status	 2019 Aug	Italian Cohort of the Nivolumab EAP in Squamous NSCLC: Efficacy and Safety in Patients With CNS Metastases.	 Anticancer Res	BACKGROUND/AIM: Brain metastases are an additional challenge in patients with non-small-cell lung cancer (NSCLC) because most chemotherapy agents cannot cross the blood-brain barrier. Nivolumab has demonstrated efficacy in patients with advanced squamous NSCLC, but because patients with central nervous system (CNS) metastases are typically excluded from registration trials, 'field-practice' data are needed.PATIENTS AND METHODS: Patients in the Italian cohort of the Expanded Access Program (EAP) who had CNS metastases at baseline were analyzed.RESULTS: Thirty-seven patients with CNS metastases received a median of six doses of nivolumab. Three patients (8%) had grade 3-4 adverse events and one patient discontinued due to an adverse event. The objective response rate was 19%. Median overall survival was 5.8 (95% confidence interval=1.9-9.8) months and median progression-free survival was 4.9 (95% confidence interval=2.7-7.1) months.CONCLUSION: The safety and efficacy of nivolumab in patients with CNS metastases appear to be similar to those seen in the overall EAP cohort in Italy.
CANIT0002609	31367835	Clinical research	Cancers	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	509	N/A	Retrospective analysis	The results is confirmed the prognostic value of neutrophil to lymphocyte ratio (NLR) in patients with advanced cancer treated with immune checkpoint inhibitors (ICI). It found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. This is the first study to demonstrate a non-linear change in NLR over time that correlates with survival. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8-33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1-16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9-9.1).	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Oct	Change in neutrophil to lymphocyte ratio during immunotherapy treatment is a non-linear predictor of patient outcomes in advanced cancers.	 J Cancer Res Clin Oncol	BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR.METHODS: A retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS.RESULTS: 509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8-33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1-16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9-9.1).CONCLUSIONS: We confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.
CANIT0002610	31377210	Case report	A 34-year-old human immunodeficiency virus-negative female with refractory PBL	Plasmablastic lymphoma	EFO:0000574	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The significance of the case presented herein is 2-fold; first, it generates plausibility that the use of checkpoint inhibition warrants further evaluation in PBL and could provide a feasible treatment strategy for such high-risk patients. Second, to our knowledge, this is the first case on the use of allogeneic HCT in the setting of HIVnegative PBL and appears to be safe with comparable toxicity in this fit patient in spite of myeloablative conditioning, albeit with short follow-up	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Oct	Therapeutic Potential of Checkpoint Inhibitors in Refractory Plasmablastic Lymphoma.	 Clin Lymphoma Myeloma Leuk	Unable to provide
CANIT0002611	31382863	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	It reports a possible acute coronary syndrome as immune-related adverse event in a lung cancer patient.	Acute coronary syndrome and recurrent colitis	N/A	N/A	N/A	N/A	N/A	 2020 Jan	Acute coronary syndrome and recurrent colitis as immune-related adverse events in a lung cancer patient.	 J Oncol Pharm Pract	Immune checkpoint inhibitors have become a target for pharmacological research in lung cancer. Immune-related adverse events (irAEs) such as pneumonitis, colitis, hepatitis and endocrinopathies have been well characterized in immune checkpoint inhibitors, but coronary toxicities, like acute coronary syndrome, are poorly described. Herein, we report a possible acute coronary syndrome as immune-related adverse event in a lung cancer patient.
CANIT0002612	31382865	Case report	A nivolumab-induced lichen planus as an immune-related adverse event in a young woman	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A nivolumab-induced lichen planus after the ninth dose of nivolumab	Lichen planus	N/A	N/A	N/A	N/A	N/A	 2020 Apr	Nivolumab-induced lichen planus.	 J Oncol Pharm Pract	INTRODUCTION: Renal cell carcinomas account for 90% of all malignant neoplasms of the kidney. The most common types of renal cancer in adults are clear cell and papillary renal cell carcinoma; sporadic cases of renal carcinomas containing chromosomal translocations are rare, more usually occurring in children and young adults. Nivolumab (a fully human immunoglobulin G4 PD-1 checkpoint inhibitor antibody) has received the Food and Drug Administration approval for the treatment of metastatic renal cell carcinoma in patients who have received prior antiangiogenic therapy. Skin reactions are the most common side-effects under treatment with anti-PD-1 antibodies and play an important role for patients.CASE REPORT: We report a nivolumab-induced lichen planus as an immune-related adverse event in a young woman who was treated for advanced renal cell carcinoma. After the ninth dose of nivolumab treatment, she was consulted to the dermatologist because of skin lesions, and lichen planus was diagnosed.MANAGEMENT AND OUTCOME: She was treated with topical corticosteroids and clobetasol propionate cream. Her lesions regressed after the local therapy within one month, allowing for uninterrupted nivolumab therapy.DISCUSSION: Skin adverse events are the most common side-effects under immunotherapy and play an important role for patients and usually develop early in the course of treatment. The most frequent skin reactions are rash, pruritus, and vitiligo. Serious skin adverse events are rare and do not usually require dose reductions or treatment discontinuation. We report a nivolumab-induced lichen planus after the ninth dose of nivolumab.
CANIT0002613	31389500	Case report	Advanced mixed cellularity Hodgkin¡¯s lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We presented a successful reintroduction of the anti-PD1 drug after the adverse immune reaction. The pathophysiology background definition was very important to elucidate the pattern of damage and therapeutic options. We recommend that patients in use of anti-PD1 drugs presenting kidney function alteration be evaluated as soon as possible by a kidney biopsy	Generalized edema, respiratory distress, and pleural effusion,interstitial nephritis	N/A	N/A	N/A	N/A	N/A	 2019 Aug 5	Interstitial nephritis associated with nivolumab in a patient with hodgkin lymphoma.	 Rev Assoc Med Bras (1992)	Unable to provide
CANIT0002614	31395089	Clinical research	Advanced tumors	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3655	N/A	Meta-analysis	The incidence of TE (neutralizing positive)antidrug antibodies (ADAs) against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab.	Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA-positive; none had neutralizing antibodies.	N/A	N/A	N/A	N/A	N/A	 2019 Aug 8	Immunogenicity of pembrolizumab in patients with advanced tumors.	 J Immunother Cancer	BACKGROUND: Pembrolizumab is a potent, humanized, monoclonal anti-programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study.PATIENTS AND METHODS: Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately.RESULTS: Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA-positive; none had neutralizing antibodies.CONCLUSIONS: The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab.TRIAL REGISTRATION: ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015).
CANIT0002615	31398081	Clinical research	Thirty patients with PMBL	Primary mediastinal B-cell lymphoma	EFO:1001938	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab plus brentuximab vedotin	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); brentuximab vedotin (DB08870); 	30	N/A	Open-label, phase I/II CheckMate 436 study	In patients with relapsed/refractory (R/R) primary mediastinal B-cell lymphoma (PMBL), the combination of nivolumab plus brentuximab vedotin represents a promising option, with high antitumor activity and a manageable safety profile	Treatment-related adverse events were reported in 25 patients (83%). Sixteen patients (53%) had grade 3 to 4 treatment-related adverse events; the most common were neutropenia (n = 9), thrombocytopenia (n = 3), and peripheral neuropathy (n = 3)	N/A	N/A	N/A	N/A	N/A	 2019 Nov 20	Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study.	 J Clin Oncol	PURPOSE: Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive non-Hodgkin lymphoma with poor outcomes in patients with relapsed/refractory (R/R) disease. PMBL is characterized by high expression of programmed death-1 ligand and variable expression of CD30. Nivolumab, an anti-programmed death-1 immune checkpoint inhibitor, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, may have synergistic activity in R/R PMBL.METHODS: The expansion cohort of the open-label, phase I/II CheckMate 436 study enrolled patients with confirmed R/R PMBL who were previously treated with either autologous hematopoietic cell transplantation or two or more prior chemotherapy regimens if ineligible for autologous hematopoietic cell transplantation. Patients received nivolumab (240 mg intravenously) and BV (1.8 mg/kg intravenously) every 3 weeks until disease progression or unacceptable toxicity. Primary end points were investigator-assessed objective response rate (ORR) per the Lugano 2014 criteria and safety.RESULTS: Thirty patients with PMBL were treated and evaluable. At a median follow-up of 11.1 months, ORR (95% CI) was 73% (54% to 88%), with a 37% complete remission rate per investigator, and ORR of 70% (51% to 85%), with a 43% complete metabolic response rate per independent review. Median duration of response, median progression-free survival, and median overall survival have not been reached. Eleven responders had consolidation with autologous (n = 5) or allogeneic (n = 6) transplantation. Treatment-related adverse events were reported in 25 patients (83%). Sixteen patients (53%) had grade 3 to 4 treatment-related adverse events; the most common were neutropenia (n = 9), thrombocytopenia (n = 3), and peripheral neuropathy (n = 3). There were no treatment-related deaths.CONCLUSION: In patients with R/R PMBL, the combination of nivolumab plus BV represents a promising option, with high antitumor activity and a manageable safety profile.
CANIT0002616	31400961	Clinical research	Newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome	Acute myeloid leukemia	EFO:0000222	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab plus idarubicin plus cytarabine	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); idarubicin (DB01177); cytarabine (DB00987); 	44	N/A	Single-arm, phase 2	Addition of nivolumab to induction chemotherapy with idarubicin and cytarabine is feasible in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. Post-transplant severe graft-versus-host disease could be improved, and earlier initiation of checkpoint inhibitor therapy is warranted in future studies. At a median follow-up of 17.25 months (IQR 0.50-30.40), median event-free survival was not reached (95% CI 7.93-NR). Median relapse-free survival of responders was 18.54 months (95% CI 8.20-23.22). The median overall survival was 18.54 months (95% CI 10.81-28.81).Before administration of therapy, a higher prevalence of live CD3-positive T cells in the bone marrow appears to predict for response, whereas nonresponders had significantly higher percentage of CD4- positive T effectors co-expressing PD-1 and TIM-3 and PD-1 and LAG-3.	Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab.	N/A	N/A	CD3 (P07766); T-Lymphocyte (NCIT:C12476); 	A higher prevalence of live CD3-positive T-cells in the bone marrow	Gene expression signature on/in immune cell	 2019 Sep	Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a single-arm, phase 2 study.	 Lancet Haematol	BACKGROUND: Outcomes for younger patients with acute myeloid leukaemia have moderately improved over the past two decades owing to better supportive care and recent introduction of novel targeted agents. Blocking PD-1 and its ligand's pathways enhances antileukaemia responses by enabling T cells in murine models. We aimed to assess the addition of nivolumab to frontline therapy with idarubicin and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome.METHODS: This single-arm, phase 2 part of the phase 1-2 study of nivolumab in combination with idarubicin and cytarabine was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 18-60 years (or >60 years if suitable for intensive chemotherapy), and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2. Induction included cytarabine 1.5 g/m2 by 24-h continuous infusion daily on days 1-4 (3 days in patients >60 years) and idarubicin 12 mg/m2 daily on days 1-3. Nivolumab 3 mg/kg was started on day 24 (range 22-26) and continued every 2 weeks for up to a year in responders. Responders received either up to five consolidation cycles of attenuated doses of idarubicin and cytarabine, or allogeneic stem cell transplantation if eligible. The primary endpoint was event-free survival. Efficacy and safety analyses were done in all patients who received at least one dose of study treatment. Secondary endpoints were relapse-free survival and overall survival. This ongoing trial is registered with ClinicalTrials.gov, number NCT02464657.FINDINGS: Between Aug 7, 2015, and June 2, 2018, 44 patients were enrolled of whom 22 (50%) had adverse genetic risk by European Leukaemia Network classification. All patients were evaluable for safety and efficacy. At a median follow-up of 17.25 months (IQR 0.50-30.40), median event-free survival was not reached (95% CI 7.93-NR). Median relapse-free survival of responders was 18.54 months (95% CI 8.20-23.22). The median overall survival was 18.54 months (95% CI 10.81-28.81). Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab.INTERPRETATION: Addition of nivolumab to induction chemotherapy with idarubicin and cytarabine is feasible in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. Post-transplant severe graft-versus-host disease could be improved, and earlier initiation of checkpoint inhibitor therapy is warranted in future studies.FUNDING: The MD Anderson Cancer Center Support Grant CA016672, and the MD Anderson Cancer Center Leukaemia SPORE CA100632 from the National Cancer Institute, Bristol Myers Squibb.
CANIT0002617	31400961	Clinical research	Newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome	Myelodysplastic syndrome	EFO:0000198	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab plus idarubicin plus cytarabine	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); idarubicin (DB01177); cytarabine (DB00987); 	44	N/A	Single-arm, phase 2	At a median follow-up of 17.25 months (IQR 0.50-30.40), median event-free survival was not reached (95% CI 7.93-NR). Median relapse-free survival of responders was 18.54 months (95% CI 8.20-23.22). The median overall survival was 18.54 months (95% CI 10.81-28.81).	Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab.	N/A	N/A	CD3 (P07766); T-Lymphocyte (NCIT:C12476); 	A higher prevalence of live CD3-positive T-cells in the bone marrow	Gene expression signature on/in immune cell	 2019 Sep	Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a single-arm, phase 2 study.	 Lancet Haematol	BACKGROUND: Outcomes for younger patients with acute myeloid leukaemia have moderately improved over the past two decades owing to better supportive care and recent introduction of novel targeted agents. Blocking PD-1 and its ligand's pathways enhances antileukaemia responses by enabling T cells in murine models. We aimed to assess the addition of nivolumab to frontline therapy with idarubicin and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome.METHODS: This single-arm, phase 2 part of the phase 1-2 study of nivolumab in combination with idarubicin and cytarabine was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 18-60 years (or >60 years if suitable for intensive chemotherapy), and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2. Induction included cytarabine 1.5 g/m2 by 24-h continuous infusion daily on days 1-4 (3 days in patients >60 years) and idarubicin 12 mg/m2 daily on days 1-3. Nivolumab 3 mg/kg was started on day 24 (range 22-26) and continued every 2 weeks for up to a year in responders. Responders received either up to five consolidation cycles of attenuated doses of idarubicin and cytarabine, or allogeneic stem cell transplantation if eligible. The primary endpoint was event-free survival. Efficacy and safety analyses were done in all patients who received at least one dose of study treatment. Secondary endpoints were relapse-free survival and overall survival. This ongoing trial is registered with ClinicalTrials.gov, number NCT02464657.FINDINGS: Between Aug 7, 2015, and June 2, 2018, 44 patients were enrolled of whom 22 (50%) had adverse genetic risk by European Leukaemia Network classification. All patients were evaluable for safety and efficacy. At a median follow-up of 17.25 months (IQR 0.50-30.40), median event-free survival was not reached (95% CI 7.93-NR). Median relapse-free survival of responders was 18.54 months (95% CI 8.20-23.22). The median overall survival was 18.54 months (95% CI 10.81-28.81). Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab.INTERPRETATION: Addition of nivolumab to induction chemotherapy with idarubicin and cytarabine is feasible in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. Post-transplant severe graft-versus-host disease could be improved, and earlier initiation of checkpoint inhibitor therapy is warranted in future studies.FUNDING: The MD Anderson Cancer Center Support Grant CA016672, and the MD Anderson Cancer Center Leukaemia SPORE CA100632 from the National Cancer Institute, Bristol Myers Squibb.
CANIT0002618	31405908	Clinical research	Cancers	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	19	N/A	Retrospective analysis	Neuropathy is a rare complication of immune checkpoint inhibitors (ICIs) that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.We identified 19 patients with irNeuropathies. ICIs included anti-programmed death-1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy.	ICI-related neuropathy (irNeuropathy)	N/A	N/A	N/A	N/A	N/A	 2019 Sep 10	Varied phenotypes and management of immune checkpoint inhibitor-associated neuropathies.	 Neurology	OBJECTIVE: To describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs).METHODS: Patients with ICI-related neuropathy (irNeuropathy) were identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents.RESULTS: We identified 19 patients with irNeuropathies. ICIs included anti-programmed death-1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy.CONCLUSION: Neuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.
CANIT0002619	31409671	Clinical research	Relapsed or refractory classic Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	210	N/A	Phase 2 KEYNOTE-087 study	Results confirmed effective antitumor activity, durability of response, and manageable safety of pembrolizumab monotherapy in refractory classic Hodgkin lymphoma (RRcHL), regardless of prior treatment and including chemoresistant cHL. The objective response rate (ORR) by blinded independent central review was 71.9% (95% CI, 65.3-77.9), the complete response rate (CRR) was 27.6%, and the partial response (PR) rate was 44.3%. Median duration of response was 16.5 months (range, 0.0+ to 27.0+ [+, no progressive disease at last assessment]) in all patients, 22.1 months in cohort 1, 11.1 months in cohort 2, and 24.4 months in cohort 3. Median progression-free survival was not reached in all patients with CR: 13.8 months (95% CI, 12.0-22.1) for patients with PR and 10.9 months (95% CI, 5.6-11.1) for patients with stable disease. Median overall survival was not reached in all patients or in any cohort.	Treatment-related adverse events (TRAEs) of any grade occurred in 153 (72.9%) patients; grades 3 and 4 occurred in 25 (12.0%) patients; none resulted in death.	N/A	N/A	N/A	N/A	N/A	 2019 Oct 3	Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087.	 Blood	Programmed death-1 inhibitors are approved for patients with relapsed or refractory classic Hodgkin lymphoma (RRcHL). We present the 2-year follow-up of the phase 2 KEYNOTE-087 study of pembrolizumab in 210 patients, based on HL progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV; cohort 1); salvage chemotherapy and BV, with ineligibility for SCT owing to chemorefractory disease (cohort 2); and progression after SCT without BV (cohort 3). With a median follow-up of 27.6 months, the objective response rate (ORR) by blinded independent central review was 71.9% (95% CI, 65.3-77.9), the complete response rate (CRR) was 27.6%, and the partial response (PR) rate was 44.3%. Median duration of response was 16.5 months (range, 0.0+ to 27.0+ [+, no progressive disease at last assessment]) in all patients, 22.1 months in cohort 1, 11.1 months in cohort 2, and 24.4 months in cohort 3. Median progression-free survival was not reached in all patients with CR: 13.8 months (95% CI, 12.0-22.1) for patients with PR and 10.9 months (95% CI, 5.6-11.1) for patients with stable disease. Median overall survival was not reached in all patients or in any cohort. Treatment-related adverse events (TRAEs) of any grade occurred in 153 (72.9%) patients; grades 3 and 4 occurred in 25 (12.0%) patients; none resulted in death. Results confirmed effective antitumor activity, durability of response, and manageable safety of pembrolizumab monotherapy in RRcHL, regardless of prior treatment and including chemoresistant cHL. This trial was registered at www.clinicaltrials.gov as #NCT02453594.
CANIT0002620	31419753	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	134	N/A	N/A	The data suggest that the genetics of melanomas arising in acral sites varies by tumour location and may influence biological behaviour. In the cohort, BRAF (30%), NRAS (28%), TERT promoter (26%), NF1 (14%) and KIT (6%) were frequently identified mutations. Comparing tumours situated on palms and soles with melanomas arising on dorsal acral sites, a higher frequency of NRAS (39.1% versus 25%) and NF1 (17.3% versus 0%) and lower frequencies of BRAF (21.7% versus 75%) and TERT promoter (8.6% versus 50%) mutations were observed. MAPK activating mutations were identified in 64% of tumours. Overall survival was longer in patients treated with immune checkpoint inhibitors as first-line treatment than in patients receiving other systemic therapies (i.e. BRAF/MEK inhibitors and chemotherapy).	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep	Clinical and genetic analysis of melanomas arising in acral sites.	 Eur J Cancer	STUDY AIM: Melanomas arising in acral sites are associated with a poorer prognosis than other melanoma subtypes. The aim of this study was to evaluate clinical-pathological and genetic characteristics as well as therapeutic responses of a larger cohort of patients with melanomas arising in acral sites.METHODS: Clinical data of 134 patients with melanomas arising in acral sites from the Dept. of Dermatology Essen were collected and analysed with regard to clinicopathological characteristics and treatment responses. Genetic analysis with targeted next-generation sequencing was done on 50 samples.RESULTS: In our cohort, BRAF (30%), NRAS (28%), TERT promoter (26%), NF1 (14%) and KIT (6%) were frequently identified mutations. Comparing tumours situated on palms and soles with melanomas arising on dorsal acral sites, a higher frequency of NRAS (39.1% versus 25%) and NF1 (17.3% versus 0%) and lower frequencies of BRAF (21.7% versus 75%) and TERT promoter (8.6% versus 50%) mutations were observed. MAPK activating mutations were identified in 64% of tumours. Overall survival was longer in patients treated with immune checkpoint inhibitors as first-line treatment than in patients receiving other systemic therapies (i.e. BRAF/MEK inhibitors and chemotherapy).CONCLUSION: Our data suggest that the genetics of melanomas arising in acral sites varies by tumour location and may influence biological behaviour.
CANIT0002621	31420468	Clinical research	Fifteen patients 	Breast cancer	MONDO:0007254	Breast	PD-L1 (Q9NZQ7); HER2 (P04626); 	PD-L1; HER2	Durvalumab plus trastuzumab	N/A	Immune checkpoint therapy plus Target therapy	Durvalumab (DB11714); trastuzumab (DB00072); 	15	N/A	Phase Ib	The  recommended phase II dose (RP2D) of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2-positive PD-L1-negative metastatic breast cancer (MBC).	No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade >=3 immune-related adverse event (grade 4 diabetes mellitus). 	N/A	N/A	HER2 (P04626); 	HER2 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Nov	A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229).	 Oncologist	BACKGROUND: Immune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD-L1)-positive, triple-negative, metastatic breast cancer (MBC). Antibody-dependent cell-mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2-positive MBC previously treated with chemotherapy and anti-HER2 antibodies to assess safety, efficacy, and correlative endpoints.PATIENTS AND METHODS: Patients with HER2-positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D.RESULTS: Fifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40-86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab-emtansine (93%) for MBC. No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade >=3 immune-related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had <1% PD-L1 expression on either archival tissue (7/15) or prestudy biopsy (8/15). In the dose expansion cohort, evaluable pretreatment and on-treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration.CONCLUSION: The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2-positive PD-L1-negative MBC.IMPLICATIONS FOR PRACTICE: This phase Ib trial with associated correlative endpoints provides insights into the lack of activity of the combination of durvalumab and trastuzumab in heavily pretreated HER2-positive metastatic breast cancer (MBC). No significant clinical activity was observed in patients with heavily pretreated HER2-positive programmed death ligand 1 (PD-L1)-negative MBC with evidence of cytotoxic T-cell exhaustion. Furthermore, all patients had no expression of PD-L1 in the tumor cells. These data support the importance of PD-L1 as an important selection biomarker and the need to assess the tumor microenvironment for immune regulatory cells. Further work is needed to understand how to activate the cold tumors to be able to combine current immune-oncology agents.
CANIT0002622	31420468	Clinical research	Fifteen patients 	Breast cancer	MONDO:0007254	Breast	PD-L1 (Q9NZQ7); HER2 (P04626); 	PD-L1; HER2	Durvalumab plus trastuzumab	N/A	Immune checkpoint therapy plus Target therapy	Durvalumab (DB11714); trastuzumab (DB00072); 	15	N/A	Phase Ib	The  recommended phase II dose (RP2D) of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2-positive PD-L1-negative metastatic breast cancer (MBC).	No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade >=3 immune-related adverse event (grade 4 diabetes mellitus). 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Nov	A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229).	 Oncologist	BACKGROUND: Immune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD-L1)-positive, triple-negative, metastatic breast cancer (MBC). Antibody-dependent cell-mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2-positive MBC previously treated with chemotherapy and anti-HER2 antibodies to assess safety, efficacy, and correlative endpoints.PATIENTS AND METHODS: Patients with HER2-positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D.RESULTS: Fifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40-86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab-emtansine (93%) for MBC. No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade >=3 immune-related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had <1% PD-L1 expression on either archival tissue (7/15) or prestudy biopsy (8/15). In the dose expansion cohort, evaluable pretreatment and on-treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration.CONCLUSION: The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2-positive PD-L1-negative MBC.IMPLICATIONS FOR PRACTICE: This phase Ib trial with associated correlative endpoints provides insights into the lack of activity of the combination of durvalumab and trastuzumab in heavily pretreated HER2-positive metastatic breast cancer (MBC). No significant clinical activity was observed in patients with heavily pretreated HER2-positive programmed death ligand 1 (PD-L1)-negative MBC with evidence of cytotoxic T-cell exhaustion. Furthermore, all patients had no expression of PD-L1 in the tumor cells. These data support the importance of PD-L1 as an important selection biomarker and the need to assess the tumor microenvironment for immune regulatory cells. Further work is needed to understand how to activate the cold tumors to be able to combine current immune-oncology agents.
CANIT0002623	31422022	Clinical research	Hepatocellular carcinoma	Hepatocellular carcinoma	EFO:0000182	Liver	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus radioembolization	N/A	Immune checkpoint therapy plus Radiotherapy	N/A	26	N/A	N/A	Radioembolization combined with checkpoint inhibitor immunotherapy in cases of hepatocellular carcinoma (HCC) appears to be safe and causes limited treatment-related toxicity. Future prospective studies are needed to identify the optimal combination treatment protocols and evaluate the efficacy of combination therapy. The median overall survival from first immunotherapy was 17.2 months (95% CI, 10.9-23.4). The median overall survival from first radioembolization was 16.5 months (95% CI, 6.6-26.4). From first radioembolization, time to tumor progression was 5.7 months (95% CI, 4.2-7.2), and progression-free survival was 5.7 months (95% CI, 4.3-7.1).	There were no early (30-day) mortality or grades 3/4 hepatobiliary or immunotherapy-related toxicities. Delayed grades 3/4 hepatobiliary toxicities (1-3 months) occurred in 2 patients in the setting of HCC disease progression. One patient developed pneumonitis.	N/A	N/A	N/A	N/A	N/A	 2020 Jan	Safety of Combined Yttrium-90 Radioembolization and Immune Checkpoint Inhibitor Immunotherapy for Hepatocellular Carcinoma.	 J Vasc Interv Radiol	PURPOSE: To investigate the safety of yttrium-90 radioembolization in combination with checkpoint inhibitor immunotherapy for the treatment of hepatocellular carcinoma (HCC).MATERIALS AND METHODS: This single-center retrospective study included 26 consecutive patients with HCC who received checkpoint inhibitor immunotherapy within 90 days of radioembolization from April 2015 to May 2018. Patients had preserved liver function (Child-Pugh scores A-B7) and either advanced HCC due to macrovascular invasion or limited extrahepatic disease (21 patients) or aggressive intermediate stage HCC that resulted in earlier incorporation of systemic immunotherapy (5 patients). Clinical documentation, laboratory results, and imaging results at 1- and 3-month follow-up intervals were reviewed to assess treatment-related adverse events and treatment responses.RESULTS: The median follow-up period after radioembolization was 7.8 months (95% confidence interval [CI], 5.6-11.8). There were no early (30-day) mortality or grades 3/4 hepatobiliary or immunotherapy-related toxicities. Delayed grades 3/4 hepatobiliary toxicities (1-3 months) occurred in 2 patients in the setting of HCC disease progression. One patient developed pneumonitis. The median overall survival from first immunotherapy was 17.2 months (95% CI, 10.9-23.4). The median overall survival from first radioembolization was 16.5 months (95% CI, 6.6-26.4). From first radioembolization, time to tumor progression was 5.7 months (95% CI, 4.2-7.2), and progression-free survival was 5.7 months (95% CI, 4.3-7.1).CONCLUSIONS: Radioembolization combined with checkpoint inhibitor immunotherapy in cases of HCC appears to be safe and causes limited treatment-related toxicity. Future prospective studies are needed to identify the optimal combination treatment protocols and evaluate the efficacy of combination therapy.
CANIT0002624	31427204	Clinical research	Previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	550	546	A randomised, controlled, phase 3 trial	The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. We observed a similar significant negative prognostic effect of the following baseline clinical risk factors on overall survival in the intention-to-treat population in both the nivolumab plus ipilimumab and sunitinib groups: lower Karnofsky performance status, higher lactate dehydrogenase concentration, higher neutrophil:lymphocyte ratio, and higher sum of reference diameters of target lesions. Higher corrected calcium concentration only significantly affected overall survival in the nivolumab plus ipilimumab group, whereas lower haemoglobin concentration, higher tumour PD-L1 expression, and no previous nephrectomy only significantly affected overall survival in the sunitinib group.	In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.	N/A	N/A	Calcium (NCIT:C331); 	Corrected calcium concentration	Metabolite	 2019 Oct	Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.	 Lancet Oncol	BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32.4 months [IQR 13.4-36.3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35.6-not estimable] vs 26.6 months [22.1-33.4]; hazard ratio [HR] 0.66 [95% CI 0.54-0.80], p<0.0001), progression-free survival (median 8.2 months [95% CI 6.9-10.0] vs 8.3 months [7.0-8.8]; HR 0.77 [95% CI 0.65-0.90], p=0.0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0.0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37.9 months [32.2-not estimable]; HR 0.71 [95% CI 0.59-0.86], p=0.0003), progression-free survival (median 9.7 months [95% CI 8.1-11.1] vs 9.7 months [8.3-11.1]; HR 0.85 [95% CI 0.73-0.98], p=0.027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0.015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
CANIT0002625	31427204	Clinical research	Previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	550	546	A randomised, controlled, phase 3 trial	The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. We observed a similar significant negative prognostic effect of the following baseline clinical risk factors on overall survival in the intention-to-treat population in both the nivolumab plus ipilimumab and sunitinib groups: lower Karnofsky performance status, higher lactate dehydrogenase concentration, higher neutrophil:lymphocyte ratio, and higher sum of reference diameters of target lesions. Higher corrected calcium concentration only significantly affected overall survival in the nivolumab plus ipilimumab group, whereas lower haemoglobin concentration, higher tumour PD-L1 expression, and no previous nephrectomy only significantly affected overall survival in the sunitinib group.	In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.	N/A	N/A	HBG2 (P69892); 	Serum HBG2 levels	Gene expression signature in serum	 2019 Oct	Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.	 Lancet Oncol	BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32.4 months [IQR 13.4-36.3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35.6-not estimable] vs 26.6 months [22.1-33.4]; hazard ratio [HR] 0.66 [95% CI 0.54-0.80], p<0.0001), progression-free survival (median 8.2 months [95% CI 6.9-10.0] vs 8.3 months [7.0-8.8]; HR 0.77 [95% CI 0.65-0.90], p=0.0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0.0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37.9 months [32.2-not estimable]; HR 0.71 [95% CI 0.59-0.86], p=0.0003), progression-free survival (median 9.7 months [95% CI 8.1-11.1] vs 9.7 months [8.3-11.1]; HR 0.85 [95% CI 0.73-0.98], p=0.027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0.015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
CANIT0002626	31427204	Clinical research	Previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	550	546	A randomised, controlled, phase 3 trial	The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. We observed a similar significant negative prognostic effect of the following baseline clinical risk factors on overall survival in the intention-to-treat population in both the nivolumab plus ipilimumab and sunitinib groups: lower Karnofsky performance status, higher lactate dehydrogenase concentration, higher neutrophil:lymphocyte ratio, and higher sum of reference diameters of target lesions. Higher corrected calcium concentration only significantly affected overall survival in the nivolumab plus ipilimumab group, whereas lower haemoglobin concentration, higher tumour PD-L1 expression, and no previous nephrectomy only significantly affected overall survival in the sunitinib group.	In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.	N/A	N/A	Karnofsky Performance Status (NCIT:C28013); 	Karnofsky performance status	Personal feature	 2019 Oct	Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.	 Lancet Oncol	BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32.4 months [IQR 13.4-36.3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35.6-not estimable] vs 26.6 months [22.1-33.4]; hazard ratio [HR] 0.66 [95% CI 0.54-0.80], p<0.0001), progression-free survival (median 8.2 months [95% CI 6.9-10.0] vs 8.3 months [7.0-8.8]; HR 0.77 [95% CI 0.65-0.90], p=0.0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0.0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37.9 months [32.2-not estimable]; HR 0.71 [95% CI 0.59-0.86], p=0.0003), progression-free survival (median 9.7 months [95% CI 8.1-11.1] vs 9.7 months [8.3-11.1]; HR 0.85 [95% CI 0.73-0.98], p=0.027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0.015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
CANIT0002627	31427204	Clinical research	Previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	550	546	A randomised, controlled, phase 3 trial	The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. We observed a similar significant negative prognostic effect of the following baseline clinical risk factors on overall survival in the intention-to-treat population in both the nivolumab plus ipilimumab and sunitinib groups: lower Karnofsky performance status, higher lactate dehydrogenase concentration, higher neutrophil:lymphocyte ratio, and higher sum of reference diameters of target lesions. Higher corrected calcium concentration only significantly affected overall survival in the nivolumab plus ipilimumab group, whereas lower haemoglobin concentration, higher tumour PD-L1 expression, and no previous nephrectomy only significantly affected overall survival in the sunitinib group.	In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Oct	Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.	 Lancet Oncol	BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32.4 months [IQR 13.4-36.3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35.6-not estimable] vs 26.6 months [22.1-33.4]; hazard ratio [HR] 0.66 [95% CI 0.54-0.80], p<0.0001), progression-free survival (median 8.2 months [95% CI 6.9-10.0] vs 8.3 months [7.0-8.8]; HR 0.77 [95% CI 0.65-0.90], p=0.0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0.0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37.9 months [32.2-not estimable]; HR 0.71 [95% CI 0.59-0.86], p=0.0003), progression-free survival (median 9.7 months [95% CI 8.1-11.1] vs 9.7 months [8.3-11.1]; HR 0.85 [95% CI 0.73-0.98], p=0.027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0.015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
CANIT0002628	31427204	Clinical research	Previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	550	546	A randomised, controlled, phase 3 trial	The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. We observed a similar significant negative prognostic effect of the following baseline clinical risk factors on overall survival in the intention-to-treat population in both the nivolumab plus ipilimumab and sunitinib groups: lower Karnofsky performance status, higher lactate dehydrogenase concentration, higher neutrophil:lymphocyte ratio, and higher sum of reference diameters of target lesions. Higher corrected calcium concentration only significantly affected overall survival in the nivolumab plus ipilimumab group, whereas lower haemoglobin concentration, higher tumour PD-L1 expression, and no previous nephrectomy only significantly affected overall survival in the sunitinib group.	In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.	N/A	N/A	Nephrectomy (NCIT:C15284); 	Previous nephrectomy	Personal feature	 2019 Oct	Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.	 Lancet Oncol	BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32.4 months [IQR 13.4-36.3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35.6-not estimable] vs 26.6 months [22.1-33.4]; hazard ratio [HR] 0.66 [95% CI 0.54-0.80], p<0.0001), progression-free survival (median 8.2 months [95% CI 6.9-10.0] vs 8.3 months [7.0-8.8]; HR 0.77 [95% CI 0.65-0.90], p=0.0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0.0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37.9 months [32.2-not estimable]; HR 0.71 [95% CI 0.59-0.86], p=0.0003), progression-free survival (median 9.7 months [95% CI 8.1-11.1] vs 9.7 months [8.3-11.1]; HR 0.85 [95% CI 0.73-0.98], p=0.027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0.015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
CANIT0002629	31427204	Clinical research	Previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	550	546	A randomised, controlled, phase 3 trial	The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. We observed a similar significant negative prognostic effect of the following baseline clinical risk factors on overall survival in the intention-to-treat population in both the nivolumab plus ipilimumab and sunitinib groups: lower Karnofsky performance status, higher lactate dehydrogenase concentration, higher neutrophil:lymphocyte ratio, and higher sum of reference diameters of target lesions. Higher corrected calcium concentration only significantly affected overall survival in the nivolumab plus ipilimumab group, whereas lower haemoglobin concentration, higher tumour PD-L1 expression, and no previous nephrectomy only significantly affected overall survival in the sunitinib group.	In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2019 Oct	Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.	 Lancet Oncol	BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32.4 months [IQR 13.4-36.3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35.6-not estimable] vs 26.6 months [22.1-33.4]; hazard ratio [HR] 0.66 [95% CI 0.54-0.80], p<0.0001), progression-free survival (median 8.2 months [95% CI 6.9-10.0] vs 8.3 months [7.0-8.8]; HR 0.77 [95% CI 0.65-0.90], p=0.0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0.0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37.9 months [32.2-not estimable]; HR 0.71 [95% CI 0.59-0.86], p=0.0003), progression-free survival (median 9.7 months [95% CI 8.1-11.1] vs 9.7 months [8.3-11.1]; HR 0.85 [95% CI 0.73-0.98], p=0.027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0.015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
CANIT0002630	31427204	Clinical research	Previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	550	546	A randomised, controlled, phase 3 trial	The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. We observed a similar significant negative prognostic effect of the following baseline clinical risk factors on overall survival in the intention-to-treat population in both the nivolumab plus ipilimumab and sunitinib groups: lower Karnofsky performance status, higher lactate dehydrogenase concentration, higher neutrophil:lymphocyte ratio, and higher sum of reference diameters of target lesions. Higher corrected calcium concentration only significantly affected overall survival in the nivolumab plus ipilimumab group, whereas lower haemoglobin concentration, higher tumour PD-L1 expression, and no previous nephrectomy only significantly affected overall survival in the sunitinib group.	In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.	N/A	N/A	Number of Lesions (NCIT:C174277); 	Sum of reference diameters of target lesions	Disease status	 2019 Oct	Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.	 Lancet Oncol	BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32.4 months [IQR 13.4-36.3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35.6-not estimable] vs 26.6 months [22.1-33.4]; hazard ratio [HR] 0.66 [95% CI 0.54-0.80], p<0.0001), progression-free survival (median 8.2 months [95% CI 6.9-10.0] vs 8.3 months [7.0-8.8]; HR 0.77 [95% CI 0.65-0.90], p=0.0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0.0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37.9 months [32.2-not estimable]; HR 0.71 [95% CI 0.59-0.86], p=0.0003), progression-free survival (median 9.7 months [95% CI 8.1-11.1] vs 9.7 months [8.3-11.1]; HR 0.85 [95% CI 0.73-0.98], p=0.027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0.015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
CANIT0002631	31427204	Clinical research	Previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Sunitinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	550	546	A randomised, controlled, phase 3 trial	The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. We observed a similar significant negative prognostic effect of the following baseline clinical risk factors on overall survival in the intention-to-treat population in both the nivolumab plus ipilimumab and sunitinib groups: lower Karnofsky performance status, higher lactate dehydrogenase concentration, higher neutrophil:lymphocyte ratio, and higher sum of reference diameters of target lesions. Higher corrected calcium concentration only significantly affected overall survival in the nivolumab plus ipilimumab group, whereas lower haemoglobin concentration, higher tumour PD-L1 expression, and no previous nephrectomy only significantly affected overall survival in the sunitinib group.	In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Oct	Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.	 Lancet Oncol	BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32.4 months [IQR 13.4-36.3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35.6-not estimable] vs 26.6 months [22.1-33.4]; hazard ratio [HR] 0.66 [95% CI 0.54-0.80], p<0.0001), progression-free survival (median 8.2 months [95% CI 6.9-10.0] vs 8.3 months [7.0-8.8]; HR 0.77 [95% CI 0.65-0.90], p=0.0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0.0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37.9 months [32.2-not estimable]; HR 0.71 [95% CI 0.59-0.86], p=0.0003), progression-free survival (median 9.7 months [95% CI 8.1-11.1] vs 9.7 months [8.3-11.1]; HR 0.85 [95% CI 0.73-0.98], p=0.027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0.015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
CANIT0002632	31430052	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	Meta-analysis	We included nine randomized controlled trials (RCTs), and we established seven different treatment comparisons according to the type of data. Two RCTs favored nivolumab as monotherapy or combined with ipilimumab on account of all primary outcomes. The efficacy data of all other comparisons were either indifferent or favored the control group.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Immunotherapy for metastatic renal cell carcinoma: A systematic review.	 J Evid Based Med	BACKGROUND: Various approaches have been developed for the treatment of metastatic renal cell carcinoma (MRCC). The objective was to assess the efficacy of immunotherapeutic approaches.METHODS: We included participants diagnosed with all types of histologically confirmed MRCC, the test intervention was immunotherapy alone or combined with other immunotherapy or targeted therapies, and the study design was restricted to randomized controlled trials (RCTs). Primary outcomes were overall survival, adverse events, and health-related quality of life. We conducted the last search in March 31, 2018.RESULTS: We included nine RCTs, and we established seven different treatment comparisons according to the type of data. Two RCTs favored nivolumab as monotherapy or combined with ipilimumab on account of all primary outcomes. The efficacy data of all other comparisons were either indifferent or favored the control group.CONCLUSION: The immune checkpoint inhibitors nivolumab as monotherapy or combined with ipilimumab appears to be the only new immunotherapy that may improve overall survival in participants with metastatic renal cell carcinoma. Interferon-a alone is unfavorable to targeted therapies with respect to overall survival and adverse events.
CANIT0002633	31430052	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	N/A	N/A	Meta-analysis	We included nine randomized controlled trials (RCTs), and we established seven different treatment comparisons according to the type of data. Two RCTs favored nivolumab as monotherapy or combined with ipilimumab on account of all primary outcomes. The efficacy data of all other comparisons were either indifferent or favored the control group.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Immunotherapy for metastatic renal cell carcinoma: A systematic review.	 J Evid Based Med	BACKGROUND: Various approaches have been developed for the treatment of metastatic renal cell carcinoma (MRCC). The objective was to assess the efficacy of immunotherapeutic approaches.METHODS: We included participants diagnosed with all types of histologically confirmed MRCC, the test intervention was immunotherapy alone or combined with other immunotherapy or targeted therapies, and the study design was restricted to randomized controlled trials (RCTs). Primary outcomes were overall survival, adverse events, and health-related quality of life. We conducted the last search in March 31, 2018.RESULTS: We included nine RCTs, and we established seven different treatment comparisons according to the type of data. Two RCTs favored nivolumab as monotherapy or combined with ipilimumab on account of all primary outcomes. The efficacy data of all other comparisons were either indifferent or favored the control group.CONCLUSION: The immune checkpoint inhibitors nivolumab as monotherapy or combined with ipilimumab appears to be the only new immunotherapy that may improve overall survival in participants with metastatic renal cell carcinoma. Interferon-a alone is unfavorable to targeted therapies with respect to overall survival and adverse events.
CANIT0002634	31434650	Case report	Metastatic melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A 62-year-old woman with metastatic melanoma treated with nivolumab was referred for major hyperglycemia, hypertriglyceridemia, and nonalcoholic steatohepatitis. She had presented with a rapidly progressive generalized loss of subcutaneous adipose tissue. Diabetes was associated with severe insulin resistance and undetectable plasma leptin. Subcutaneous biopsy revealed atrophic adipose tissue infiltrated with cytotoxic CD8+ T lymphocytes and fibrosis.	Acquired generalized lipodystrophy	N/A	N/A	N/A	N/A	N/A	 2019 Oct	Acquired Generalized Lipodystrophy: A New Cause of Anti-PD-1 Immune-Related Diabetes.	 Diabetes Care	OBJECTIVE: Anti-programmed cell death-1 (anti-PD-1) antibodies have revolutionized advanced cancer therapy. Anti-PD-1 therapy is responsible for immune-related adverse events, with frequent endocrine manifestations, including acute-onset type 1 diabetes. Acquired generalized lipodystrophy (AGL) is a rare disease, believed to be immune mediated, characterized by loss of adipose tissue and insulin resistance-associated complications.RESEARCH DESIGN AND METHODS: We describe the first reported case of AGL induced by immune checkpoint therapy.RESULTS: A 62-year-old woman with metastatic melanoma treated with nivolumab was referred for major hyperglycemia, hypertriglyceridemia, and nonalcoholic steatohepatitis. She had presented with a rapidly progressive generalized loss of subcutaneous adipose tissue. Diabetes was associated with severe insulin resistance and undetectable plasma leptin. Subcutaneous biopsy revealed atrophic adipose tissue infiltrated with cytotoxic CD8+ T lymphocytes and fibrosis.CONCLUSIONS: AGL is an additional immune-related adverse event of anti-PD-1 therapy that leads to severe insulin resistance-associated complications.
CANIT0002635	31435660	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	187	N/A	Retrospective analysis	Among patients with non-small-cell lung cancer (NSCLCs) and PD-L1 expression of >=50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of >=90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design. The ORR was 44.4% [95% confidence interval (CI) 37.1% to 51.8%], the mPFS was 6.5 months (95% CI 4.5-8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%-89% (N = 107), patients with an expression level of 90%-100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS [14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33-0.74), P < 0.01], and a significantly longer mOS [not reached versus 15.9 months, HR 0.39 (95% CI 0.21-0.70), P = 0.002].	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Oct 1	Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression.	 Ann Oncol	BACKGROUND: In non-small-cell lung cancers with programmed death-ligand 1 (PD-L1) expression on >=50% of tumor cells, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared with platinum-doublet chemotherapy. Whether higher PD-L1 levels within the expression range of 50%-100% predict for even greater benefit to pembrolizumab is currently unknown.PATIENTS AND METHODS: In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment of non-small-cell lung cancer (NSCLC) with a PD-L1 expression of >=50% and negative for genomic alterations in the EGFR and ALK genes .RESULTS: Among 187 patients included in this analysis, the ORR was 44.4% [95% confidence interval (CI) 37.1% to 51.8%], the mPFS was 6.5 months (95% CI 4.5-8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%-89% (N = 107), patients with an expression level of 90%-100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS [14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33-0.74), P < 0.01], and a significantly longer mOS [not reached versus 15.9 months, HR 0.39 (95% CI 0.21-0.70), P = 0.002].CONCLUSION: Among patients with NSCLC and PD-L1 expression of >=50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of >=90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.
CANIT0002636	31436330	Case report	An 80-year-old woman with no history of diabetes	Mucosal melanoma	MONDO:0000544	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	This is a unique case of delayed acute-onset T1DM without ketoacidosis that occurred after a long duration of nivolumab administration in a patient with mucosal melanoma. T1DM should be considered even in patients undergoing longterm anti-PD-1 immunotherapy.	Type 1 diabetes mellitus (T1DM)	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Case of acute-onset type 1 diabetes induced by long-term immunotherapy with nivolumab in a patient with mucosal melanoma.	 J Dermatol	Unable to provide
CANIT0002637	31439050	Case report	Colon cancer	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); PD-1 (Q15116); TNFA (P01375); 	CTLA-4 ;  PD-1 ;  TNFA 	Ipilimumab plus Nivolumab plus TNFA blockade	N/A	Immune checkpoint therapy plus Immune cytokine	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Case	Concurrent treatment with anti-TNFA and ICI appears to be safe, facilitates steroid tapering, and prevents Immune related enterocolitis (irEC). Prospective clinical trials are needed to assess the outcomes of this treatment modality.	All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.	N/A	N/A	N/A	N/A	N/A	 2019 Aug 22	Concurrent therapy with immune checkpoint inhibitors and TNFa blockade in patients with gastrointestinal immune-related adverse events.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFa) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFa and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFa and one or two ICIs.CASE PRESENTATIONS: Five patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.CONCLUSIONS: Concurrent treatment with anti-TNFa and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.
CANIT0002638	31439050	Case report	Cutaneous squamous cell carcinoma	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); TNFA (P01375); 	PD-1; TNFA	Cemiplimab plus TNFA blockade	N/A	Immune checkpoint therapy plus Immune cytokine	Cemiplimab (DB14707); 	1	N/A	Case	Concurrent treatment with anti-TNFA and ICI appears to be safe, facilitates steroid tapering, and prevents Immune related enterocolitis (irEC). Prospective clinical trials are needed to assess the outcomes of this treatment modality.	All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.	N/A	N/A	N/A	N/A	N/A	 2019 Aug 22	Concurrent therapy with immune checkpoint inhibitors and TNFa blockade in patients with gastrointestinal immune-related adverse events.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFa) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFa and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFa and one or two ICIs.CASE PRESENTATIONS: Five patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.CONCLUSIONS: Concurrent treatment with anti-TNFa and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.
CANIT0002639	31439050	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); TNFA (P01375); 	CTLA-4 ;  PD-1 ;  TNFA 	Ipilimumab plus Nivolumab plus TNFA blockade	N/A	Immune checkpoint therapy plus Immune cytokine	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Case	Concurrent treatment with anti-TNFA and ICI appears to be safe, facilitates steroid tapering, and prevents Immune related enterocolitis (irEC). Prospective clinical trials are needed to assess the outcomes of this treatment modality.	All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.	N/A	N/A	N/A	N/A	N/A	 2019 Aug 22	Concurrent therapy with immune checkpoint inhibitors and TNFa blockade in patients with gastrointestinal immune-related adverse events.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFa) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFa and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFa and one or two ICIs.CASE PRESENTATIONS: Five patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.CONCLUSIONS: Concurrent treatment with anti-TNFa and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.
CANIT0002640	31439050	Case report	Melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); TNFA (P01375); 	CTLA-4; TNFA	Ipilimumab plus TNFA blockade	N/A	Immune checkpoint therapy plus Immune cytokine	Ipilimumab (DB06186); 	1	N/A	Case	Concurrent treatment with anti-TNFA and ICI appears to be safe, facilitates steroid tapering, and prevents Immune related enterocolitis (irEC). Prospective clinical trials are needed to assess the outcomes of this treatment modality.	All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.	N/A	N/A	N/A	N/A	N/A	 2019 Aug 22	Concurrent therapy with immune checkpoint inhibitors and TNFa blockade in patients with gastrointestinal immune-related adverse events.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFa) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFa and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFa and one or two ICIs.CASE PRESENTATIONS: Five patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.CONCLUSIONS: Concurrent treatment with anti-TNFa and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.
CANIT0002641	31439050	Case report	Meningioma	Meningioma	Orphanet:2495	Brain	PD-1 (Q15116); TNFA (P01375); 	PD-1; TNFA	Pembrolizumab plus TNFA blockade	N/A	Immune checkpoint therapy plus Immune cytokine	Pembrolizumab (DB09037); 	1	N/A	Case	Concurrent treatment with anti-TNFA and ICI appears to be safe, facilitates steroid tapering, and prevents Immune related enterocolitis (irEC). Prospective clinical trials are needed to assess the outcomes of this treatment modality.	All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.	N/A	N/A	N/A	N/A	N/A	 2019 Aug 22	Concurrent therapy with immune checkpoint inhibitors and TNFa blockade in patients with gastrointestinal immune-related adverse events.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFa) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFa and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFa and one or two ICIs.CASE PRESENTATIONS: Five patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.CONCLUSIONS: Concurrent treatment with anti-TNFa and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.
CANIT0002642	31439251	Clinical research	One hundred and four patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	104	N/A	Multicentre retrospective study	The present study showed that the outcome of NSCLC treated with immunotherapy can be assessed by baseline CTHA for prognostication of OS and PFS	Toxicity	N/A	N/A	N/A	N/A	N/A	 2019 Sep	Prognostic and predictive value of histogram analysis in patients with non-small cell lung cancer refractory to platinum treated by nivolumab: A multicentre retrospective study.	 Eur J Radiol	PURPOSE: The aim of this study was to assess computed-tomography histogram analysis (CTHA) as prognostic and predictive factor in platinum-refractory non-small cell lung carcinoma (NSCLC) treated with immune checkpoint inhibitor Nivolumab.METHOD: One hundred and four patients were enrolled from 3 different centers. CT was performed using similar parameters among different scanners. CTHA was performed with the proprietary software TexRAD, which extracts histogram features at different spatial scale (spatial scale filters, SSF) producing 30 CTHA features per patients. Cross-validated Least Absolute Shrinkage and Selection Operator LASSO was used to select those features which were related to overall and progression-free survival (OS and PFS, respectively). High- and low-risk subgroups were identified using the best cutoff.RESULTS: Median follow-up was 13.8 weeks. Median OS and PFS were 7.3 and 3 months, respectively. LASSO selected kurtosis obtained by SSF = 4 mm as the single feature related to OS, leading to an hazard ratio (HR) of 0.476 (95%CI 0.29-0.77). PFS was related with kurtosis SSF = 6 mm, with HR of 0.556 (95%CI 0.36-0.86).CONCLUSION: Despite its limitations, this study is the first which suggests that CTHA could play a role in stratifying prognosis and treatment response in patients with NSCLC treated with Nivolumab.
CANIT0002643	31439558	Case report	Advanced urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We describe two rare immune-related adverse events occurring in a 70-year-old caucasian man who was treated with nivolumab for an advanced urothelial cancer of the left kidney. He developed an isolated adrenocorticotropic hormone deficiency that was diagnosed at week 19 and a neurological complication that appeared at week 79 and initially confounded with a lumbar spinal stenosis. Diagnosis of Guillain-Barr¨¦ syndrome was finally confirmed with the complete resolution of symptoms after 5 days of intravenous immunoglobulin and corticosteroids.	Isolated adrenocorticotropic hormone (ACTH) deficiency and Guillain-Barr¨¦ syndrome	N/A	N/A	N/A	N/A	N/A	 2019 Aug 21	Isolated adrenocorticotropic hormone (ACTH) deficiency and Guillain-Barr¨¦ syndrome occurring in a patient treated with nivolumab.	 BMJ Case Rep	The increased use of immune checkpoint inhibitors (ICIs) has led to the observation of a variety of immune-related adverse events (irAEs). These irAEs occur usually within the first months after ICIs onset and can involve theorically all organs. We describe two rare irAEs occurring in a 70-year-old caucasian man who was treated with nivolumab for an advanced urothelial cancer of the left kidney. He developed an isolated adrenocorticotropic hormone deficiency that was diagnosed at week 19 and a neurological complication that appeared at week 79 and initially confounded with a lumbar spinal stenosis. Diagnosis of Guillain-Barr¨¦ syndrome was finally confirmed with the complete resolution of symptoms after 5 days of intravenous immunoglobulin and corticosteroids. We highlight the importance of quickly recognising these potential life-threatening irAEs such as cortisol insufficiency and neurologic adverse events whose initially presentation could be non-specific.
CANIT0002644	31440238	Clinical research	N/A	Pancreatic carcinoma	EFO:0002618	Pancreas	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	N/A	N/A	Phase Ib	We describe a clinical study where we use pancreatic cancer as a model, and we hypothesize that effective vaccination in pancreatic cancer patients, along with interventions that can reprogram important immunosuppressive factors in the tumor microenvironment, can enhance tumor immune recognition, thus enhancing response to PD-1/PD-L1 blockade.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Aug 8	A Phase Ib Study of the Combination of Personalized Autologous Dendritic Cell Vaccine, Aspirin, and Standard of Care Adjuvant Chemotherapy Followed by Nivolumab for Resected Pancreatic Adenocarcinoma-A Proof of Antigen Discovery Feasibility in Three Patients.	 Front Immunol	Despite the promising therapeutic effects of immune checkpoint blockade (ICB), most patients with solid tumors treated with anti-PD-1/PD-L1 monotherapy do not achieve objective responses, with most tumor regressions being partial rather than complete. It is hypothesized that the absence of pre-existing antitumor immunity and/or the presence of additional tumor immune suppressive factors at the tumor microenvironment are responsible for such therapeutic failures. It is therefore clear that in order to fully exploit the potential of PD-1 blockade therapy, antitumor immune response should be amplified, while tumor immune suppression should be further attenuated. Cancer vaccines may prime patients for treatments with ICB by inducing effective anti-tumor immunity, especially in patients lacking tumor-infiltrating T-cells. These non-inflamed non-permissive tumors that are resistant to ICB could be rendered sensitive and transformed into inflamed tumor by vaccination. In this article we describe a clinical study where we use pancreatic cancer as a model, and we hypothesize that effective vaccination in pancreatic cancer patients, along with interventions that can reprogram important immunosuppressive factors in the tumor microenvironment, can enhance tumor immune recognition, thus enhancing response to PD-1/PD-L1 blockade. We incorporate into the schedule of standard of care (SOC) chemotherapy adjuvant setting a vaccine platform comprised of autologous dendritic cells loaded with personalized neoantigen peptides (PEP-DC) identified through our own proteo-genomics antigen discovery pipeline. Furthermore, we add nivolumab, an antibody against PD-1, to boost and maintain the vaccine's effect. We also demonstrate the feasibility of identifying personalized neoantigens in three pancreatic ductal adenocarcinoma (PDAC) patients, and we describe their optimal incorporation into long peptides for manufacturing into vaccine products. We finally discuss the advantages as well as the scientific and logistic challenges of such an exploratory vaccine clinical trial, and we highlight its novelty.
CANIT0002645	31441319	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	56	N/A	N/A	Overall, 96% of respondents were 'very satisfied' and 4% 'satisfied' with the service. All respondents would recommend the service to others.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Sep	Putting patients first: an inventive service delivering cancer treatment at home.	 J Comp Eff Res	Aim: This study evaluated the patient experience of receiving subcutaneous chemotherapy at home via a unique 'Cancer Treatment at Home' outreach service adapted by the UK Clatterbridge Cancer Centre NHS Foundation Trust. Patients & methods: The service involved using highly trained nurses to deliver cancer treatments to patients in their own homes. Patient outcomes were monitored over 12 months via the Systemic Anti-Cancer Therapy at Home (SACT) survey using handheld electronic devices. Results: Of the 56 participating cancer patients, 53 provided responses. Patients received subcutaneous trastuzumab, denosumab, pembrolizumab, fulvestrant and goserelin. Overall, 96% of respondents were 'very satisfied' and 4% 'satisfied' with the service. All respondents would recommend the service to others. Conclusion: The 'Cancer Treatment at Home' service has improved the patient experience for cancer care and has been recognized nationally for its achievements.
CANIT0002646	31445231	Basic research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	IDO1 (P14902); 	IDO1; 	Phosphonamidate IDO1 inhibitors	N/A	Immune checkpoint therapy	N/A	Cell lines	N/A	Basic research	In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC50 = 10-21 nM, hIDO1 IC50 = 78-121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Nov 15	Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer.	 Eur J Med Chem	Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC50 = 10-21 nM, hIDO1 IC50 = 78-121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.
CANIT0002647	31449984	Clinical research	Advanced gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab plus apatinib	Paclitaxel plus ramucirumab	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); apatinib (DB14765); ramucirumab (DB05578); paclitaxel (DB01229); 	N/A	N/A	Meta-analysis	Paclitaxel plus ramucirumab is the optimal second-line regimen. Both apatinib and nivolumab could be potentially recommended as refractory regimens.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Systemic therapy for previously treated advanced gastric cancer: A systematic review and network meta-analysis.	 Crit Rev Oncol Hematol	Although paclitaxel plus ramucirumab has been recommended as the preferred second-line strategy, other regimens also display potentially comparable efficacies. Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO and ESMO meeting libraries. Randomized controlled trials featuring comparisons between different systemic treatments among previously treated patients with advanced gastric cancer were eligible for our systematic review. Network calculation were based on random-effects model and the relative ranking of each regimen was numerically indicated by P-score (CRD42018104672). Concerning second-line regimens, paclitaxel plus olaparib and paclitaxel plus ramucirumab dominated the overall survival ranking while paclitaxel plus ramucirumab additionally topped the hierarchy for progression-free survival. Among refractory or third-line only cases, apatinib reigned the hierarchy by significantly and insignificantly surpassing placebo and nivolumab respectively. In conclusion, paclitaxel plus ramucirumab is the optimal second-line regimen. Both apatinib and nivolumab could be potentially recommended as refractory regimens.
CANIT0002648	31455681	Clinical research	Ninety-six patients 	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); CCR4 (Q9ULM6); 	PD-1; CCR4	Nivolumab plus mogamulizumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); mogamulizumab (DB12498); 	3	N/A	Phase I 	This is the first clinical report to provide evidence for the mechanism of tumor immunity activation by Treg depletion in the tumor microenvironment. Combination therapy with mogamulizumab and nivolumab resulted in a clear depletion of effector Tregs and the expansion of CD8+ T cells in tumor-infiltrating lymphocytes. In addition, a manageable safety profile and several tumor responses were observed in patients with solid tumors. These results provide clinical evidence for the safety and potential efficacy of mogamulizumab and nivolumab combination therapy, as well as the potential role of biomarkers in mediating the antitumor effects.	Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD8 (P01732); T-Lymphocyte (NCIT:C12484); 	Populations of effector Tregs (CD4(+)CD45RA-FoxP3high) decreased and CD8(+) T-cell in tumor-infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 15	A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.	 Clin Cancer Res	PURPOSE: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-na ve patients with advanced/metastatic solid tumors.PATIENTS AND METHODS: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.RESULTS: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
CANIT0002649	31455681	Clinical research	Ninety-six patients 	Esophageal carcinoma	EFO:0002916	Stomach	PD-1 (Q15116); CCR4 (Q9ULM6); 	PD-1; CCR4	Nivolumab plus mogamulizumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); mogamulizumab (DB12498); 	15	N/A	Phase I 	This is the first clinical report to provide evidence for the mechanism of tumor immunity activation by Treg depletion in the tumor microenvironment. Combination therapy with mogamulizumab and nivolumab resulted in a clear depletion of effector Tregs and the expansion of CD8+ T cells in tumor-infiltrating lymphocytes. In addition, a manageable safety profile and several tumor responses were observed in patients with solid tumors. These results provide clinical evidence for the safety and potential efficacy of mogamulizumab and nivolumab combination therapy, as well as the potential role of biomarkers in mediating the antitumor effects.	Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD8 (P01732); T-Lymphocyte (NCIT:C12480); 	Populations of effector Tregs (CD4(+)CD45RA-FoxP3high) decreased and CD8(+) T-cell in tumor-infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 15	A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.	 Clin Cancer Res	PURPOSE: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-na ve patients with advanced/metastatic solid tumors.PATIENTS AND METHODS: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.RESULTS: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
CANIT0002650	31455681	Clinical research	Ninety-six patients 	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); CCR4 (Q9ULM6); 	PD-1; CCR4	Nivolumab plus mogamulizumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); mogamulizumab (DB12498); 	15	N/A	Phase I 	This is the first clinical report to provide evidence for the mechanism of tumor immunity activation by Treg depletion in the tumor microenvironment. Combination therapy with mogamulizumab and nivolumab resulted in a clear depletion of effector Tregs and the expansion of CD8+ T cells in tumor-infiltrating lymphocytes. In addition, a manageable safety profile and several tumor responses were observed in patients with solid tumors. These results provide clinical evidence for the safety and potential efficacy of mogamulizumab and nivolumab combination therapy, as well as the potential role of biomarkers in mediating the antitumor effects.	Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD8 (P01732); T-Lymphocyte (NCIT:C12479); 	Populations of effector Tregs (CD4(+)CD45RA-FoxP3high) decreased and CD8(+) T-cell in tumor-infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 15	A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.	 Clin Cancer Res	PURPOSE: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-na ve patients with advanced/metastatic solid tumors.PATIENTS AND METHODS: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.RESULTS: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
CANIT0002651	31455681	Clinical research	Ninety-six patients 	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); CCR4 (Q9ULM6); 	PD-1; CCR4	Nivolumab plus mogamulizumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); mogamulizumab (DB12498); 	15	N/A	Phase I 	This is the first clinical report to provide evidence for the mechanism of tumor immunity activation by Treg depletion in the tumor microenvironment. Combination therapy with mogamulizumab and nivolumab resulted in a clear depletion of effector Tregs and the expansion of CD8+ T cells in tumor-infiltrating lymphocytes. In addition, a manageable safety profile and several tumor responses were observed in patients with solid tumors. These results provide clinical evidence for the safety and potential efficacy of mogamulizumab and nivolumab combination therapy, as well as the potential role of biomarkers in mediating the antitumor effects.	Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD8 (P01732); T-Lymphocyte (NCIT:C12481); 	Populations of effector Tregs (CD4(+)CD45RA-FoxP3high) decreased and CD8(+) T-cell in tumor-infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 15	A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.	 Clin Cancer Res	PURPOSE: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-na ve patients with advanced/metastatic solid tumors.PATIENTS AND METHODS: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.RESULTS: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
CANIT0002652	31455681	Clinical research	Ninety-six patients 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); CCR4 (Q9ULM6); 	PD-1; CCR4	Nivolumab plus mogamulizumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); mogamulizumab (DB12498); 	15	N/A	Phase I 	This is the first clinical report to provide evidence for the mechanism of tumor immunity activation by Treg depletion in the tumor microenvironment. Combination therapy with mogamulizumab and nivolumab resulted in a clear depletion of effector Tregs and the expansion of CD8+ T cells in tumor-infiltrating lymphocytes. In addition, a manageable safety profile and several tumor responses were observed in patients with solid tumors. These results provide clinical evidence for the safety and potential efficacy of mogamulizumab and nivolumab combination therapy, as well as the potential role of biomarkers in mediating the antitumor effects.	Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Populations of effector Tregs (CD4(+)CD45RA-FoxP3high) decreased and CD8(+) T-cell in tumor-infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 15	A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.	 Clin Cancer Res	PURPOSE: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-na ve patients with advanced/metastatic solid tumors.PATIENTS AND METHODS: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.RESULTS: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
CANIT0002653	31455681	Clinical research	Ninety-six patients 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); CCR4 (Q9ULM6); 	PD-1; CCR4	Nivolumab plus mogamulizumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); mogamulizumab (DB12498); 	15	N/A	Phase I 	This is the first clinical report to provide evidence for the mechanism of tumor immunity activation by Treg depletion in the tumor microenvironment. Combination therapy with mogamulizumab and nivolumab resulted in a clear depletion of effector Tregs and the expansion of CD8+ T cells in tumor-infiltrating lymphocytes. In addition, a manageable safety profile and several tumor responses were observed in patients with solid tumors. These results provide clinical evidence for the safety and potential efficacy of mogamulizumab and nivolumab combination therapy, as well as the potential role of biomarkers in mediating the antitumor effects.	Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD8 (P01732); T-Lymphocyte (NCIT:C12477); 	Populations of effector Tregs (CD4(+)CD45RA-FoxP3high) decreased and CD8(+) T-cell in tumor-infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 15	A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.	 Clin Cancer Res	PURPOSE: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-na ve patients with advanced/metastatic solid tumors.PATIENTS AND METHODS: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.RESULTS: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
CANIT0002654	31455681	Clinical research	Ninety-six patients 	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); CCR4 (Q9ULM6); 	PD-1; CCR4	Nivolumab plus mogamulizumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); mogamulizumab (DB12498); 	3	N/A	Phase I 	This is the first clinical report to provide evidence for the mechanism of tumor immunity activation by Treg depletion in the tumor microenvironment. Combination therapy with mogamulizumab and nivolumab resulted in a clear depletion of effector Tregs and the expansion of CD8+ T cells in tumor-infiltrating lymphocytes. In addition, a manageable safety profile and several tumor responses were observed in patients with solid tumors. These results provide clinical evidence for the safety and potential efficacy of mogamulizumab and nivolumab combination therapy, as well as the potential role of biomarkers in mediating the antitumor effects.	Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD8 (P01732); T-Lymphocyte (NCIT:C12483); 	Populations of effector Tregs (CD4(+)CD45RA-FoxP3high) decreased and CD8(+) T-cell in tumor-infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 15	A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.	 Clin Cancer Res	PURPOSE: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-na ve patients with advanced/metastatic solid tumors.PATIENTS AND METHODS: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.RESULTS: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
CANIT0002655	31455681	Clinical research	Ninety-six patients 	Pancreatic adenocarcinoma	EFO:1000044	Pancreas	PD-1 (Q15116); CCR4 (Q9ULM6); 	PD-1; CCR4	Nivolumab plus mogamulizumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); mogamulizumab (DB12498); 	15	N/A	Phase I 	This is the first clinical report to provide evidence for the mechanism of tumor immunity activation by Treg depletion in the tumor microenvironment. Combination therapy with mogamulizumab and nivolumab resulted in a clear depletion of effector Tregs and the expansion of CD8+ T cells in tumor-infiltrating lymphocytes. In addition, a manageable safety profile and several tumor responses were observed in patients with solid tumors. These results provide clinical evidence for the safety and potential efficacy of mogamulizumab and nivolumab combination therapy, as well as the potential role of biomarkers in mediating the antitumor effects.	Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD8 (P01732); T-Lymphocyte (NCIT:C12482); 	Populations of effector Tregs (CD4(+)CD45RA-FoxP3high) decreased and CD8(+) T-cell in tumor-infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 15	A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.	 Clin Cancer Res	PURPOSE: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-na ve patients with advanced/metastatic solid tumors.PATIENTS AND METHODS: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.RESULTS: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
CANIT0002656	31455681	Clinical research	Ninety-six patients 	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); CCR4 (Q9ULM6); 	PD-1; CCR4	Nivolumab plus mogamulizumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); mogamulizumab (DB12498); 	15	N/A	Phase I 	This is the first clinical report to provide evidence for the mechanism of tumor immunity activation by Treg depletion in the tumor microenvironment. Combination therapy with mogamulizumab and nivolumab resulted in a clear depletion of effector Tregs and the expansion of CD8+ T cells in tumor-infiltrating lymphocytes. In addition, a manageable safety profile and several tumor responses were observed in patients with solid tumors. These results provide clinical evidence for the safety and potential efficacy of mogamulizumab and nivolumab combination therapy, as well as the potential role of biomarkers in mediating the antitumor effects.	Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%).	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Treg cells (CL:0000815); CD8 (P01732); T-Lymphocyte (NCIT:C12478); 	Populations of effector Tregs (CD4(+)CD45RA-FoxP3high) decreased and CD8(+) T-cell in tumor-infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 15	A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.	 Clin Cancer Res	PURPOSE: Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-na ve patients with advanced/metastatic solid tumors.PATIENTS AND METHODS: This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.RESULTS: Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4+CD45RA-FoxP3high) decreased and CD8+ T cells in tumor-infiltrating lymphocytes increased.CONCLUSIONS: Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
CANIT0002657	31460818	Clinical research	Recurrent or metastatic head and neck cancer	Head and neck carcinoma	MONDO:0002038	Head and neck	PD-1 (Q15116); 	PD-1; 	Platinum followed by Nivolumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Nivolumab (DB09035); Platinum (DB12257); 	100	N/A	Retrospective multicentre study	The 1-year survival rate was better in patients who developed immune-related adverse events (irAEs). This is a new finding for head and neck cancer. Appearance of irAEs could also be used as an indicator of expected therapeutic effect in head and neck cancer. Nivolumab was administered to 100 patients with a history of receiving platinum-based drugs. ORR was 13.5% and disease control rate was 49.0%. Median PFS was 3.7 months. Median OS was 9.6 months.	For all grades, irAEs occurred in 30 patients. The 1-year survival rate in the subgroup without irAEs was 34.0%, compared to 52.6% with irAEs (p = .041).	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2019 Oct	Efficacy and safety of nivolumab in 100 patients with recurrent or metastatic head and neck cancer - a retrospective multicentre study.	 Acta Otolaryngol	Background: No large-scale retrospective studies have examined the efficacy and safety of nivolumab. Objective: This retrospective study aimed to investigate the efficacy and safety of nivolumab administered to patients in multiple facilities. Material and methods: The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS) and overall survival (OS). For safety, adverse event occurrence rates by grade, deaths and severe adverse events were investigated. OS and PFS were also examined according to whether immune-related adverse events (irAEs) appeared. Statistical analysis was conducted using log-rank testing, with values of p < .05 considered significant. Results: Nivolumab was administered to 100 patients with a history of receiving platinum-based drugs. ORR was 13.5% and disease control rate was 49.0%. Median PFS was 3.7 months. Median OS was 9.6 months. For all grades, irAEs occurred in 30 patients. The 1-year survival rate in the subgroup without irAEs was 34.0%, compared to 52.6% with irAEs (p = .041). Conclusions and significance: The 1-year survival rate was better in patients who developed irAEs. This is a new finding for head and neck cancer. Appearance of irAEs could also be used as an indicator of expected therapeutic effect in head and neck cancer.
CANIT0002658	31461377	Clinical research	Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer	Endometrial cancer	MONDO:0011962	Uterus	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	33	N/A	Phase II study	Avelumab exhibited promising activity in mismatch repair deficient (MMRD) endometrial cancer regardless of PD-L1 status. IHC for mismatch repair assessment is a useful tool for patient selection. The activity of avelumab in mismatch repair-proficient (MMRP)/non-POLE-mutated endometrial cancers was low.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Mismatch-repair status (NCIT:C20639); 	DNA mismatch repair-deficient	Mutational status	 2019 Oct 20	Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer.	 J Clin Oncol	PURPOSE: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC).METHODS: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase ¦Å) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity.RESULTS: Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing.CONCLUSION: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-POLE-mutated ECs was low.
CANIT0002659	31461377	Clinical research	Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer	Endometrial cancer	MONDO:0011962	Uterus	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	33	N/A	Phase II study	Avelumab exhibited promising activity in mismatch repair deficient (MMRD) endometrial cancer regardless of PD-L1 status. IHC for mismatch repair assessment is a useful tool for patient selection. The activity of avelumab in mismatch repair-proficient (MMRP)/non-POLE-mutated endometrial cancers was low.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Oct 20	Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer.	 J Clin Oncol	PURPOSE: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC).METHODS: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase ¦Å) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity.RESULTS: Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing.CONCLUSION: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-POLE-mutated ECs was low.
CANIT0002660	31461377	Clinical research	Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer	Endometrial cancer	MONDO:0011962	Uterus	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	33	N/A	Phase II study	Avelumab exhibited promising activity in mismatch repair deficient (MMRD) endometrial cancer regardless of PD-L1 status. IHC for mismatch repair assessment is a useful tool for patient selection. The activity of avelumab in mismatch repair-proficient (MMRP)/non-POLE-mutated endometrial cancers was low.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	POLE (Q07864); 	POLE mutational status	Mutational status	 2019 Oct 20	Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer.	 J Clin Oncol	PURPOSE: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC).METHODS: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase ¦Å) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity.RESULTS: Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing.CONCLUSION: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-POLE-mutated ECs was low.
CANIT0002661	31462410	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	31	N/A	Retrospective analysis	Among patients with serial pulmonary function tests, lung function improved with time. Although symptoms of anti-PD-1-induced pneumonitis resolved quickly, scarring or inflammation frequently persisted on computerized tomography. Therefore, further study of subclinical pulmonary effects of anti-PD-1 is needed. Median time to radiographic findings was 4.8 months. Twenty-three patients (74%) presented with respiratory symptoms, whereas 8 (26%) were asymptomatic, and 11 (35%) were hospitalized. With 22.1 months median follow-up, 27 patients (87%) had resolution of symptoms, whereas 4 had persistent cough, dyspnea, and/or wheezing. By contrast, the rate of radiographic resolution was lower: Only 11 (35%) had complete radiographic resolution, whereas 14 (45%) had improvement of pneumonitis with persistent scarring or opacities, and 6 (19%) had persistent or worsened ground-glass opacities and/or nodular densities. Persistence (vs. resolution) of radiographic findings was associated with older age and initial need for steroids but not with need for hospitalization, timing of onset, or treatment regimen (combination vs. monotherapy). Among patients with serial pulmonary function tests, lung function improved with time. Although symptoms of anti-PD-1-induced pneumonitis resolved quickly, scarring or inflammation frequently persisted on computerized tomography. Therefore, further study of subclinical pulmonary effects of anti-PD-1 is needed.	Anti-PD-1-Induced Pneumonitis	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Anti-PD-1-Induced Pneumonitis Is Associated with Persistent Imaging Abnormalities in Melanoma Patients.	 Cancer Immunol Res	Pneumonitis may complicate anti-programmed death-1 (PD-1) therapy, although symptoms usually resolve with steroids. The long-term effects on respiratory function, however, are not well defined. We screened melanoma patients treated with anti-PD-1, with and without ipilimumab (anti-CTLA-4), and identified 31 patients with pneumonitis. Median time to radiographic findings was 4.8 months. Twenty-three patients (74%) presented with respiratory symptoms, whereas 8 (26%) were asymptomatic, and 11 (35%) were hospitalized. With 22.1 months median follow-up, 27 patients (87%) had resolution of symptoms, whereas 4 had persistent cough, dyspnea, and/or wheezing. By contrast, the rate of radiographic resolution was lower: Only 11 (35%) had complete radiographic resolution, whereas 14 (45%) had improvement of pneumonitis with persistent scarring or opacities, and 6 (19%) had persistent or worsened ground-glass opacities and/or nodular densities. Persistence (vs. resolution) of radiographic findings was associated with older age and initial need for steroids but not with need for hospitalization, timing of onset, or treatment regimen (combination vs. monotherapy). Among patients with serial pulmonary function tests, lung function improved with time. Although symptoms of anti-PD-1-induced pneumonitis resolved quickly, scarring or inflammation frequently persisted on computerized tomography. Therefore, further study of subclinical pulmonary effects of anti-PD-1 is needed.
CANIT0002662	31464522	Case report	Cervical carcinoma	Cervical carcinoma	EFO:0001416	Cervix	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Exceptional Response to Nivolumab in a 13-Year-Old Female with Metastatic HPV-Negative Cervical Carcinoma	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Oct	Exceptional Response to Nivolumab in a 13-Year-Old Female with Metastatic HPV-Negative Cervical Carcinoma.	 DNA Cell Biol	Cervical carcinoma is associated with high-risk human papillomavirus (HPV) DNA integration and usually occurs after age 21 (peak 45 years), as reflected in screening guidelines. Between 1999 and 2008, cervical carcinoma rate in adolescents aged 15-19 years was 0.15 per 100,000. HPV-negative cervical carcinoma is rare in adolescents. The youngest previously reported case was 15 years old. Treatment options for cervical carcinoma are limited after first-line therapy. Immune checkpoint inhibitors blocking programmed death receptor (PD-1) and its ligand, PD-L1, have shown objective clinical responses and are tolerable in adults with gynecologic cancers. This class of agents is well tolerated in pediatric patients. PD-1/PD-L1 is commonly expressed in gynecologic cancers but its expression may not predict clinical response. We describe an exceptional response to single agent nivolumab postradiation therapy in a 13-year-old adolescent with poorly differentiated cervical carcinoma and widespread metastatic disease.
CANIT0002663	31467059	Clinical research	Adult T-cell leukemia/lymphoma (ATLL)	Adult T-cell leukemia/lymphoma	MONDO:0019471	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	N/A	Analyses of clonality, somatic mutations, and gene expression in the malignant cells confirmed the report of rapid clonal expansion after PD-1 blockade in these patients, revealed a previously unappreciated origin of these malignant cells, identified a novel connection between ATLL cells and tumor-resident regulatory T cells (Tregs), and exposed a tumor-suppressive role for PD-1 in ATLL.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Oct 24	Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade.	 Blood	Immune checkpoint inhibitors are a powerful new tool in the treatment of cancer, with prolonged responses in multiple diseases, including hematologic malignancies, such as Hodgkin lymphoma. However, in a recent report, we demonstrated that the PD-1 inhibitor nivolumab led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL) (NCT02631746). We obtained primary cells from these patients to determine the cause of this hyperprogression. Analyses of clonality, somatic mutations, and gene expression in the malignant cells confirmed the report of rapid clonal expansion after PD-1 blockade in these patients, revealed a previously unappreciated origin of these malignant cells, identified a novel connection between ATLL cells and tumor-resident regulatory T cells (Tregs), and exposed a tumor-suppressive role for PD-1 in ATLL. Identifying the mechanisms driving this alarming outcome in nivolumab-treated ATLL may be broadly informative for the growing problem of rapid progression with immune checkpoint therapies.
CANIT0002664	31470128	Basic research	Small cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	PD-L1 (Q9NZQ7); CHK1 (O14757); 	PD-L1; CHK1	Durvalumab plus SRA737 plus gemcitabine	N/A	Immune checkpoint therapy plus Chemotherapy	Durvalumab (DB11714); 	Cell lines/ animal models	N/A	Basic research	Given that anti-PD-L1/anti-PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Dec	Combination Treatment of the Oral CHK1 Inhibitor, SRA737, and Low-Dose Gemcitabine Enhances the Effect of Programmed Death Ligand 1 Blockade by Modulating the Immune Microenvironment in SCLC.	 J Thorac Oncol	INTRODUCTION: Despite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC.METHODS AND RESULTS: Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti-programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti-PD-L1/anti-PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFN¦Â, and chemokines, CCL5 and CXCL10.CONCLUSIONS: Given that anti-PD-L1/anti-PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.
CANIT0002665	31474214	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	24	N/A	N/A	Although small, our study suggests that inactivated influenza vaccine may be safely administered to patients receiving immune checkpoint inhibitors. The majority of immune-mediated adverse events (imAEs) following inactivated influenza vaccination were Grades 1-2 and did not require changes in immune checkpoint inhibitor therapy.	Seven patients experienced any grade imAE (one patient having 2) within 60 days following inactivated influenza vaccination. The majority were Grades 1-2, including rash (n = 3), hypothyroidism, myalgia, and colitis (n = 1 each). Two patients experienced severe imAEs (grade 3 nephritis and grade 4 diabetes). No significant changes (p > 0.05) in serum cytokine or chemokine concentrations were observed.	N/A	N/A	N/A	N/A	N/A	 2020 Apr	Immune-mediated adverse events following influenza vaccine in cancer patients receiving immune checkpoint inhibitors.	 J Oncol Pharm Pract	OBJECTIVES: The emergence of immune checkpoint inhibitors has transformed treatment paradigms for various malignancies. Patients with cancer are at increased risk of complications and hospitalizations from influenza; therefore, it is recommended that they receive inactivated influenza vaccination. However, efficacy and safety of inactivated influenza vaccination in patients receiving immune checkpoint inhibitors is uncertain. The objective of this prospective case series was to evaluate the incidence of immune-mediated adverse events (imAEs) following inactivated influenza vaccination in patients receiving immune checkpoint inhibitors. Changes in cytokine and chemokine levels were also evaluated.METHODS: Patients receiving immune checkpoint inhibitors during the 2017-2018 influenza season were eligible for study participation. Peripheral blood samples were collected prior to administration of inactivated influenza vaccine and two post-vaccination time points. Evaluation of new or worsening imAEs occurred via patient questionnaire and review of medical records for 60 days following inactivated influenza vaccination. Baseline imAEs were evaluated from review of medical records for 60 days prior to inactivated influenza vaccination. Serum cytokines and chemokines were measured using a multiplex Luminex assay.RESULTS: Twenty-four patients were enrolled in this study. Seven patients experienced any grade imAE (one patient having 2) within 60 days following inactivated influenza vaccination. The majority were Grades 1-2, including rash (n = 3), hypothyroidism, myalgia, and colitis (n = 1 each). Two patients experienced severe imAEs (grade 3 nephritis and grade 4 diabetes). No significant changes (p > 0.05) in serum cytokine or chemokine concentrations were observed.CONCLUSIONS: Although small, our study suggests that inactivated influenza vaccine may be safely administered to patients receiving immune checkpoint inhibitors. The majority of imAEs following inactivated influenza vaccination were Grades 1-2 and did not require changes in immune checkpoint inhibitor therapy.
CANIT0002666	31474998	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	It reports the case of a female Caucasian patient who developed bullous pemphigoid (BP) during treatment with the programmed cell death protein 1 (PD-1) inhibitor nivolumab. Intriguingly, the patient exclusively generated anti-LAD-1 IgG, suggesting that anti-LAD-1 IgG was responsible for the development of her autoimmune blistering dermatosis.	Anti-LAD-1 IgG	N/A	N/A	N/A	N/A	N/A	 2019 Aug 14	Checkpoint Inhibition May Trigger the Rare Variant of Anti-LAD-1 IgG-Positive, Anti-BP180 NC16A IgG-Negative Bullous Pemphigoid.	 Front Immunol	Bullous pemphigoid (BP) is an autoimmune blistering skin disease characterized by an autoimmune response to type XVII collagen (BP180). The generation of anti-BP180-NC16A IgG autoantibodies is considered to be central to the pathogenesis of BP, in part due to the close correlation between serum concentration and disease activity. However, ~60% of BP patients also generate IgG autoantibodies against LAD-1, the soluble 120 kDa ectodomain of BP180. Whilst the pathogenic significance of anti-LAD-1 IgG remains unclear, it may be sufficient to precipitate the development of BP, even in the absence of anti-BP180-NC16A IgG, based on several case reports in Japanese patients. There is increasing recognition that immune-checkpoint inhibitors may trigger and/or exacerbate BP as an immune-related adverse event (irAE). Until now, all of these cases have been associated with the induction of anti-BP180-NC16A IgG. Here, we report the case of a female Caucasian patient who developed BP during treatment with the programmed cell death protein 1 (PD-1) inhibitor nivolumab. Intriguingly, the patient exclusively generated anti-LAD-1 IgG, suggesting that anti-LAD-1 IgG was responsible for the development of her autoimmune blistering dermatosis. This is the first such case documented in a non-Japanese patient, thus, lending further support to the pathogenic relevance of anti-LAD-1 IgG in BP.
CANIT0002667	31476529	Clinical research	N/A	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	N/A	N/A	N/A	Incremental cost-effectiveness ratio (ICER) yield by pembrolizumab monotherapy among different  tumor proportion scores (TPS) populations were beyond the threshold we set, three times of the Gross Domestic Product per Capita of China in 2018 ($26,508/QALY). It is not a cost effective choice compared with standard chemotherapy for patients with locally advanced or metastatic NSCLC from the perspective of Chinese payer, regardless of TPS. 	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Oct	Cost-effectiveness analysis of pembrolizumab monotherapy and chemotherapy in the non-small-cell lung cancer with different PD-L1 tumor proportion scores.	 Lung Cancer	OBJECTIVES: This study aimed to assess the cost-effectiveness of pembrolizumab monotherapy compared with chemotherapy as first-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with different tumor proportion scores (TPS), from perspectives of payers in China.MATERIALS AND METHODS: Basic information was derived from the KEYNOTE-042 trial. A Markov model was developed to simulate the process of NSCLC. Model inputs were based on published clinical trials and previous literatures. Costs were calculated from perspectives of payers in China. Sensitivity analyses were conducted to explore the impact of uncertainty.RESULTS: Treatment with pembrolizumab monotherapy for patients with high TPS (>=50%) was estimated to increase costs by $65,322 compared with chemotherapy, with a gain of 1.79 quality adjusted life years (QALYs) for an incremental cost-effectiveness ratio (ICER) of $36,493 per QALY. For patient population with TPS >= 20%, the ICER was $42,311 per QALY, while the corresponding ICER was $39,404 per QALY for patients with TPS >= 1%. Sensitive analyses for three different TPS populations were similar, which indicated the cost of PFS state in pembrolizumab arm and the price of pembrolizumab were the most influential factors in our study.CONCLUSION: ICERs yield by pembrolizumab monotherapy among different TPS populations were beyond the threshold we set, three times of the Gross Domestic Product per Capita of China in 2018 ($26,508/QALY). It is not a cost effective choice compared with standard chemotherapy for patients with locally advanced or metastatic NSCLC from the perspective of Chinese payer, regardless of TPS. Deeper discount of its current price would make pembrolizumab a preferable choice.
CANIT0002668	31479702	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Prospective phase 2 trial	Local therapy continues to play an important role in the management of melanoma patients with brain metastases being treated with immunotherapy. These patients should be closely monitored via serial brain imaging, with a multidisciplinary team involved in clinical decision making to ensure each patient's neurologic safety. In total, 13 out of 23 patients (57%) received local therapy immediately before or during the trial-4 patients received local therapy before the trial owing to lesion size or location in sensitive areas; 6 during the trial because of tumor growth, hemorrhage, or radiation necrosis/cystic changes; and 3 both before and during the trial. Of the 10 patients who did not receive local therapy immediately before or during the trial, 8 patients (35%) did not later receive local therapy owing to rapid disease progression, and only 2 patients (9%) lived for 2 years without requiring any local therapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec 1	Frequent Use of Local Therapy Underscores Need for Multidisciplinary Care in the Management of Patients With Melanoma Brain Metastases Treated With PD-1 Inhibitors.	 Int J Radiat Oncol Biol Phys	PURPOSE: An increasing number of clinical trials are studying immunotherapy for the treatment of brain metastases. The role of local therapy in this setting has not been well described.METHODS AND MATERIALS: Twenty-three melanoma patients with brain metastases were treated with pembrolizumab in a prospective phase 2 trial, NCT02085070, and included in this secondary analysis. Patients had at least 1 untreated or progressive brain metastasis, 5 to 20 mm in size, without any associated neurologic symptoms. Local therapy (stereotactic radiosurgery, surgery, or laser interstitial thermal therapy) was used to treat concerning lesions immediately before trial enrollment and was also allowed on trial in patients whose brain metastases were progressing, but who were otherwise deriving benefit.RESULTS: In total, 13 out of 23 patients (57%) received local therapy immediately before or during the trial-4 patients received local therapy before the trial owing to lesion size or location in sensitive areas; 6 during the trial because of tumor growth, hemorrhage, or radiation necrosis/cystic changes; and 3 both before and during the trial. Of the 10 patients who did not receive local therapy immediately before or during the trial, 8 patients (35%) did not later receive local therapy owing to rapid disease progression, and only 2 patients (9%) lived for 2 years without requiring any local therapy.CONCLUSIONS: Local therapy continues to play an important role in the management of melanoma patients with brain metastases being treated with immunotherapy. These patients should be closely monitored via serial brain imaging, with a multidisciplinary team involved in clinical decision making to ensure each patient's neurologic safety.
CANIT0002669	31482678	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Avelumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); pembrolizumab (DB09037); nivolumab (DB09035); 	71	N/A	Retrospective analysis	Severe grade checkpoint inhibitor pneumonitis (CIP) is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether immune checkpoint inhibitors (ICIs) should be administered to patients with CIP risk factors, such as an ECOG PS score of ?Y2 or pre-existing interstitial lung disease (ILD), should be carefully assessed. All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP-related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of >=2 and pre-existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5-2.0 vs. 3.5 months, 95% CI 2.0-5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5-13 vs. 12.7 months, 95% CI 8.0-21.0 months, P = 0.011).	Checkpoint inhibitor pneumonitis	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Severe grade checkpoint inhibitor pneumonitis	Adverse events	 2019 Oct	High mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: The treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non-small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP.METHODS: In this retrospective cohort study, CIP severity, CIP-related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients' medical charts.RESULTS: All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP-related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of >=2 and pre-existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5-2.0 vs. 3.5 months, 95% CI 2.0-5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5-13 vs. 12.7 months, 95% CI 8.0-21.0 months, P = 0.011).CONCLUSION: CIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of >=2 or pre-existing ILD, should be carefully assessed.
CANIT0002670	31482678	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Avelumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); pembrolizumab (DB09037); nivolumab (DB09035); 	71	N/A	Retrospective analysis	Severe grade checkpoint inhibitor pneumonitis (CIP) is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether immune checkpoint inhibitors (ICIs) should be administered to patients with CIP risk factors, such as an ECOG PS score of ?Y2 or pre-existing interstitial lung disease (ILD), should be carefully assessed. All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP-related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of >=2 and pre-existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5-2.0 vs. 3.5 months, 95% CI 2.0-5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5-13 vs. 12.7 months, 95% CI 8.0-21.0 months, P = 0.011).	Checkpoint inhibitor pneumonitis	N/A	N/A	Interstitial lung disease (NCIT:C27006); 	Pre-existing interstitial lung disease	Disease status	 2019 Oct	High mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: The treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non-small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP.METHODS: In this retrospective cohort study, CIP severity, CIP-related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients' medical charts.RESULTS: All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP-related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of >=2 and pre-existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5-2.0 vs. 3.5 months, 95% CI 2.0-5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5-13 vs. 12.7 months, 95% CI 8.0-21.0 months, P = 0.011).CONCLUSION: CIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of >=2 or pre-existing ILD, should be carefully assessed.
CANIT0002671	31482678	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Avelumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); pembrolizumab (DB09037); nivolumab (DB09035); 	71	N/A	Retrospective analysis	Severe grade checkpoint inhibitor pneumonitis (CIP) is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether immune checkpoint inhibitors (ICIs) should be administered to patients with CIP risk factors, such as an ECOG PS score of ?Y2 or pre-existing interstitial lung disease (ILD), should be carefully assessed. All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP-related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of >=2 and pre-existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5-2.0 vs. 3.5 months, 95% CI 2.0-5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5-13 vs. 12.7 months, 95% CI 8.0-21.0 months, P = 0.011).	Checkpoint inhibitor pneumonitis	N/A	N/A	Performance status (NCIT:C20641); 	Performance Status	Disease status	 2019 Oct	High mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non-small cell lung cancer.	 Thorac Cancer	BACKGROUND: The treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non-small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP.METHODS: In this retrospective cohort study, CIP severity, CIP-related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients' medical charts.RESULTS: All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP-related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of >=2 and pre-existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5-2.0 vs. 3.5 months, 95% CI 2.0-5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5-13 vs. 12.7 months, 95% CI 8.0-21.0 months, P = 0.011).CONCLUSION: CIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of >=2 or pre-existing ILD, should be carefully assessed.
CANIT0002672	31488241	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	1	N/A	Case	This case alarmed us once more to the importance of irAE management under cancer immunotherapy	Pneumonitis, thrombocytopenia, and cardiac dysfunction	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Fatal outcome of atezolizumab in a patient with immune-mediated pneumonitis, thrombocytopenia, and cardiac dysfunction: A case report .	 Int J Clin Pharmacol Ther	The anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab is a promising agent for various cancers. Although immune-related adverse events (irAEs) induced by atezolizumab are rare, they can be severe. Clinical experience in irAE management is presently insufficient. Herein, we present a case of a patient with non-small cell lung cancer (NSCLC) who developed life-threatening irAEs including pneumonitis, thrombocytopenia, and cardiac dysfunction under immunotherapy with atezolizumab. Under expectant treatment and corticosteroid regimen, pneumonitis was totally resolved. However, thrombocytopenia and cardiac dysfunction did not improve. The patient sadly passed away 28 days after a single dose of atezolizumab. This case alarmed us once more to the importance of irAE management under cancer immunotherapy. .
CANIT0002673	31494530	Clinical research	Small-cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); paclitaxel (DB01229); 	26	N/A	Multi-center, phase II study	Pembrolizumab and paclitaxel combination therapy showed a moderate activity with acceptable toxicity in patients with refractory extensive disease (ED) small-cell lung cancer (SCLC). Of the 26 patients enrolled, the confirmed ORR was 23.1% (95%CI: 6.9%-39.3%); complete response: 3.9%, confirmed partial response [PR]: 19.2%, stable disease: 57.7%, progressive disease: 7.7%, and not evaluable: 11.5%. Including 4 cases of unconfirmed PRs, 38.5% of patients were responding and the disease control rate was 80.7%. The median PFS and OS were 5.0 months (95% CI: 2.7-6.7) and 9.1 months (95% CI: 6.5-15.0), respectively. Targeted gene sequencing identified no specific genetic alterations correlated with the treatment, except for the MET copy number gain (PFS 10.5 versus 3.4 months, p = 0.019).	The grade 3 or 4 adverse events observed included febrile neutropenia (7.7%), neutropenia (7.7%), asthenia (7.7%), hyponatremia (7.7%), and type I diabetes (7.7%).	N/A	N/A	MET (P08581); 	MET copy number gain	Mutational status	 2019 Oct	A phase II study of pembrolizumab and paclitaxel in patients with relapsed or refractory small-cell lung cancer.	 Lung Cancer	OBJECTIVE: Patients with etoposide/platinum-refractory extensive disease (ED) small-cell lung cancer (SCLC) have a dismal prognosis. We aimed to evaluate the efficacy and safety of pembrolizumab and paclitaxel combination therapy in these patients.METHODS: In this multi-center, phase II study, ED-SCLC patients who showed progression after etoposide/platinum chemotherapy received paclitaxel 175 mg/m2 every 3 weeks for up to six cycles. Pembrolizumab 200 mg was added from the second cycle and continued until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and biomarker analyses including programmed death-ligand 1 (PD-L1) expression, next-generation sequencing, and flow cytometric analysis of peripheral blood cells.RESULTS: Of the 26 patients enrolled, the confirmed ORR was 23.1% (95%CI: 6.9%-39.3%); complete response: 3.9%, confirmed partial response [PR]: 19.2%, stable disease: 57.7%, progressive disease: 7.7%, and not evaluable: 11.5%. Including 4 cases of unconfirmed PRs, 38.5% of patients were responding and the disease control rate was 80.7%. The median PFS and OS were 5.0 months (95% CI: 2.7-6.7) and 9.1 months (95% CI: 6.5-15.0), respectively. The grade 3 or 4 adverse events observed included febrile neutropenia (7.7%), neutropenia (7.7%), asthenia (7.7%), hyponatremia (7.7%), and type I diabetes (7.7%). Targeted gene sequencing identified no specific genetic alterations correlated with the treatment, except for theMET copy number gain (PFS 10.5 versus 3.4 months, p = 0.019).CONCLUSIONS: Pembrolizumab and paclitaxel combination therapy showed a moderate activity with acceptable toxicity in patients with refractory ED-SCLC.
CANIT0002674	31497994	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Chemotherapy	Immune checkpoint therapy	Nivolumab (DB09035); 	9656	N/A	Retrospective analysis	Platinum-based therapy was the most common first-line therapy, and immunotherapy was the most common second- and third-line therapy. Median OS of patients with metastatic NSCLC was <1 year. Carboplatin plus paclitaxel was the most common first-line therapy (18.6%), and nivolumab was the most common second- (31.0%) and third-line (38.4%) therapy; 26.7% of all patients were untreated. Median OS from initial metastatic diagnosis was 11.1 months (95% CI: 10.8-11.5). Second-line immunotherapy extended OS by over 3 months versus second-line chemotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Oct	Treatment patterns and overall survival in metastatic non-small-cell lung cancer in a real-world, US setting.	 Future Oncol	Aim: To conduct a retrospective analysis of electronic medical record data to understand real-world treatment patterns and overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC). Materials & methods: We included n = 9656 adults (>=18 years) with metastatic NSCLC and no prior therapy. Data from 1 January 2013 to 31 January 2017 were analyzed. Results: Carboplatin plus paclitaxel was the most common first-line therapy (18.6%), and nivolumab was the most common second- (31.0%) and third-line (38.4%) therapy; 26.7% of all patients were untreated. Median OS from initial metastatic diagnosis was 11.1 months (95% CI: 10.8-11.5). Second-line immunotherapy extended OS by over 3 months versus second-line chemotherapy. Conclusion: Platinum-based therapy was the most common first-line therapy, and immunotherapy was the most common second- and third-line therapy. Median OS of patients with metastatic NSCLC was <1 year.
CANIT0002675	31501401	Case report	Left renal cell carcinoma and lymphadenopathy	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Cytological examination of the pericardial effusion demonstrated leukocytes and no malignant cells. computed tomographic (CT) scan two weeks after cardiocentesis showed no recurrent pericardial effusion. She became stable with nivolumab, but the administration of nivolumab was discontinued and she started receiving axitinib.	After receiving 5 cycles of nivolumab, she was admitted to our emergency room for chest discomfort and appetite loss	N/A	N/A	N/A	N/A	N/A	 2019 Aug	[A Case of Pericardial Effusion Induced by Nivolumab for Metastatic Renal Cell Carcinoma].	 Hinyokika Kiyo	A 72-year-old female with left renal cell carcinoma and lymphadenopathy had undergone hand-assisted laparoscopic left nephrectomy and dissection of the lymph node (papillary renal cell carcinoma, type 2, pT3a pN2 M1). She had been treated with adjuvant chemotherapy with sunitinib, temsirolimus and pazopanib. However, the patient was started on nivolumab due to disease progression. After receiving 5 cycles of nivolumab, she was admitted to our emergency room for chest discomfort and appetite loss. Since computed tomographic (CT) scan showed pericardial effusion, we performed pericardiocentesis. Cytological examination of the pericardial effusion demonstrated leukocytes and no malignant cells. CT scan two weeks after cardiocentesis showed no recurrent pericardial effusion. She became stable with nivolumab, but the administration of nivolumab was discontinued and she started receiving axitinib.
CANIT0002676	31511088	Basic research	Primary human immune cell	Cancer	EFO:0000311	Other	TLR7 (Q9NYK1); TLR8 (Q9NR97)	TLR7; TLR8	MEDI9197 (3M-052)	N/A	Immune checkpoint therapy	N/A	Cell lines/ animal models	N/A	Basic research	Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Sep 11	Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies.	 J Immunother Cancer	BACKGROUND: Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically cold tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated.METHODS: The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models.RESULTS: Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNa, IL-12 and IFN¦Ã. In contrast, a STING or a TLR9 agonist primarily induces release of IFNa. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8+ T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models.CONCLUSION: Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.
CANIT0002677	31511565	Basic research	Cancer	Cancer	EFO:0000311	Other	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	Cell lines	N/A	Basic research	Altogether, these results shed light on the role of PD-L1 in cancer cells and suggest that PD-L1_1 and its high affinity variants could become powerful antitumor weapons to be used alone or in combination with other drugs such as the anti-ErbB2 cAb already successfully tested in in vitro combinatorial treatments.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Sep 11	Novel Human Anti-PD-L1 mAbs Inhibit Immune-Independent Tumor Cell Growth and PD-L1 Associated Intracellular Signalling.	 Sci Rep	The novel antibody-based immunotherapy in oncology exploits the activation of immune system mediated by immunomodulatory antibodies specific for immune checkpoints. Among them, the programmed death ligand-1 (PD-L1) is of particular interest as it is expressed not only on T-cells, but also on other immune cells and on a large variety of cancer cells, such as breast cancer cells, considering its high expression in both ErbB2-positive and Triple Negative Breast Cancers. We demonstrate here that PD-L1_1, a novel anti-PD-L1 T -cell stimulating antibody, inhibits PD-L1-tumor cell growth also by affecting the intracellular MAPK pathway and by activating caspase 3. Similar in vitro results were obtained for the first time here also with the clinically validated anti-PD-L1 mAb Atezolizumab and in vivo with another validated anti-mouse anti-PD-L1 mAb. Moreover, we found that two high affinity variants of PD-L1_1 inhibited tumor cell viability more efficiently than the parental PD-L1_1 by affecting the same MAPK pathways with a more potent effect. Altogether, these results shed light on the role of PD-L1 in cancer cells and suggest that PD-L1_1 and its high affinity variants could become powerful antitumor weapons to be used alone or in combination with other drugs such as the anti-ErbB2 cAb already successfully tested in in vitro combinatorial treatments.
CANIT0002678	31512006	Clinical research	Sixty-five mRCC patients treated with nivolumab were enrolled	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	65	N/A	Retrospective analysis	Both the neutrophil-to-lymphocyte ratios and serum c-reactive protein levels were significantly associated with the clinical outcome of nivolumab in metastatic renal cell carcinoma patients. The potential prognostic impact of those markers needs to be further prospectively investigated.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2020 Jan	C-reactive protein and the neutrophil-to-lymphocyte ratio are prognostic biomarkers in metastatic renal cell carcinoma patients treated with nivolumab.	 Int J Clin Oncol	BACKGROUND: Association between systemic inflammation and clinical outcome of immune checkpoint inhibitors (ICIs) has received focus. Our objective was to evaluate the utility of the neutrophil-to-lymphocyte ratio (NLR) in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab as well as the prognostic impact of the C-reactive protein (CRP) level.MATERIALS AND METHODS: Sixty-five mRCC patients treated with nivolumab were enrolled. We retrospectively investigated several factors, including the NLR and the CRP level, for their association with progression-free survival (PFS) and overall survival (OS). In addition, we evaluated their impact on the objective response.RESULTS: The CRP level was confirmed to be positively correlated with the NLR in a correlation analysis. An NLR >= 5 was significantly associated with a worse PFS (hazard ratio [HR]: 4.54, 95% confidence interval [CI] 1.93-10.7; p < 0.001), and an NLR >= 5 and a CRP >= 2.1 mg/dL were identified as a significant factors predicting worse OS with HRs of 4.88 (95% CI 1.35-17.7; p < 0.016) and 3.89 (95% CI 1.01-15.0; p = 0.049), respectively. In addition, patients with a >= 25% decrease in the NLR and CRP level showed a significantly better response to nivolumab than those without a >= 25% decrease in the NLR and CRP level, with odds ratios of 9.54 (95% CI 2.09-49.8, p = 0.001) and 4.36 (95% CI 1.03-18.9, p = 0.032), respectively.CONCLUSION: Both the NLR and CRP levels were significantly associated with the clinical outcome of nivolumab in mRCC patients. The potential prognostic impact of those markers needs to be further prospectively investigated.
CANIT0002679	31512006	Clinical research	Sixty-five mRCC patients treated with nivolumab were enrolled	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	65	N/A	Retrospective analysis	Both the neutrophil-to-lymphocyte ratios and serum c-reactive protein levels were significantly associated with the clinical outcome of nivolumab in mRCC patients. The potential prognostic impact of those markers needs to be further prospectively investigated.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2020 Jan	C-reactive protein and the neutrophil-to-lymphocyte ratio are prognostic biomarkers in metastatic renal cell carcinoma patients treated with nivolumab.	 Int J Clin Oncol	BACKGROUND: Association between systemic inflammation and clinical outcome of immune checkpoint inhibitors (ICIs) has received focus. Our objective was to evaluate the utility of the neutrophil-to-lymphocyte ratio (NLR) in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab as well as the prognostic impact of the C-reactive protein (CRP) level.MATERIALS AND METHODS: Sixty-five mRCC patients treated with nivolumab were enrolled. We retrospectively investigated several factors, including the NLR and the CRP level, for their association with progression-free survival (PFS) and overall survival (OS). In addition, we evaluated their impact on the objective response.RESULTS: The CRP level was confirmed to be positively correlated with the NLR in a correlation analysis. An NLR >= 5 was significantly associated with a worse PFS (hazard ratio [HR]: 4.54, 95% confidence interval [CI] 1.93-10.7; p < 0.001), and an NLR >= 5 and a CRP >= 2.1 mg/dL were identified as a significant factors predicting worse OS with HRs of 4.88 (95% CI 1.35-17.7; p < 0.016) and 3.89 (95% CI 1.01-15.0; p = 0.049), respectively. In addition, patients with a >= 25% decrease in the NLR and CRP level showed a significantly better response to nivolumab than those without a >= 25% decrease in the NLR and CRP level, with odds ratios of 9.54 (95% CI 2.09-49.8, p = 0.001) and 4.36 (95% CI 1.03-18.9, p = 0.032), respectively.CONCLUSION: Both the NLR and CRP levels were significantly associated with the clinical outcome of nivolumab in mRCC patients. The potential prognostic impact of those markers needs to be further prospectively investigated.
CANIT0002680	31519206	Clinical research	164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients)	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	164	N/A	N/A	The median overall survival of all cancer of unknown primary site (CUP)  patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented.CONCLUSIONS: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); T-Lymphocyte (NCIT:C12476); 	Prominent PD-L1 expression on tumor-infiltrating lymphocyte	Gene expression signature on/in immune cell	 2019 Sep 13	Clinical and immune profiling for cancer of unknown primary site.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy.METHODS: A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They included 92 patients for whom pretreatment tumor tissue was available both for determination of programmed cell death-ligand 1 expression and tumor-infiltrating lymphocyte (TIL) density by immunohistochemistry (IHC) and for immune-related gene expression profiling (irGEP). The results of irGEP for CUP were compared with published data for ICI-treated solid cancers classified into progressive disease (PD) and non-PD subsets according to their best response to ICIs.RESULTS: The median overall survival of all CUP patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented.CONCLUSIONS: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.
CANIT0002681	31519206	Clinical research	164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients)	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	164	N/A	N/A	The median overall survival of all cancer of unknown primary site (CUP)  patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented.CONCLUSIONS: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.	N/A	N/A	N/A	VEGF (P15692); 	Serum VEGF expression levels	Gene expression signature on/in immune cell	 2019 Sep 13	Clinical and immune profiling for cancer of unknown primary site.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy.METHODS: A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They included 92 patients for whom pretreatment tumor tissue was available both for determination of programmed cell death-ligand 1 expression and tumor-infiltrating lymphocyte (TIL) density by immunohistochemistry (IHC) and for immune-related gene expression profiling (irGEP). The results of irGEP for CUP were compared with published data for ICI-treated solid cancers classified into progressive disease (PD) and non-PD subsets according to their best response to ICIs.RESULTS: The median overall survival of all CUP patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented.CONCLUSIONS: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.
CANIT0002682	31519605	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus docetaxel plus ramucirumab	Ramucirumab plus docetaxel	Immune checkpoint therapy plus Target therapy plus Chemotherapy	Ramucirumab (DB05578); docetaxel (DB01248); 	18	21	N/A	Despite increased toxicity concerns, docetaxel and ramucirumab (DOC+RAM) therapy in pre-immune checkpoint inhibitor (ICI)+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80].	Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients.	N/A	N/A	N/A	N/A	N/A	 2019 Sep	Previous Immune Checkpoint Inhibitor Treatment to Increase the Efficacy of Docetaxel and Ramucirumab Combination Chemotherapy.	 Anticancer Res	BACKGROUND/AIM: For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment.PATIENTS AND METHODS: From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history.RESULTS: Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients.CONCLUSION: Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS.
CANIT0002683	31521609	Basic research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	Cell lines/ animal models	N/A	Basic research	The dynamic changes in CXCR3+ T cells in blood may be a prognostic factor in anti-PD-1 immunotherapy, and promotion of CXCR3-mediated signaling may be beneficial to the anti-PD-1 therapy. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	CXCR3 (P49682); T-Lymphocyte (NCIT:C12476); 	Percentage of CXCR3(+) T-cells	Cell percentage/counts in blood	 2019 Oct	Role of CXCR3 signaling in response to anti-PD-1 therapy.	 EBioMedicine	BACKGROUND: Tumor mutations and tumor microenvironment are associated with resistance to cancer immunotherapies. However, peripheral T cell in effective anti-programmed death 1 (PD-1) antibody treatment is poorly understood.METHODS: Mass spectrometry and conventional flow cytometry were used to investigate peripheral blood cells isolated from patients. Furthermore, melanoma mouse model was performed to assess the role of CXCR3 signaling in anti-PD-1 antibody treatment.FINDINGS: We revealed a marked increase in the percentage of CXCR3+ T cells in the blood of cancer patients after the first pembrolizumab infusion. This percentage decreased after the second infusion in responsive patients, whereas a sustained high percentage of CXCR3+ T cells was observed in patients with progressive disease. A low percentage of CXCR3+ T cells presented in patients with stable disease or a partial response was confirmed by conventional flow cytometry. Intriguingly, blockade of CXCR3 signaling exacerbated tumor growth in mice. Intratumoral injection with recombinant CXCL9/10 plus intraperitoneal injection of anti-PD1 antibody inhibited the tumor growth in mice.INTERPRETATION: The dynamic changes in CXCR3+ T cells in blood may be a prognostic factor in anti-PD-1 immunotherapy, and promotion of CXCR3-mediated signaling may be beneficial to the anti-PD-1 therapy. FUND: This work was supported by the National Natural Science Foundation of China (Nos. 81722047, 81871944, 81670553, 81874317, 81572389, 81730100) and Jiangsu province key medical talents (Nos. ZDRCA2016026), The Deng Feng Distinguished Scholars Program, National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China (Number: 2018ZX09201002), and the Fundamental Research Funds for the Central Universities (020814380117).
CANIT0002684	31529107	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	143	N/A	N/A	Semiconductor electronic nose (eNose) sensors contributed significantly (P < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82-0.96]. This AUC was confirmed in the validation set: 0.85 (CI 0.75-0.96).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Oct 1	Prediction of response to anti-PD-1 therapy in patients with non-small-cell lung cancer by electronic nose analysis of exhaled breath.	 Ann Oncol	BACKGROUND: Immune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLC patients.METHODS: This was a prospective observational study in patients receiving checkpoint inhibitor therapy using both a training and validation set of NSCLC patients. At baseline, breath profiles were collected in duplicate by a metal oxide semiconductor electronic nose (eNose) positioned at the rear end of a pneumotachograph. Patients received nivolumab or pembrolizumab of which the efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. Data analysis involved advanced signal-processing and statistics based on independent t-tests followed by linear discriminant and receiver operating characteristic (ROC) analysis.RESULTS: Exhaled breath data of 143 NSCLC patients (training: 92, validation: 51) were available at baseline. ENose sensors contributed significantly (P < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82-0.96]. This AUC was confirmed in the validation set: 0.85 (CI 0.75-0.96).CONCLUSION: ENose assessment was effective in the noninvasive prediction of individual patient responses to immunotherapy. The predictive accuracy and efficacy of the eNose for discrimination of immunotherapy responder types were replicated in an independent validation set op patients. This finding can potentially avoid application of ineffective treatment in identified probable nonresponders.
CANIT0002685	31540935	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	60	N/A	Prospective observational study	Inflammatory arthritis (IA) was less likely to improve in those with longer duration of ICI use, in those receiving combination ICI therapy, and in patients with multiple other immune-related adverse events. Tumour response did not appear to be impacted by immunosuppression. Although not statistically significant, persistent IA was correlated with a better tumour response (complete or partial response).	Immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA)	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Inflammatory arthritis	Adverse events	 2020 Mar	Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation.	 Ann Rheum Dis	OBJECTIVE: We sought to investigate the long-term outcomes of patients who develop immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA), to define factors associated with IA persistence after ICI cessation, the need for immunosuppressants and the impact of these medications on underlying malignancies.METHODS: We conducted a prospective observational study of patients referred for IA associated with ICIs. Patients were recruited from June 2015 to December 2018. Information was obtained at the baseline visit, and follow-up visits occurred at varying intervals for up to 24 months from ICI cessation. Kaplan-Meier curves were developed to characterise IA persistence. Cox proportional hazards models were used to assess the influence of various factors on IA persistence. Logistic regression was used to evaluate the impact of IA treatment on tumour response.RESULTS: Sixty patients were monitored with a median follow-up after ICI cessation of 9 months. A majority (53.3%) had active IA at their most recent follow-up. IA was less likely to improve in those with longer duration of ICI use, in those receiving combination ICI therapy, and in patients with multiple other immune-related adverse events. Tumour response did not appear to be impacted by immunosuppression. Although not statistically significant, persistent IA was correlated with a better tumour response (complete or partial response).CONCLUSION: ICI-induced IA can become a long-term disease necessitating management by rheumatology for immunomodulatory treatment. Importantly, the use of immunomodulatory treatment has not been shown to impact cancer outcomes in this study.
CANIT0002686	31549264	Clinical research	Gastric cancer/gastroesophageal junction cancers	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	742	N/A	Retrospective analysis	Researchers successfully developed real-world (RW) cohorts for comparison with data from clinical trials, with comparable baseline characteristics. Survival in US patients receiving RW care was similar to that seen in Asian patients receiving placebo in ATTRACTION-2; survival with nivolumab in CheckMate 032 appeared favorable compared with US RW clinical practice. Of 742 adv/met GC/GEJC patients with at least 2 prior lines of therapy, matching generated 90 US RW ATTRACTION-2-matched patients (median OS: 3.5 months) versus 163 ATTRACTION-2 placebo patients (median OS: 4.1 months), and 100 US RW CheckMate 032-matched patients (median OS: 2.9 months) versus 42 CheckMate 032 nivolumab-treated patients (median OS: 8.5 months). Baseline characteristics were generally similar between clinical trial arms and RW-matched cohorts.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer.	 Gastric Cancer	BACKGROUND: There are few third-line or later (3L+) treatment options for advanced/metastatic (adv/met) gastric cancer/gastroesophageal junction cancers (GC/GEJC). 3L+ Nivolumab demonstrated encouraging results in Asian patients in the ATTRACTION-2 study compared with placebo (12-month survival, 26% vs 11%), and in Western patients in the single-arm CheckMate 032 study (12-month survival, 44%). This analysis aimed to establish comparator cohorts of US patients receiving routine care in real-world (RW) clinical practice.METHODS: A 2-step matching process generated RW cohorts from Flatiron Health's oncology database (January 1, 2011-April 30, 2017), for comparison with each trial: (1) clinical trial eligibility criteria were applied; (2) patients were frequency-matched with trial arms for baseline variables significantly associated with survival. Median overall survival (OS) was calculated by Kaplan-Meier analysis from last treatment until death.RESULTS: Of 742 adv/met GC/GEJC patients with at least 2 prior lines of therapy, matching generated 90 US RW ATTRACTION-2-matched patients (median OS: 3.5 months) versus 163 ATTRACTION-2 placebo patients (median OS: 4.1 months), and 100 US RW CheckMate 032-matched patients (median OS: 2.9 months) versus 42 CheckMate 032 nivolumab-treated patients (median OS: 8.5 months). Baseline characteristics were generally similar between clinical trial arms and RW-matched cohorts.CONCLUSIONS: We successfully developed RW cohorts for comparison with data from clinical trials, with comparable baseline characteristics. Survival in US patients receiving RW care was similar to that seen in Asian patients receiving placebo in ATTRACTION-2; survival with nivolumab in CheckMate 032 appeared favorable compared with US RW clinical practice.
CANIT0002687	31551142	Clinical research	Three studies (two on nivolumab and one on pembrolizumab) with a total of 400 patients were included	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	400	N/A	Meta-analysis	The summary response rate (RR) was 17.3% [95% confidence interval (CI): 13.2%-21.4%]. The summary disease control rate (DCR) was 56.6% (95% CI: 44.7%-68.5%). Summary progression free survival (PFS) was 3.5 months (95% CI: 2.8-4.2 months). Summary overall survival (OS) was 10.4 months (95% CI: 3.5-17.2 months).Pembrolizumab and nivolumab are the only checkpoint inhibitors with data in HCC. Meta-analysis of their effectiveness discloses rates not dissimilar to other systemic therapies available for this disease. Of interest also are the observed long responses in a sub-set of responders. Further development is clearly warranted.	Adverse effect rate was low and also consistent with the adverse effect profile of PD-L1/PD-1 inhibitors in other disease locations.	N/A	N/A	N/A	N/A	N/A	 2019 Dec	PD-1 inhibitors monotherapy in hepatocellular carcinoma: Meta-analysis and systematic review.	 Hepatobiliary Pancreat Dis Int	BACKGROUND: Immunity plays a major role in carcinogenesis and this is the case also for hepatocellular carcinomas (HCC). Checkpoint inhibitors, novel drugs that enhance the immune system's ability to attack cancers, have been successfully introduced for the therapy of various malignancies including HCC. An important target of these drugs is the PD-L1/PD-1 ligand/receptor pair and several clinically available inhibitors of this pair exist.DATA SOURCES: A search of the literature until April 20, 2019 was performed in the MEDLINE/PubMed database, the Embase database and the Cochrane Central Register of Controlled Trials. The clinical studies describing treatment with PD-L1/PD-1 inhibitors as monotherapy in HCC patients were retrieved. Patient characteristics with relevance for treatment efficacy, such as liver function, disease extend and previous treatment, were extracted from identified articles. Response and survival outcomes were the primary focus of the meta-analysis. Summary estimates of response rates and survival were calculated using a random or fixed effect model, depending on heterogeneity. Most common adverse effects were also recorded and summarized.RESULTS: Three studies (two on nivolumab and one on pembrolizumab) with a total of 400 patients were included in the analysis. The summary response rate (RR) was 17.3% [95% confidence interval (CI): 13.2%-21.4%]. The summary disease control rate (DCR) was 56.6% (95% CI: 44.7%-68.5%). Summary progression free survival (PFS) was 3.5 months (95% CI: 2.8-4.2 months). Summary overall survival (OS) was 10.4 months (95% CI: 3.5-17.2 months). Adverse effect rate was low and also consistent with the adverse effect profile of PD-L1/PD-1 inhibitors in other disease locations.CONCLUSIONS: Pembrolizumab and nivolumab are the only checkpoint inhibitors with data in HCC. Meta-analysis of their effectiveness discloses rates not dissimilar to other systemic therapies available for this disease. Of interest also are the observed long responses in a sub-set of responders. Further development is clearly warranted.
CANIT0002688	31551142	Clinical research	Three studies (two on nivolumab and one on pembrolizumab) with a total of 400 patients were included	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	400	N/A	Meta-analysis	The summary response rate (RR) was 17.3% [95% confidence interval (CI): 13.2%-21.4%]. The summary disease control rate (DCR) was 56.6% (95% CI: 44.7%-68.5%). Summary progression free survival (PFS) was 3.5 months (95% CI: 2.8-4.2 months). Summary overall survival (OS) was 10.4 months (95% CI: 3.5-17.2 months).Pembrolizumab and nivolumab are the only checkpoint inhibitors with data in HCC. Meta-analysis of their effectiveness discloses rates not dissimilar to other systemic therapies available for this disease. Of interest also are the observed long responses in a sub-set of responders. Further development is clearly warranted.	Adverse effect rate was low and also consistent with the adverse effect profile of PD-L1/PD-1 inhibitors in other disease locations.	N/A	N/A	N/A	N/A	N/A	 2019 Dec	PD-1 inhibitors monotherapy in hepatocellular carcinoma: Meta-analysis and systematic review.	 Hepatobiliary Pancreat Dis Int	BACKGROUND: Immunity plays a major role in carcinogenesis and this is the case also for hepatocellular carcinomas (HCC). Checkpoint inhibitors, novel drugs that enhance the immune system's ability to attack cancers, have been successfully introduced for the therapy of various malignancies including HCC. An important target of these drugs is the PD-L1/PD-1 ligand/receptor pair and several clinically available inhibitors of this pair exist.DATA SOURCES: A search of the literature until April 20, 2019 was performed in the MEDLINE/PubMed database, the Embase database and the Cochrane Central Register of Controlled Trials. The clinical studies describing treatment with PD-L1/PD-1 inhibitors as monotherapy in HCC patients were retrieved. Patient characteristics with relevance for treatment efficacy, such as liver function, disease extend and previous treatment, were extracted from identified articles. Response and survival outcomes were the primary focus of the meta-analysis. Summary estimates of response rates and survival were calculated using a random or fixed effect model, depending on heterogeneity. Most common adverse effects were also recorded and summarized.RESULTS: Three studies (two on nivolumab and one on pembrolizumab) with a total of 400 patients were included in the analysis. The summary response rate (RR) was 17.3% [95% confidence interval (CI): 13.2%-21.4%]. The summary disease control rate (DCR) was 56.6% (95% CI: 44.7%-68.5%). Summary progression free survival (PFS) was 3.5 months (95% CI: 2.8-4.2 months). Summary overall survival (OS) was 10.4 months (95% CI: 3.5-17.2 months). Adverse effect rate was low and also consistent with the adverse effect profile of PD-L1/PD-1 inhibitors in other disease locations.CONCLUSIONS: Pembrolizumab and nivolumab are the only checkpoint inhibitors with data in HCC. Meta-analysis of their effectiveness discloses rates not dissimilar to other systemic therapies available for this disease. Of interest also are the observed long responses in a sub-set of responders. Further development is clearly warranted.
CANIT0002689	31558236	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus carboplatin and nabpaclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	1	N/A	Case	The patient was treated with pembrolizumab combined with carboplatin and nabpaclitaxel as the first-line chemotherapy.  Histopathological examination of a biopsy specimen obtained from the tumor revealed variable squamous cell tumor cells and upregulation of PD-L1 expression on tumor cells, potentially induced by increasing infiltration of CD8-positive lymphocytes. The patient continued undergoing pembrolizumab combination therapy, and the tumor shrinkage was maintained.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Oct	Extrinsic Upregulation of PD-L1 Induced by Pembrolizumab Combination Therapy in Patients with NSCLC with Low Tumor PD-L1 Expression.	 J Thorac Oncol	Unable to provide
CANIT0002690	31558236	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus carboplatin and nabpaclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	1	N/A	Case	The patient was treated with pembrolizumab combined with carboplatin and nabpaclitaxel as the first-line chemotherapy.  Histopathological examination of a biopsy specimen obtained from the tumor revealed variable squamous cell tumor cells and upregulation of PD-L1 expression on tumor cells, potentially induced by increasing infiltration of CD8-positive lymphocytes. The patient continued undergoing pembrolizumab combination therapy, and the tumor shrinkage was maintained.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	CD8(+) T-cell tumor-infiltrating lymphocytes	Tumor-infiltrating immune cell	 2019 Oct	Extrinsic Upregulation of PD-L1 Induced by Pembrolizumab Combination Therapy in Patients with NSCLC with Low Tumor PD-L1 Expression.	 J Thorac Oncol	Unable to provide
CANIT0002691	31562796	Clinical research	1189 patients with advanced non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Chemotherapy	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	583	583	Open-label, phase 3 trial	First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up.	The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Nov 21	Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.	 N Engl J Med	BACKGROUND: In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC.METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more.RESULTS: Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.CONCLUSIONS: First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.).
CANIT0002692	31562797	Clinical research	Previously untreated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	314	315	Phase 3 trial	Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. Among patients with tumors with BRAF mutations and those with tumors without BRAF mutations, overall survival at 5 years was 60% and 48%, respectively, in the nivolumab-plus-ipilimumab group; 46% and 43% in the nivolumab group; and 30% and 25% in the ipilimumab group. 	No new late toxic effects were noted.	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	2019 Oct 17	Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.	N Engl J Med. 	BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
CANIT0002693	31562797	Clinical research	Previously untreated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	314	315	Phase 3 trial	Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. Five-year overall survival among patients with normal lactate dehydrogenase levels was 60%, 53%, and 34% in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab groups, respectively; among patients with elevated lactate dehydrogenase levels, these rates were 38%, 28%, and 15%.	No new late toxic effects were noted.	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Oct 17	Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.	 N Engl J Med	BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
CANIT0002694	31562797	Clinical research	Previously untreated advanced melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	314	315	Phase 3 trial	Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. Tumor PD-L1 expression alone was not predictive of efficacy outcomes. 	No new late toxic effects were noted.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Oct 17	Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.	 N Engl J Med	BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
CANIT0002695	31562797	Clinical research	Previously untreated advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	316	315	Phase 3 trial	Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. Among patients with tumors with BRAF mutations and those with tumors without BRAF mutations, overall survival at 5 years was 60% and 48%, respectively, in the nivolumab-plus-ipilimumab group; 46% and 43% in the nivolumab group; and 30% and 25% in the ipilimumab group. 	No new late toxic effects were noted.	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2019 Oct 17	Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.	 N Engl J Med	BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
CANIT0002696	31562797	Clinical research	Previously untreated advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	316	315	Phase 3 trial	Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. Five-year overall survival among patients with normal lactate dehydrogenase levels was 60%, 53%, and 34% in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab groups, respectively; among patients with elevated lactate dehydrogenase levels, these rates were 38%, 28%, and 15%.	No new late toxic effects were noted.	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Oct 17	Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.	 N Engl J Med	BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
CANIT0002697	31562797	Clinical research	Previously untreated advanced melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	316	315	Phase 3 trial	Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. Tumor PD-L1 expression alone was not predictive of efficacy outcomes. 	No new late toxic effects were noted.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Oct 17	Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.	 N Engl J Med	BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
CANIT0002698	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Nivolumab plus Pegilodecakin	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); Pegilodecakin (DB15162); 	1	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002699	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Pembrolizumab plus Pegilodecakin	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); IL2 (NCIT:C24498); 	1	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002700	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Nivolumab plus Pegilodecakin	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); Pegilodecakin (DB15162); 	37	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002701	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Pembrolizumab plus Pegilodecakin	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); IL2 (NCIT:C24498); 	37	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002702	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Nivolumab plus Pegilodecakin	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); Pegilodecakin (DB15162); 	34	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002703	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Pembrolizumab plus Pegilodecakin	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); IL2 (NCIT:C24498); 	34	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002704	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Nivolumab plus Pegilodecakin	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); Pegilodecakin (DB15162); 	38	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002705	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Pembrolizumab plus Pegilodecakin	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); IL2 (NCIT:C24498); 	38	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002706	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Triple-negative breast cancer	EFO:0005537	Breast	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Nivolumab plus Pegilodecakin	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); Pegilodecakin (DB15162); 	1	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002707	31563517	Clinical research	111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer.	Triple-negative breast cancer	EFO:0005537	Breast	PD-1 (Q15116); IL10R (Q13651); 	PD-1; IL10R	Pembrolizumab plus Pegilodecakin	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); IL2 (NCIT:C24498); 	1	N/A	Multicentre, multicohort, open-label, phase 1b trial (IVY)	In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).	At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments.	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial.	 Lancet Oncol	BACKGROUND: IL-10 has anti-inflammatory and CD8+ T-cell stimulating activities. Pegilodecakin (pegylated IL-10) is a first-in-class, long-acting IL-10 receptor agonist that induces oligoclonal T-cell expansion and has single-agent activity in advanced solid tumours. We assessed the safety and activity of pegilodecakin with anti-PD-1 monoclonal antibody inhibitors in patients with advanced solid tumours.METHODS: We did a multicentre, multicohort, open-label, phase 1b trial (IVY) at 12 cancer research centres in the USA. Patients were assigned sequentially into cohorts. Here, we report on all enrolled patients from two cohorts treated with pegilodecakin combined with anti-PD-1 inhibitors. Eligible patients were aged at least 18 years with histologically or cytologically confirmed advanced malignant solid tumours refractory to previous therapies, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with uncontrolled infectious diseases were excluded. Pegilodecakin was provided in single-use 3 mL vials and was self-administered subcutaneously by injection at home at 10 ¦Ìg/kg or 20 ¦Ìg/kg once per day in combination with pembrolizumab (2 mg/kg every 3 weeks or 200 mg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks or 240 mg every 2 weeks or 480 mg every 4 weeks at the approved dosing), both of which were given intravenously at the study site. Patients received pembrolizumab or nivolumab with pegilodecakin until disease progression, toxicity necessitating treatment discontinuation, patient withdrawal of consent, or study end. The primary endpoints were safety and tolerability, assessed in all patients enrolled in the study who received any amount of study medication including at least one dose of pegilodecakin, and pharmacokinetics (previously published). Secondary endpoints included objective response by immune-related response criteria in all patients who were treated and had evaluable measurements. The study is active but no longer recruiting, and is registered with ClinicalTrials.gov, NCT02009449.FINDINGS: Between Feb 13, 2015, and Sept 12, 2017, 111 patients were enrolled in the two cohorts. 53 received pegilodecakin plus pembrolizumab, and 58 received pegilodecakin plus nivolumab. 34 (31%) of 111 patients had non-small-cell lung cancer, 37 (33%) had melanoma, and 38 (34%) had renal cell carcinoma; one (<1%) patient had triple-negative breast cancer and one (<1%) had bladder cancer. Data cutoff was July 1, 2018. Median follow-up was 26.9 months (IQR 22.3-31.5) for patients with non-small-cell lung cancer, 33.0 months (29.2-35.1) for those with melanoma, and 22.7 months (20.9-27.0) for those with renal cell carcinoma. At least one treatment-related adverse event occurred in 103 (93%) of 111 patients. Grade 3 or 4 events occurred in 73 (66%) of 111 patients (35 [66%] of 53 in the pembrolizumab group and 38 [66%] of 58 in the nivolumab group), the most common of which were anaemia (12 [23%] in the pembrolizumab group and 16 [28%] in the nivolumab group), thrombocytopenia (14 [26%] in the pembrolizumab group and 12 [21%] in the nivolumab group), fatigue (11 [21%] in the pembrolizumab group and 6 [10%] in the nivolumab group) and hypertriglyceridaemia (three [6%] in the pembrolizumab group and eight [14%] in the nivolumab group). There were no fatal adverse events determined to be related to the study treatments. Of the patients evaluable for response, objective responses were 12 (43%) of 28 (non-small-cell lung cancer), three (10%) of 31 (melanoma), and 14 (40%) of 35 (renal cell carcinoma).INTERPRETATION: In this patient population, pegilodecakin with anti-PD-1 monoclonal antibodies had a manageable toxicity profile and preliminary antitumour activity. Pegilodecakin with pembrolizumab or nivolumab could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.FUNDING: ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.
CANIT0002708	31570881	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	215	N/A	N/A	The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	Microsatellite instability	Mutational status	 2019 Oct	The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs.	 Nature	The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.
CANIT0002709	31570881	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	215	N/A	N/A	The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Oct	The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs.	 Nature	The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.
CANIT0002710	31574417	Clinical research	Recurrent/metastatic squamous cell carcinoma of the head and neck	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus salvage chemotherapy	Salvage chemotherapy	Immune checkpoint therapy plus Chemotherapy	N/A	82	N/A	Retrospective analysis	In recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), the objective response rate to salvage chemotherapy was high (30%) suggesting that exposure to immune checkpoint inhibitor may increase tumour sensitivity to chemotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.	 Eur J Cancer	BACKGROUND: Immune checkpoint inhibitors (ICI) are active in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Recent data suggest that exposure to ICI improves response to salvage chemotherapy (SCT) in advanced non-small-cell lung cancer. We evaluated response to chemotherapy in patients who had progressed on ICI in patients with R/M SCCHN.PATIENTS AND METHODS: A retrospective study was conducted at 4 French centres. Eligibility criteria were patients who progressed after treatment with ICI for R/M SCCHN and received SCT and for whom efficacy data were available between September 2014 and January 2018.RESULTS: Of 232 patients treated with ICI, 82 met eligibility criteria: 84% were male. ICI was given as monotherapy in 45% of patients or as combination in 55%. SCT included taxanes (56.1%), cetuximab in combination with taxanes or platinum (50%), platinum-based regimen (36.6%). The median number of treatment lines before SCT was 2 (range 1-6). The objective response rate (ORR) to SCT was 30%. Three patients (4%) presented complete response and 22 patients (27%) had partial response. Median progression-free survival was 3.6 months and median overall survival was 7.8 months. The age at SCT, initial tumour location, number of prior chemotherapy regimens, type of chemotherapy before ICI, best response to ICI, site of relapse and Eastern Cooperative Oncology Group at SCT were not associated with response to SCT on univariate analysis.CONCLUSION: In R/M SCCHN, the ORR to SCT was high (30%) suggesting that exposure to ICI may increase tumour sensitivity to chemotherapy.
CANIT0002711	31575354	Case report	An 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	A rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet's disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet's-like syndrome presentation.	Corneal erosions, oral and genital ulcerations	N/A	N/A	N/A	N/A	N/A	 2020 Jun	Behcet's-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy.	 J Oncol Pharm Pract	INTRODUCTION: The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system.CASE REPORT: We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations.MANAGEMENT AND OUTCOME: Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer.DISCUSSION: Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet's disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet's-like syndrome presentation.
CANIT0002712	31577767	Case report	Metastatic pancreatic cancer harboring a germline BRCA2 mutation	Pancreatic carcinoma	EFO:0002618	Pancreas	PD-1 (Q15116); PARP1 (P09874); 	PD-1; PARP1	Nivolumab plus chemotherapy plus olaparib	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); olaparib (DB09074); 	1	N/A	Case	We observed the patient had a good progression-free survival (7.4 months); the lesion of the pancreas was classified as partial disease through Olaparib treatment, which indicated significant shrinkage. But it is difficult to conclude whether such therapy could help prolong the overall survival for such patients. The targeted therapy Olaparib showed early signs of potential in treating pancreatic cancer (PC) in patients with mutations of the BRCA genes. With emerging therapeutic modalities and next-generation sequencing development, it is increasingly relevant to consider mutation screenings of patients with PC.	N/A	N/A	N/A	BRCA (P46736); 	BRCA mutational status	Mutational status	 2019 Oct	A case report of a dramatic response to olaparib in a patient with metastatic pancreatic cancer harboring a germline BRCA2 mutation.	 Medicine (Baltimore)	RATIONALE: Pancreatic cancer (PC) is considered as one of the deadliest cancers all over the world. Germline and somatic BRCA1/2 mutations have been widely studied in breast and ovarian carcinomas as they have been found to enhance the risk for disease progression. Olaparib, an oral poly(adenosine diphosphate-ribose)polymerase (PARP) inhibitor, has been approved for the treatment strategy of ovarian cancer with any BRCA1/2 mutations. There is a lack of studies which focus on the treatment of other cancer with BRCA-Mutation.PATIENT CONCERNS: This report describes a patient whose presenting complaints were Physical examination showed that the pancreas was occupied for one month. He initially was diagnosed with stage IV PC based on conventional imaging and pathologic assessment. He had a known germline BRCA 2 mutation, which exhibited a good response to PARP inhibitor therapy.DIAGNOSIS: Through the biopsy histopathological examination, imaging examination, and genetic testing, the patient was diagnosed as metastatic PC with BRCA2 mutation.INTERVENTIONS: He received gemcitabine and albumin-bound paclitaxel chemotherapy from March 15, 2017 to June 30, 2017, and Nivolumab immunotherapy as the maintenance therapy. After serum CA-199 level increased, Olaparib was orally administered from August 17, 2017 to March. After tumor relapsed, he received multiple lines of chemotherapy, including Trametinib Oxaliplatin, S-1, bevacizumab, and irinotecan liposome injection till July 17, 2018.OUTCOMES: We observed the patient had a good progression-free survival (7.4 months); the lesion of the pancreas was classified as partial disease through Olaparib treatment, which indicated significant shrinkage. But it is difficult to conclude whether such therapy could help prolong the overall survival for such patients.LESSONS: The targeted therapy Olaparib showed early signs of potential in treating PC in patients with mutations of the BRCA genes. With emerging therapeutic modalities and next-generation sequencing development, it is increasingly relevant to consider mutation screenings of patients with PC.
CANIT0002713	31582355	Clinical research	Advanced oesophageal squamous cell carcinoma	Oesophageal squamous cell carcinoma	Orphanet:2198 	Oral cavity	PD-1 (Q15116); 	PD-1; 	Nivolumab	Chemotherapy	Immune checkpoint therapy	Nivolumab (DB09035); 	210	209	Multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3)	Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17.6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10.9 months, 95% CI 9.2-13.3 vs 8.4 months, 7.2-9.9; hazard ratio for death 0.77, 95% CI 0.62-0.96; p=0.019). 	38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease).	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.	 Lancet Oncol	BACKGROUND: Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma.METHODS: We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0-1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing.FINDINGS: Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10.5 months (IQR 4.5-19.0) in the nivolumab group and 8.0 months (4.6-15.2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17.6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10.9 months, 95% CI 9.2-13.3 vs 8.4 months, 7.2-9.9; hazard ratio for death 0.77, 95% CI 0.62-0.96; p=0.019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease).INTERPRETATION: Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients.FUNDING: ONO Pharmaceutical Company and Bristol-Myers Squibb.
CANIT0002714	31584197	Clinical research	259 muscle-invasive bladder cancer t characteristics and relationship with IL22+ cells infiltration	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	259	N/A	N/A	CD8+ cells infiltration possessed thepotential to predict responsiveness to the PD-1 blockade in muscle-invasive bladder cancer patients	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	Immunosuppressive contexture with CD8(+) T-cell dysfunction	Tumor-infiltrating immune cell	 2020 Jan 15	Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses.	 Int J Cancer	Our previous researches have identified immunoevasive subtype muscle-invasive bladder cancer (MIBC) characterized with immune cells infiltration patterns. Our study explored the clinical significance, immunoregulatory role and therapeutic value of intratumoral IL22-producing cells in MIBC. Two hundred and fifty-nine formalin-fixed paraffin-embedded MIBC samples and 83 freshly resected MIBC tissues and 391 TCGA MIBC samples were retrospectively evaluated. Immunohistochemistry and flow cytometry were applied to identify immune cell infiltration and functional status. In vitro intervention studies were to test the therapeutic and predictive potential of IL22+ cells. Our data revealed patients with high IL22+ cells infiltration suffered poor overall survival and recurrence-free survival in both training and validation cohorts. Only pT2 patients of combined cohort with low IL22+ cells infiltration gained survival benefits from adjuvant chemotherapy (ACT) significantly. Besides, immune contexture featured with increased pro-tumor cells and immunosuppressive cytokines was identified in patients with high IL22+ cells density. The expression pattern of exhausted and effector markers in CD8+ T cells from high IL22+ cells subgroup indicated their dysfunctional status. Importantly, nivolumab showed tumor-killing efficacy in tumors with high IL22+ cells infiltration, and immunosuppressive contexture with CD8+ T cells exhaustion was abrogated in tumors treated with anti-IL22 antibody. In summary, IL22+ cells infiltration determined immunosuppressive contexture with CD8+ T cell dysfunction. Tumor-infiltrating IL22+ cells could be used as an independent marker to predict prognosis and ACT responses. IL22+ cells infiltration possessed the potential to be a favorable predictor for nivolumab application and IL22 blockade could be a novel therapeutic strategy in MIBC.
CANIT0002715	31584197	Clinical research	259 muscle-invasive bladder cancer t characteristics and relationship with IL22+ cells infiltration	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	259	N/A	N/A	IL10+ cells infiltration possessed thepotential to predict responsiveness to the PD-1 blockade in muscle-invasive bladder cancer patients	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	IL10 (P22301); 	IL10 expression levels on T-Lymphocyte	Tumor-infiltrating immune cell	 2020 Jan 15	Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses.	 Int J Cancer	Our previous researches have identified immunoevasive subtype muscle-invasive bladder cancer (MIBC) characterized with immune cells infiltration patterns. Our study explored the clinical significance, immunoregulatory role and therapeutic value of intratumoral IL22-producing cells in MIBC. Two hundred and fifty-nine formalin-fixed paraffin-embedded MIBC samples and 83 freshly resected MIBC tissues and 391 TCGA MIBC samples were retrospectively evaluated. Immunohistochemistry and flow cytometry were applied to identify immune cell infiltration and functional status. In vitro intervention studies were to test the therapeutic and predictive potential of IL22+ cells. Our data revealed patients with high IL22+ cells infiltration suffered poor overall survival and recurrence-free survival in both training and validation cohorts. Only pT2 patients of combined cohort with low IL22+ cells infiltration gained survival benefits from adjuvant chemotherapy (ACT) significantly. Besides, immune contexture featured with increased pro-tumor cells and immunosuppressive cytokines was identified in patients with high IL22+ cells density. The expression pattern of exhausted and effector markers in CD8+ T cells from high IL22+ cells subgroup indicated their dysfunctional status. Importantly, nivolumab showed tumor-killing efficacy in tumors with high IL22+ cells infiltration, and immunosuppressive contexture with CD8+ T cells exhaustion was abrogated in tumors treated with anti-IL22 antibody. In summary, IL22+ cells infiltration determined immunosuppressive contexture with CD8+ T cell dysfunction. Tumor-infiltrating IL22+ cells could be used as an independent marker to predict prognosis and ACT responses. IL22+ cells infiltration possessed the potential to be a favorable predictor for nivolumab application and IL22 blockade could be a novel therapeutic strategy in MIBC.
CANIT0002716	31584197	Clinical research	259 muscle-invasive bladder cancer t characteristics and relationship with IL22+ cells infiltration	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	259	N/A	N/A	IL22+ cells infiltration possessed thepotential to predict responsiveness to the PD-1 blockade in muscle-invasive bladder cancer patients	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	IL22 (Q9GZX6); 	High IL22(+) cells infiltration	Tumor-infiltrating immune cell	 2020 Jan 15	Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses.	 Int J Cancer	Our previous researches have identified immunoevasive subtype muscle-invasive bladder cancer (MIBC) characterized with immune cells infiltration patterns. Our study explored the clinical significance, immunoregulatory role and therapeutic value of intratumoral IL22-producing cells in MIBC. Two hundred and fifty-nine formalin-fixed paraffin-embedded MIBC samples and 83 freshly resected MIBC tissues and 391 TCGA MIBC samples were retrospectively evaluated. Immunohistochemistry and flow cytometry were applied to identify immune cell infiltration and functional status. In vitro intervention studies were to test the therapeutic and predictive potential of IL22+ cells. Our data revealed patients with high IL22+ cells infiltration suffered poor overall survival and recurrence-free survival in both training and validation cohorts. Only pT2 patients of combined cohort with low IL22+ cells infiltration gained survival benefits from adjuvant chemotherapy (ACT) significantly. Besides, immune contexture featured with increased pro-tumor cells and immunosuppressive cytokines was identified in patients with high IL22+ cells density. The expression pattern of exhausted and effector markers in CD8+ T cells from high IL22+ cells subgroup indicated their dysfunctional status. Importantly, nivolumab showed tumor-killing efficacy in tumors with high IL22+ cells infiltration, and immunosuppressive contexture with CD8+ T cells exhaustion was abrogated in tumors treated with anti-IL22 antibody. In summary, IL22+ cells infiltration determined immunosuppressive contexture with CD8+ T cell dysfunction. Tumor-infiltrating IL22+ cells could be used as an independent marker to predict prognosis and ACT responses. IL22+ cells infiltration possessed the potential to be a favorable predictor for nivolumab application and IL22 blockade could be a novel therapeutic strategy in MIBC.
CANIT0002717	31584197	Clinical research	259 muscle-invasive bladder cancer t characteristics and relationship with IL22+ cells infiltration	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	259	N/A	N/A	TGFB+ cells infiltration possessed thepotential to predict responsiveness to the PD-1 blockade in muscle-invasive bladder cancer patients	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	TGFB (P01137); 	TGFB1 expression on T-Lymphocyte	Tumor-infiltrating immune cell	 2020 Jan 15	Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses.	 Int J Cancer	Our previous researches have identified immunoevasive subtype muscle-invasive bladder cancer (MIBC) characterized with immune cells infiltration patterns. Our study explored the clinical significance, immunoregulatory role and therapeutic value of intratumoral IL22-producing cells in MIBC. Two hundred and fifty-nine formalin-fixed paraffin-embedded MIBC samples and 83 freshly resected MIBC tissues and 391 TCGA MIBC samples were retrospectively evaluated. Immunohistochemistry and flow cytometry were applied to identify immune cell infiltration and functional status. In vitro intervention studies were to test the therapeutic and predictive potential of IL22+ cells. Our data revealed patients with high IL22+ cells infiltration suffered poor overall survival and recurrence-free survival in both training and validation cohorts. Only pT2 patients of combined cohort with low IL22+ cells infiltration gained survival benefits from adjuvant chemotherapy (ACT) significantly. Besides, immune contexture featured with increased pro-tumor cells and immunosuppressive cytokines was identified in patients with high IL22+ cells density. The expression pattern of exhausted and effector markers in CD8+ T cells from high IL22+ cells subgroup indicated their dysfunctional status. Importantly, nivolumab showed tumor-killing efficacy in tumors with high IL22+ cells infiltration, and immunosuppressive contexture with CD8+ T cells exhaustion was abrogated in tumors treated with anti-IL22 antibody. In summary, IL22+ cells infiltration determined immunosuppressive contexture with CD8+ T cell dysfunction. Tumor-infiltrating IL22+ cells could be used as an independent marker to predict prognosis and ACT responses. IL22+ cells infiltration possessed the potential to be a favorable predictor for nivolumab application and IL22 blockade could be a novel therapeutic strategy in MIBC.
CANIT0002718	31590988	Clinical research	Extensive-stage small-cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab plus platinum-etoposide	Platinum-etoposide	Immune checkpoint therapy	Durvalumab (DB11714); 	268	269	A randomised, open-label, phase 3 trial	Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0.73 (95% CI 0.59-0.91; p=0.0047]); median overall survival was 13.0 months (95% CI 11.5-14.8) in the durvalumab plus platinum-etoposide group versus 10.3 months (9.3-11.2) in the platinum-etoposide group, with 34% (26.9-41.0) versus 25% (18.4-31.6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received.	Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.	N/A	N/A	N/A	N/A	N/A	 2019 Nov 23	Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.	 Lancet	BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC.METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing.FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0.73 (95% CI 0.59-0.91; p=0.0047]); median overall survival was 13.0 months (95% CI 11.5-14.8) in the durvalumab plus platinum-etoposide group versus 10.3 months (9.3-11.2) in the platinum-etoposide group, with 34% (26.9-41.0) versus 25% (18.4-31.6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received.FUNDING: AstraZeneca.
CANIT0002719	31601496	Clinical research	Unresectable, stage III non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Chemoradiotherapy followed by durvalumab	Chemoradiotherapy followed by placebo	Chemoradiotherapy followed by Immune checkpoint therapy	Durvalumab (DB11714); Chemoradiotherapy (NCIT:C94626); 	476	237	International, multicentre, double-blind, randomised, controlled, phase 3 trial	Our findings suggest that a clinical benefit with durvalumab can be attained without compromising patient-reported outcomes (PROs). This result is of note because the previous standard of care was observation alone, with no presumed detriment to PROs. Between baseline and 12 months, the prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1.8 [95% CI 0.06 to 3.54] in the durvalumab group vs 0.7 [-1.91 to 3.30] in the placebo group), dyspnoea (3.1 [1.75 to 4.36] vs 1.4 [-0.51 to 3.34]), chest pain (-3.1 [-4.57 to -1.60] vs -3.5 [-5.68 to -1.29]), fatigue (-3.0 [-4.53 to -1.50] vs -5.2 [-7.45 to -2.98]), appetite loss (-5.8 [-7.28 to -4.36] vs -7.0 [-9.17 to -4.87]), physical functioning (0.1 [-1.10 to 1.28] vs 2.0 [0.22 to 3.73]), and global health status or quality of life (2.6 [1.21 to 3.94] vs 1.8 [-0.25 to 3.81]) remained stable with both treatments, with no clinically relevant changes from baseline. The between-group differences in changes from baseline to 12 months in cough (difference in adjusted mean changes 1.1, 95% CI -1.89 to 4.11), dyspnoea (1.6, -0.58 to 3.87), chest pain (0.4, -2.13 to 2.93), fatigue (2.2, -0.38 to 4.78), appetite loss (1.2, -1.27 to 3.67), physical functioning (-1.9, -3.91 to 0.15), or global health status or quality of life (0.8, -1.55 to 3.14) were not clinically relevant. Generally, there were no clinically important between-group differences in time to deterioration of prespecified key PRO endpoints.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study.	 Lancet Oncol	BACKGROUND: In the ongoing, phase 3 PACIFIC trial, durvalumab improved the primary endpoints of progression-free survival and overall survival compared with that for placebo, with similar safety, in patients with unresectable, stage III non-small-cell lung cancer. In this analysis, we aimed to evaluate one of the secondary endpoints, patient-reported outcomes (PROs).METHODS: PACIFIC is an ongoing, international, multicentre, double-blind, randomised, controlled, phase 3 trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0 or 1, with histologically or cytologically documented stage III, unresectable non-small-cell lung cancer, for which they had received at least two cycles of platinum-based chemoradiotherapy, with no disease progression after this treatment. We randomly assigned patients (2:1) using an interactive voice response system and a blocked design (block size=3) stratified by age, sex, and smoking history to receive 10 mg/kg intravenous durvalumab or matching placebo 1-42 days after concurrent chemoradiotherapy, then every 2 weeks up to 12 months. The primary endpoints of progression-free survival and overall survival have been reported previously. PROs were a prespecified secondary outcome. We assessed PRO symptoms, functioning, and global health status or quality of life in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) at the time of random allocation to groups, at weeks 4 and 8, every 8 weeks until week 48, and then every 12 weeks until progression. Changes from baseline to 12 month in key symptoms were analysed with mixed model for repeated measures (MMRM) and time-to-event analyses. A 10-point or greater change from baseline (deterioration or improvement) was deemed clinically relevant. This study is registered with ClinicalTrials.gov, NCT02125461, and EudraCT, 2014-000336-42.FINDINGS: Between May 9, 2014, and April 22, 2016, 476 patients were assigned to receive durvalumab, and 237 patients were assigned to receive placebo. As of March 22, 2018, the median follow-up was 25.2 months (IQR 14.1-29.5). More than 79% of patients given durvalumab and more than 82% of patients given placebo completed questionnaires up to week 48. Between baseline and 12 months, the prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1.8 [95% CI 0.06 to 3.54] in the durvalumab group vs 0.7 [-1.91 to 3.30] in the placebo group), dyspnoea (3.1 [1.75 to 4.36] vs 1.4 [-0.51 to 3.34]), chest pain (-3.1 [-4.57 to -1.60] vs -3.5 [-5.68 to -1.29]), fatigue (-3.0 [-4.53 to -1.50] vs -5.2 [-7.45 to -2.98]), appetite loss (-5.8 [-7.28 to -4.36] vs -7.0 [-9.17 to -4.87]), physical functioning (0.1 [-1.10 to 1.28] vs 2.0 [0.22 to 3.73]), and global health status or quality of life (2.6 [1.21 to 3.94] vs 1.8 [-0.25 to 3.81]) remained stable with both treatments, with no clinically relevant changes from baseline. The between-group differences in changes from baseline to 12 months in cough (difference in adjusted mean changes 1.1, 95% CI -1.89 to 4.11), dyspnoea (1.6, -0.58 to 3.87), chest pain (0.4, -2.13 to 2.93), fatigue (2.2, -0.38 to 4.78), appetite loss (1.2, -1.27 to 3.67), physical functioning (-1.9, -3.91 to 0.15), or global health status or quality of life (0.8, -1.55 to 3.14) were not clinically relevant. Generally, there were no clinically important between-group differences in time to deterioration of prespecified key PRO endpoints.INTERPRETATION: Our findings suggest that a clinical benefit with durvalumab can be attained without compromising PROs. This result is of note because the previous standard of care was observation alone, with no presumed detriment to PROs.FUNDING: AstraZeneca.
CANIT0002720	31607699	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Platinum-based combination chemotherapy followed by Nivolumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Nivolumab (DB09035); Platinum (DB12257); 	29	N/A	Single-center prospective study	The median survival duration was 101 days, and OS rate in the study was 51.7%. Six patients (20.7%) had stable disease response, five patients (17.2%) had partial response, and three patients (10.3%) were lost to follow-up.Data from the study suggest nivolumab is well-tolerated and effective in Indian patients with recurrent advanced NSCLC after failure of the multiple first lines of platinum-based combination chemotherapy.	Asthenia and cough were the most common nonhematological toxicities. Only three patients developed hematological toxicities (anemia and thrombocytopenia).	N/A	N/A	N/A	N/A	N/A	 2019 Oct-Dec	An observational single-center study of nivolumab in Indian patients with recurrent advanced non-small cell lung cancer.	 Indian J Cancer	PURPOSE: Limited treatment options are available for patients with advanced non-small cell lung cancer (NSCLC) after failure of first-line platinum-based chemotherapy. The treatment of recurrent advanced NSCLC progressed with the arrival of nivolumab and other immunotherapeutic agents. Our single-center prospective study aimed to present the effectiveness and safety of nivolumab in second-line setting after first-line platinum doublet in Indian patients with advanced NSCLC.PATIENTS AND METHODS: Twenty-nine adult patients with stage IV NSCLC treated with nivolumab after failure of first-line platinum-based chemotherapy at Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, India, between October 2016 and January 2018, were included in the study. Overall survival (OS), hematological, and nonhematological toxicities were evaluated.RESULTS: A total of 29 patients (mean age of 59.6 years at enrollment) were evaluated. Histological evaluation revealed adenocarcinoma (44.8%) and squamous (55.2%) type of cancer. The Eastern Cooperative Oncology Group performance score was II in 7 patients (24.1%) and I in 22 (75.9%) patients. Patients received an average of four cycles of nivolumab. The median survival duration was 101 days, and OS rate in the study was 51.7%. Six patients (20.7%) had stable disease response, five patients (17.2%) had partial response, and three patients (10.3%) were lost to follow-up. Asthenia and cough were the most common nonhematological toxicities. Only three patients developed hematological toxicities (anemia and thrombocytopenia).CONCLUSION: Data from our study suggest nivolumab is well-tolerated and effective in Indian patients with recurrent advanced NSCLC after failure of the multiple first lines of platinum-based combination chemotherapy.
CANIT0002721	31609651	Clinical research	Relapsed or refractory primary mediastinal large B-cell lymphoma	Mediastinal large B-cell lymphoma	EFO:0000403	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	74	N/A	Phase IB KEYNOTE-013 and phase II KEYNOTE-170 studies	Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.. The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival.	Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths.	N/A	N/A	Magnitude of the 9p24 gene abnormality ()	Magnitude of the 9p24 gene abnormality	Gene expression signature on/in tumor cell	 2019 Dec 1	Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma.	 J Clin Oncol	PURPOSE: Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade.METHODS: In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity.RESULTS: The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival.CONCLUSION: Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.
CANIT0002722	31609651	Clinical research	Relapsed or refractory primary mediastinal large B-cell lymphoma	Mediastinal large B-cell lymphoma	EFO:0000403	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	74	N/A	Phase IB KEYNOTE-013 and phase II KEYNOTE-170 studies	Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.. The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival.	Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Dec 1	Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma.	 J Clin Oncol	PURPOSE: Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade.METHODS: In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity.RESULTS: The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival.CONCLUSION: Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.
CANIT0002723	31610828	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Chemotherapy	Immune checkpoint therapy	Pembrolizumab (DB09037); 	N/A	N/A	Phase III randomized controlled trial (KEYNOTE-042; ClinicalTrials.gov; NCT02220894)	Compared with chemotherapy, patients treated with pembrolizumab provided an additional 1.13, 1.01, and 0.59 quality-adjusted life years (QALYs) in patients with PD-L1 expression levels of >=50%, >=20%, and >=1%, with corresponding incremental cost of 53,784, 47,479, and 39,827, respectively. The resultant incremental cost-effectiveness ratios (ICERs) of pembrolizumab versus chemotherapy were 47,596, 47,184, and 68,061/QALY, in three expression levels of PD-L1, respectively, all of which did not exceed the WTP threshold of 180,000/QALY. Probability sensitivity analysis outcome supported that pembrolizumab exhibited evident advantage over chemotherapy to be cost-effective. One-way sensitivity analysis found that ICERs were most sensitive to utility value of pembrolizumab in progression survival state. All the adjustment of parameters did not qualitatively change the result. For treatment-naive, metastatic NSCLC patients with PD-L1+, pembrolizumab was estimated to be cost-effective compared with chemotherapy for all PD-L1 expression levels at a WTP threshold of 180,000/QALY in the context of the US health care system.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Mar 27	Cost-Utility Analysis of Pembrolizumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer With Different PD-L1 Expression Levels.	 Oncol Res	To evaluate the cost-utility of pembrolizumab versus chemotherapy as the first-line setting for metastatic non-small cell lung cancer (NSCLC) from the US health care system perspective, a Markov model was developed to compare the lifetime cost and effectiveness of pembrolizumab versus chemotherapy for untreated metastatic NSCLC, based on the clinical data derived from phase III randomized controlled trial (KEYNOTE-042; ClinicalTrials.gov; NCT02220894). Weibull distribution was fitted to simulate the parametric survival functions. Drug costs were collected from official websites, and utility values were obtained from published literature. Total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were computed as primary output indicators. The impact of different PD-L1 expression levels on ICER was also evaluated. One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. Compared with chemotherapy, patients treated with pembrolizumab provided an additional 1.13, 1.01, and 0.59 QALYs in patients with PD-L1 expression levels of >=50%, >=20%, and >=1%, with corresponding incremental cost of 53,784, 47,479, and 39,827, respectively. The resultant ICERs of pembrolizumab versus chemotherapy were 47,596, 47,184, and 68,061/QALY, in three expression levels of PD-L1, respectively, all of which did not exceed the WTP threshold of 180,000/QALY. Probability sensitivity analysis outcome supported that pembrolizumab exhibited evident advantage over chemotherapy to be cost-effective. One-way sensitivity analysis found that ICERs were most sensitive to utility value of pembrolizumab in progression survival state. All the adjustment of parameters did not qualitatively change the result. For treatment-naive, metastatic NSCLC patients with PD-L1+, pembrolizumab was estimated to be cost-effective compared with chemotherapy for all PD-L1 expression levels at a WTP threshold of 180,000/QALY in the context of the US health care system.
CANIT0002724	31612909	Clinical research	Triple-negative breast cancer	Triple-negative breast cancer	EFO:0005537	Breast	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab plus nab-paclitaxel	Nab-paclitaxel plus placebo	Immune checkpoint therapy plus Chemotherapy	Atezolizumab (DB11595); nab-paclitaxel (DB01229); 	34	31	Randomised Phase 3 IMpassion130 trial	Atezolizumab plus nab-paclitaxel (atezo + nab-P)  efficacy in Japanese patients was consistent with the overall IMpassion130 population. No new safety signals were observed, and tolerability was consistent with that of the overall population. The PD-L1-positive subgroup included 25 patients (12 atezo + nab-P; 13 placebo plus nab-paclitaxel (plac + nab-P)). Median PFS was 7.4 months (atezo + nab-P) versus 4.6 months (plac + nab-P; hazard ratio [HR], 0.47; 95% CI, 0.25-0.90). In the PD-L1-positive subgroup, median PFS was 10.8 months (atezo + nab-P) versus 3.8 months (plac + nab-P; HR, 0.04; 95% CI, <0.01-0.35).	Safety results in the Japanese subgroup were consistent with those in the overall population. The Japanese subgroup had a lower incidence of adverse events leading to treatment withdrawal than the overall population. More patients in the atezo + nab-P arm had neutrophil count decreases and stomatitis than patients in the plac + nab-P arm.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Dec 27	Subgroup analysis of Japanese patients in a Phase 3 study of atezolizumab in advanced triple-negative breast cancer (IMpassion130).	 Jpn J Clin Oncol	BACKGROUND: In the randomised Phase 3 IMpassion130 trial, atezolizumab combined with nab-paclitaxel (atezo + nab-P) in 902 patients with triple-negative breast cancer (TNBC) showed prolonged progression-free survival (PFS) in both the intention-to-treat (ITT) population and programmed death-ligand 1 (PD-L1)-positive subgroup compared with placebo plus nab-P (plac + nab-P). This study assessed the efficacy and safety of atezo + nab-P in the IMpassion130 Japanese subpopulation.METHODS: Eligible patients had unresectable locally advanced or metastatic TNBC previously untreated with chemotherapy for metastatic disease. Patients were randomised 1:1 to receive either atezo + nab-P or plac + nab-P. Co-primary endpoints were investigator-assessed PFS and overall survival (ITT population and PD-L1-positive subgroup). These were also assessed in the Japanese subpopulation.RESULTS: There were 65 Japanese patients (34 atezo + nab-P; 31 plac + nab-P). The PD-L1-positive subgroup included 25 patients (12 atezo + nab-P; 13 plac + nab-P). Median PFS was 7.4 months (atezo + nab-P) versus 4.6 months (plac + nab-P; hazard ratio [HR], 0.47; 95% CI, 0.25-0.90). In the PD-L1-positive subgroup, median PFS was 10.8 months (atezo + nab-P) versus 3.8 months (plac + nab-P; HR, 0.04; 95% CI, <0.01-0.35). Safety results in the Japanese subgroup were consistent with those in the overall population. The Japanese subgroup had a lower incidence of adverse events leading to treatment withdrawal than the overall population. More patients in the atezo + nab-P arm had neutrophil count decreases and stomatitis than patients in the plac + nab-P arm.CONCLUSIONS: Atezo + nab-P efficacy in Japanese patients was consistent with the overall IMpassion130 population. No new safety signals were observed, and tolerability was consistent with that of the overall population.
CANIT0002725	31619231	Case report	Squamous non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus gemcitabine	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); gemcitabine (DB00441); 	1	N/A	Case	In this study, the co-mutations of TP53 and KRAS in a 64-year-old non-smoking man with squamous-cell NSCLC patient was described using the next-generation sequencing (NGS) technology. The patient was treated with the pembrolizumab combined with gemcitabine as the salvage therapy, and a marked partial response could be attained, which had persisted for over 7 months.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	TP53 (P04637); KRAS (P01116); 	Co-mutations of TP53 and KRAS	Mutational status	 2019 Oct 16	Co-mutations of TP53 and KRAS serve as potential biomarkers for immune checkpoint blockade in squamous-cell non-small cell lung cancer: a case report.	 BMC Med Genomics	BACKGROUND: Unprecedented durable responses are identified in clinical studies to target the signaling of programmed cell death protein-1 (PD-1) as well as its ligand (PD-L1) in patients with squamous-cell non-small cell lung cancer (NSCLC). However, factors predicting the patient subtypes that are responsive to PD-1/PD-L1inhibitors have not been fully understood yet. Biomarkers, like PD-L1 expression, tumor mutational burden(TMB), DNA mismatch repair deficiency (dMMR), and tumor-infiltrating lymphocytes (TILs), have been utilized to select patients responsive to PD-1/PD-L1inhibitors in the clinic, but each of them has limited use. Lung adenocarcinoma patients with a mutation of TP53 or KRAS, particularly those with co-mutations of TP53 and KRAS, can benefit from anti-PD-1 treatment.CASE PRESENTATION: In this study, the co-mutations of TP53 and KRAS in a 64-year-old non-smoking man with squamous-cell NSCLC patient was described using the next-generation sequencing (NGS) technology. The patient was treated with the pembrolizumab combined with gemcitabine as the salvage therapy, and a marked partial response could be attained, which had persisted for over 7 months.CONCLUSION: In addition to testing common driving genes, like EGFR, ALK, ROS1 and BRAF, both TP53, and KRAS should also be considered in advanced or metastatic squamous-cell NSCLC.TP53 and KRAS co-mutations in squamous-cell NSCLC can be a potential factor to assess possible response to PD-1 blockade immunotherapy, but further studies with more cases are needed to confirm the prediction power.
CANIT0002726	31621883	Clinical research	A total of 88 patients with 196 total brain metastases were included	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	88	N/A	Retrospective analysis	Higher-order MRI radiomic features in patients with melanoma brain metastases receiving ICI were associated with a trend toward improved OS. Eighty-eight patients with 196 total brain metastases were identified. Median age was 63.5 years (range, 19¨C91 y). Ninety percent of patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and 35% had elevated lactate dehydrogenase. Sixty-three patients (72%) received ipilimumab, 11 patients (13%) received programmed cell death protein 1 blockade, and 14 patients (16%) received nivolumab plus ipilimumab. Multiple features were associated with increased overall survival (OS), and LoG edge features best explained the variation in outcome (hazard ratio: 0.68, P = 0.001). In multivariate analysis, a similar trend with LoG was seen, but no longer significant with OS. Findings were confirmed in an independent cohort. 	N/A	N/A	N/A	Magnetic resonance images (); 	Higher-order MRI radiomic features	Disease status	 2019 Dec 17	MRI radiomic features are associated with survival in melanoma brain metastases treated with immune checkpoint inhibitors.	 Neuro Oncol	BACKGROUND: Melanoma brain metastases historically portend a dismal prognosis, but recent advances in immune checkpoint inhibitors (ICIs) have been associated with durable responses in some patients. There are no validated imaging biomarkers associated with outcomes in patients with melanoma brain metastases receiving ICIs. We hypothesized that radiomic analysis of magnetic resonance images (MRIs) could identify higher-order features associated with survival.METHODS: Between 2010 and 2019, we retrospectively reviewed patients with melanoma brain metastases who received ICI. After volumes of interest were drawn, several texture and edge descriptors, including first-order, Haralick, Gabor, Sobel, and Laplacian of Gaussian (LoG) features were extracted. Progression was determined using Response Assessment in Neuro-Oncology Brain Metastases. Univariate Cox regression was performed for each radiomic feature with adjustment for multiple comparisons followed by Lasso regression and multivariate analysis.RESULTS: Eighty-eight patients with 196 total brain metastases were identified. Median age was 63.5 years (range, 19-91 y). Ninety percent of patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and 35% had elevated lactate dehydrogenase. Sixty-three patients (72%) received ipilimumab, 11 patients (13%) received programmed cell death protein 1 blockade, and 14 patients (16%) received nivolumab plus ipilimumab. Multiple features were associated with increased overall survival (OS), and LoG edge features best explained the variation in outcome (hazard ratio: 0.68, P = 0.001). In multivariate analysis, a similar trend with LoG was seen, but no longer significant with OS. Findings were confirmed in an independent cohort.CONCLUSION: Higher-order MRI radiomic features in patients with melanoma brain metastases receiving ICI were associated with a trend toward improved OS.
CANIT0002727	31624262	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus sirolimus	Pembrolizumab	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	1	1	Case	In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)G+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFNG+ CD4+ T cells and serum IFNG levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.	Organ rejection and colitis	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD4 (P01730); IFNG (P01579); T-Lymphocyte (NCIT:C12478); 	Numbers of IFNG(+) CD4(+) T-cells	Gene expression signature on/in immune cell	 2019 Oct 17	Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation.	 Nat Commun	Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-¦Ã+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-¦Ã+ CD4+ T cells and serum IFN-¦Ã levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.
CANIT0002728	31624262	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus sirolimus	Pembrolizumab	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); 	1	1	Case	In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)G+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFNG+ CD4+ T cells and serum IFNG levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.	Organ rejection and colitis	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	IFNG (P01579); 	Serum IFNG expression levels	Gene expression signature in serum	 2019 Oct 17	Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation.	 Nat Commun	Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-¦Ã+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-¦Ã+ CD4+ T cells and serum IFN-¦Ã levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.
CANIT0002729	31628220	Clinical research	45 patients	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	45	N/A	Retrospective analysis	In relapsed or refractory Hodgkin lymphoma patients treated with anti-PD-1 mAbs, the first early PET/CT assessment using either Lugano or LYRIC predicted OS and allowed early risk stratification, suggesting that PET/CT might be used to develop risk-adapted strategies	N/A	N/A	N/A	N/A	N/A	N/A	 2020 May	Early (18)F-FDG PET/CT Response Predicts Survival in Relapsed or Refractory Hodgkin Lymphoma Treated with Nivolumab.	 J Nucl Med	Monoclonal antibodies (mAbs) against programmed cell death 1 (PD-1), such as nivolumab and pembrolizumab, are associated with high response rates in patients with relapsed or refractory classic Hodgkin lymphoma (HL). To date, no prognostic factor for overall survival (OS) has been established with these agents in HL. We examined whether the first early response assessment evaluated using 18F-FDG PET/CT may be associated with OS in this setting. Methods: This retrospective study included 45 patients from 34 institutions. In a masked, centralized review, 3 independent radiologists classified PET/CT scans obtained at a median of 2.0 mo (interquartile range, 1.7-3.7 mo) after nivolumab initiation using existing criteria (i.e., 2014 Lugano classification and 2016 LYRIC). Patients were classified according to 4 possible response categories: complete metabolic response (CMR), partial metabolic response (PMR), no metabolic response (NMR), or progressive metabolic disease (PMD). Because the OS of patients with NMR and PMR was similar, they were grouped together. OS was estimated using the Kaplan-Meier method and compared between groups using log-rank testing. Results: Eleven patients (24%) died after a median follow-up of 21.2 mo. The classification was identical between Lugano and LYRIC because all 16 progression events classified as indeterminate response per LYRIC were confirmed on subsequent evaluations. Both Lugano and LYRIC classified patients as CMR in 13 cases (29%), PMD in 16 (36%), NMR in 4 (9%), and PMR in 12 (27%). The 2-y OS probability was significantly different in patients with PMD (0.53; 95% confidence interval [95%CI], 0.32-0.87), NMR or PMR (0.80; 95%CI, 0.63-1.00), and CMR (1.00; 95%CI, 1.00-1.00) in the overall population (P = 0.02, 45 patients), as well as according to a landmark analysis at 3 mo (P = 0.05, 32 patients). Conclusion: In relapsed or refractory HL patients treated with anti-PD-1 mAbs, the first early PET/CT assessment using either Lugano or LYRIC predicted OS and allowed early risk stratification, suggesting that PET/CT might be used to develop risk-adapted strategies.
CANIT0002730	31630986	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	229	N/A	Retrospective, multicentre data analysis	Efficacy and safety results observed in this retrospective analysis were consistent with observations reported in clinical trials and from other centres. Out of 229 patients, data was available for 219 patients (3 patients did not start treatment, while data was unavailable in 7 patients); of the 219 patients, 15.5% were not evaluated for radiological tumour assessment, 1.4% had complete response (CR), 21% partial response (PR), 31% stable disease (SD) and 31.1% progressive disease (PD). Thus, the ORR was 22.4% and DCR was 53.4% in this population. At the time of survival analysis the median PFS was 4.91 months (95% CI, 3.89-6.11) and median OS was 13.21 months (95% CI, 9.89-16.53).	The safety profile was in line with clinical trial data.	N/A	N/A	N/A	N/A	N/A	 2020 Jan-Feb	Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).	 Pulmonology	OBJECTIVE: The main aim of the study was to evaluate the efficacy and safety profile of Nivolumab, an immune-checkpoint-inhibitor antibody, in advanced, previously treated, Non-Small Cell Lung Cancer (NSCLC) patients, in a real world setting.METHODS: We performed a retrospective, multicentre data analysis of patients who were included in the Portuguese Nivolumab Expanded Access Program (EAP). Eligibility criteria included histologically or citologically confirmed NSCLC, stage IIIB and IV, evaluable disease, sufficient organ function and at least one prior line of chemotherapy. The endpoints included Overall Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Safety analysis was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and immune-related Adverse Events (irAEs) were treated according to protocol treatment guidelines. Tumour response was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Data was analysed using SPSS, version 21.0 (IBM Statistics).RESULTS: From June 2015 to December 2016, a total of 229 patients with advanced NSCLC were enrolled at 30 Portuguese centres. Clinical data were collected up to the end of July 2018. The baseline median age was 64 years (range 37-83) and the majority of patients were males (70.3%) and former/current smokers (69.4%). Patients with non-squamous histology predominated (88.1%), and 67.6% of the patients had received 2 or more prior lines of chemotherapy. Out of 229 patients, data was available for 219 patients (3 patients did not start treatment, while data was unavailable in 7 patients); of the 219 patients, 15.5% were not evaluated for radiological tumour assessment, 1.4% had complete response (CR), 21% partial response (PR), 31% stable disease (SD) and 31.1% progressive disease (PD). Thus, the ORR was 22.4% and DCR was 53.4% in this population. At the time of survival analysis the median PFS was 4.91 months (95% CI, 3.89-6.11) and median OS was 13.21 months (95% CI, 9.89-16.53). The safety profile was in line with clinical trial data.CONCLUSIONS: Efficacy and safety results observed in this retrospective analysis were consistent with observations reported in clinical trials and from other centres.
CANIT0002731	31634214	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); MEK (Q02750); 	PD-1 ;  BRAF ;  MEK 	Pembrolizumab plus RAF or MEK inhibitors	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We describe the case of a patient with BRAF-mutant melanoma who received an initial infusion of anti-PD-1 therapy while taking RAF/MEK inhibitors and experienced severe acute kidney injury, an otherwise infrequent side effect of any of these drugs alone. Treatment with corticosteroids rapidly reversed this process, indicating an underlying immune-mediated complication. A deeper understanding of potential adverse effects of combination therapies and their potential mechanisms should be carefully considered in the treatment landscape for melanoma and other cancers.	Severe acute kidney injury	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2020 Apr	Rapid evolution of acute kidney injury after initial infusion of pembrolizumab in a melanoma patient concurrently treated with RAF/MEK inhibitors.	 Melanoma Res	The use of either immune checkpoint blockade or RAF/MEK inhibitors represents standard of care treatment options for metastatic melanoma. Each class of these drugs has distinct response kinetics, adverse effects, and unique clinical challenges. Combination of immune checkpoint blockade and RAF/MEK inhibitors may result in rapid and durable responses, however, the potential adverse effects of such combinations are poorly characterized. Here, we describe the case of a patient with BRAF-mutant melanoma who received an initial infusion of anti-PD-1 therapy while taking RAF/MEK inhibitors and experienced severe acute kidney injury, an otherwise infrequent side effect of any of these drugs alone. Treatment with corticosteroids rapidly reversed this process, indicating an underlying immune-mediated complication. A deeper understanding of potential adverse effects of combination therapies and their potential mechanisms should be carefully considered in the treatment landscape for melanoma and other cancers.
CANIT0002732	31637475	Case report	Anaplastic thyroid cancer	Anaplastic thyroid carcinoma	EFO:1000595	Thyroid	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Following treatment, a marked expansion in CD20+ B cell, CD16+ CD56lo NK cell and CD45RO+ CCR7+ central memory CD4+ T-cell populations was observed in the peripheral blood. Proportions of cells expressing the co-receptors TIGIT, OX40 and CD86 also increased during treatment. A high abundance of bacteria of the order Bacteroidales, specifically from the Bacteroidaceae and Rikenellaceae families, was identified in the faecal microbiota. Moreover, the patient's microbiome was enriched in Clostridiales order members Ruminococcaceae, Veillonellaceae and Lachnospiraceae. A diversity of the gut microbiome was significantly higher following initiation of checkpoint therapy as assessed by the Shannon and Simpson index.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Pembrolizumab for anaplastic thyroid cancer: a case study.	 Cancer Immunol Immunother	Blockade of the PD-1/PD-L1 pathway with targeted monoclonal antibodies has demonstrated encouraging anti-tumour activity in multiple cancer types. We present the case of a patient with BRAF-negative stage IVC anaplastic thyroid cancer (ATC) treated with the anti-PD-1 monoclonal antibody, pembrolizumab, following radiographic progression on chemoradiation. Blood samples were collected prior to and at four time points during treatment with pembrolizumab. Mass cytometry was used to determine expression of relevant biomarkers by peripheral blood mononuclear cells. Faecal samples were collected at baseline and 4 weeks following treatment initiation; taxonomic profiling using 16S ribosomal RNA (rRNA) gene sequencing was performed. Following treatment, a marked expansion in CD20+ B cell, CD16+ CD56lo NK cell and CD45RO+ CCR7+ central memory CD4+ T-cell populations was observed in the peripheral blood. Proportions of cells expressing the co-receptors TIGIT, OX40 and CD86 also increased during treatment. A high abundance of bacteria of the order Bacteroidales, specifically from the Bacteroidaceae and Rikenellaceae families, was identified in the faecal microbiota. Moreover, the patient's microbiome was enriched in Clostridiales order members Ruminococcaceae, Veillonellaceae and Lachnospiraceae. Alpha diversity of the gut microbiome was significantly higher following initiation of checkpoint therapy as assessed by the Shannon and Simpson index. Our results suggest that treatment with pembrolizumab promotes expansion of T-, B- and NK cell populations in the peripheral blood at the time of tumour regression and have the potential to be implemented as predictive biomarkers in the context of checkpoint blockade therapy. Larger studies to confirm these findings are warranted.
CANIT0002733	31638282	Clinical research	Resected stage III or IV melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Nivolumab	Ipilimumab	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	18	10	Phase 3 CheckMate 238 trial	Results were consistent with those from the CheckMate 238 global population, indicating that nivolumab has the potential to be a treatment option for Japanese patients with resected melanoma who are at high risk of recurrence. Both the 12- and 18-month recurrence-free survival rates were 56% for nivolumab and 30% for ipilimumab (hazard ratio, 0.66; 97.56% confidence interval, 0.19-2.24; P = 0.4390).	No new safety signals were reported for Japanese patients.	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Adjuvant therapy with nivolumab versus ipilimumab after complete resection of stage III/IV melanoma: Japanese subgroup analysis from the phase 3 CheckMate 238 study.	 J Dermatol	The multinational phase 3 CheckMate 238 trial compared adjuvant therapy with nivolumab versus ipilimumab among patients with resected stage III or IV melanoma (N = 906). In this Japanese subgroup analysis of CheckMate 238 (n = 28; nivolumab, n = 18; ipilimumab, n = 10), both the 12- and 18-month recurrence-free survival rates were 56% for nivolumab and 30% for ipilimumab (hazard ratio, 0.66; 97.56% confidence interval, 0.19-2.24; P = 0.4390). No new safety signals were reported for Japanese patients. Results were consistent with those from the CheckMate 238 global population, indicating that nivolumab has the potential to be a treatment option for Japanese patients with resected melanoma who are at high risk of recurrence.
CANIT0002734	31642136	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	13	N/A	Retrospective analysis	Patients receiving PD-1 inhibitors may develop oral oral immune-related adverse events (irAEs) characterized by lichenoid lesions, ulcers, or erythema multiforme (EM). Topical and systemic steroids appear to be effective in managing oral lesions although the severity of irAEs may necessitate PD-1 inhibitor therapy dose modification. Oral immune-related adverse events included lichenoid lesions (n = 10), EM (n = 2), and acute graft-versus-host disease reactivation (n = 1), with or without ulcerations (n = 8). Four patients (31%) presented with only oral immune-related adverse events. Oral biopsies showed lichenoid mucositis (n = 4). Management with topical and systemic steroids led to complete symptomatic response in most patients (n = 12). PD-1 inhibitor therapy was temporarily discontinued (n = 3) and discontinued indefinitely (n = 2) due to severe oral immune-related adverse events.	Oral immune-related adverse events	N/A	N/A	N/A	N/A	N/A	 2020 Mar	Oral immune-related adverse events associated with PD-1 inhibitor therapy: A case series.	 Oral Dis	OBJECTIVE: The aim of this study was to characterize clinical and histopathological features, and management outcomes of patients with oral immune-related adverse events (irAEs) secondary to programmed cell death-1 (PD-1) inhibitors.METHODS: This was a case series of cancer patients receiving PD-1 inhibitor therapy who were referred to oral medicine for the development of oral irAEs. Demographic, clinical, and histopathological data were collected from electronic medical records.RESULTS: There were 13 patients (7 males) with a median age of 68 years (range: 39-82) who were treated with nivolumab (n = 7) or pembrolizumab (n = 6). Oral irAEs included lichenoid lesions (n = 10), erythema multiforme (EM) (n = 2), and acute graft-versus-host disease reactivation (n = 1), with or without ulcerations (n = 8). Four patients (31%) presented with only oral irAEs. Oral biopsies showed lichenoid mucositis (n = 4). Management with topical and systemic steroids led to complete symptomatic response in most patients (n = 12). PD-1 inhibitor therapy was temporarily discontinued (n = 3) and discontinued indefinitely (n = 2) due to severe oral irAEs.CONCLUSION: Patients receiving PD-1 inhibitors may develop oral irAEs characterized by lichenoid lesions, ulcers, or EM. Topical and systemic steroids appear to be effective in managing oral lesions although the severity of irAEs may necessitate PD-1 inhibitor therapy dose modification.
CANIT0002735	31645587	Basic research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Plant-produced nivolumab	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	Plant-produced nivolumab binds to human PD1 protein with high affinity and specificity, blocks the PD-1/PD-L1 interaction, and enhances T cell function, comparable to commercial nivolumab. These results confirmed that plant-produced anti-PD1 antibody has the potential to be effective agent for cancer immunotherapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2019 Oct 23	Structural and In Vitro Functional Analyses of Novel Plant-Produced Anti-Human PD1 Antibody.	 Sci Rep	Immunotherapy has emerged as a promising and effective treatment for cancer. The frequently used immunotherapy agents are immune checkpoint inhibitors, such as antibodies specific to PD1, PD-L1, or CTLA-4. However, these drugs are highly expensive, and most people in the world cannot access the treatment. The development of recombinant protein production platforms that are cost-effective, scalable, and safe is needed. Plant platforms are attractive because of their low production cost, speed, scalability, lack of human and animal pathogens, and post-translational modifications that enable them to produce effective monoclonal antibodies. In this study, an anti-PD1 IgG4 monoclonal antibody (mAb) was transiently produced in Nicotiana benthamiana leaves. The plant-produced anti-PD1 mAb was compared to the commercial nivolumab produced in CHO cells. Our results showed that both antibodies have similar protein structures, and the N-glycans on the plant-produced antibody lacks plant-specific structures. The PD1 binding affinity of the plant-produced and commercial nivolumab, determined by two different techniques, that is, enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR), are also comparable. Plant-produced nivolumab binds to human PD1 protein with high affinity and specificity, blocks the PD-1/PD-L1 interaction, and enhances T cell function, comparable to commercial nivolumab. These results confirmed that plant-produced anti-PD1 antibody has the potential to be effective agent for cancer immunotherapy.
CANIT0002736	31648184	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	Disproportionality analysis	Thyroid dysfunction may occur after immune checkpoint inhibitors (ICIs), and severe thyrotoxic crisis may even occur. Raising awareness of ICI-associated thyroid dysfunction can improve the detection and treatment of these diseases. Compared with the full database, the following ICI-associated thyroid dysfunctions were over-reported: hypothyroidism (1125 reports for ICIs vs 12495 for all drugs; Information Component 4.28 (95% CI: 4.18-4.35)), hyperthyroidism (926 vs 7538; 4.66 (95% CI: 4.55-4.74)), thyroiditis (294 vs 1237; 5.40 (95% CI: 5.21-5.54)), thyrotoxic crisis (11 vs 288; 3.55 (95% CI: 2.61-4.20)). Hypothyroidism was over-reported for patients treated with ICI combination therapy versus those treated with ICI monotherapy (ROR 1.3 (95% CI: 1.1-1.7)), and the same was observed for hyperthyroidism (ROR: 1.9 (95% CI: 1.5-2.4)), thyroiditis (ROR: 3.3 (95% CI: 2.3-4.8)), thyrotoxic crisis (ROR: 11.5 (95% CI: 2.4-53.8)). All 11 thyrotoxic crisis cases were malignant melanoma patients, of which seven occurred under ICI combination therapy.	Immune checkpoint inhibitor-associated thyroid dysfunction	N/A	N/A	N/A	N/A	N/A	 2020 Jan	Immune checkpoint inhibitor-associated thyroid dysfunction: a disproportionality analysis using the WHO Adverse Drug Reaction Database, VigiBase.	 Eur J Endocrinol	OBJECTIVE: Our study aimed to identify and characterize thyroid dysfunctions associated with immune checkpoint inhibitors (ICIs).DESIGN: Data were obtained from VigiBase, between January 1, 2011 to March 6, 2019.METHODS: All thyroid drug-adverse events are classified by group queries according to the Medical Dictionary for Regulatory Activities. Information component (IC) and reporting odds ratio (ROR) were considered as measures of disproportionality for the assessment of association between ICIs and thyroid dysfunctions. We used IC to identify meaningful drug-adverse events while using ROR to compare differences in the reporting of drug-adverse events caused by different ICI subgroups. Positive IC values are deemed significant.RESULTS: Compared with the full database, the following ICI-associated thyroid dysfunctions were over-reported: hypothyroidism (1125 reports for ICIs vs 12495 for all drugs; Information Component 4.28 (95% CI: 4.18-4.35)), hyperthyroidism (926 vs 7538; 4.66 (95% CI: 4.55-4.74)), thyroiditis (294 vs 1237; 5.40 (95% CI: 5.21-5.54)), thyrotoxic crisis (11 vs 288; 3.55 (95% CI: 2.61-4.20)). Hypothyroidism was over-reported for patients treated with ICI combination therapy versus those treated with ICI monotherapy (ROR 1.3 (95% CI: 1.1-1.7)), and the same was observed for hyperthyroidism (ROR: 1.9 (95% CI: 1.5-2.4)), thyroiditis (ROR: 3.3 (95% CI: 2.3-4.8)), thyrotoxic crisis (ROR: 11.5 (95% CI: 2.4-53.8)). All 11 thyrotoxic crisis cases were malignant melanoma patients, of which seven occurred under ICI combination therapy.CONCLUSIONS: Thyroid dysfunction may occur after ICI therapies, and severe thyrotoxic crisis may even occur. Raising awareness of ICI-associated thyroid dysfunction can improve the detection and treatment of these diseases.
CANIT0002737	31648585	Clinical research	Advanced malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	21	N/A	Retrospective analysis 	Baseline serum lactate dehydrogenase levels may be considered useful in predicting the prognosis and monitoring the effects of the nivolumab therapy in advanced malignant melanoma.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Dec	Serum 5-S-cysteinyl-dopa levels as a predictive marker for the efficacy of nivolumab in advanced malignant melanoma.	 Int J Biol Markers	PURPOSE: With the recent developments in novel molecular targeted therapy such as immune-checkpoint blockades, serine/threonine-protein kinase B-Raf, and mitogen-activated protein kinase kinase inhibitors, the prognosis of advanced malignant melanoma has been improving. 5-S-cysteinyl-dopa (5-S-CD), a precursor of pheomelanin, has been previously revealed to be a useful biomarker for advanced-stage malignant melanoma, especially in patients with distant metastases. Here, we aimed to assess and compare the utility of serum 5-S-CD and lactate dehydrogenase levels as markers for predicting the effects of nivolumab in advanced malignant melanoma.METHODS: Baseline serum 5-S-CD and lactate dehydrogenase levels in patients with unresectable stage IIIC and IV malignant melanoma treated with nivolumab (n = 21) were analyzed to determine their utility as predictive markers for survival. We also analyzed the prognostic value of these markers among patients with only stage IV malignant melanoma (n = 17).RESULTS: Our analysis showed that patients with baseline serum 5-S-CD levels >25.0 nmol/L had significantly poor prognosis. In contrast, serum lactate dehydrogenase levels at the upper limit of the normal range did not exhibit such changes.CONCLUSIONS: Serum 5-S-CD levels have the potential to be an excellent predictive marker for the efficacy of nivolumab therapy in patients with advanced malignant melanoma.
CANIT0002738	31648585	Clinical research	In patients with advanced MM receiving nivolumab (n =21), baseline serum 5-S-CD levels ranged from 2.4 to 361.8 nmol/L (median; 17.1 nmol/L). 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	21	N/A	Retrospective analysis 	Serum 5-S-CD levels may be considered useful in predicting the prognosis and monitoring the effects of the nivolumab therapy in advanced malignant melanoma.	N/A	N/A	N/A	5-S-Cysteinyl-DOPA (CHEBI:81392 ); 	Serum 5-S-cysteinyl-dopa levels	Metabolite	 2019 Dec	Serum 5-S-cysteinyl-dopa levels as a predictive marker for the efficacy of nivolumab in advanced malignant melanoma.	 Int J Biol Markers	PURPOSE: With the recent developments in novel molecular targeted therapy such as immune-checkpoint blockades, serine/threonine-protein kinase B-Raf, and mitogen-activated protein kinase kinase inhibitors, the prognosis of advanced malignant melanoma has been improving. 5-S-cysteinyl-dopa (5-S-CD), a precursor of pheomelanin, has been previously revealed to be a useful biomarker for advanced-stage malignant melanoma, especially in patients with distant metastases. Here, we aimed to assess and compare the utility of serum 5-S-CD and lactate dehydrogenase levels as markers for predicting the effects of nivolumab in advanced malignant melanoma.METHODS: Baseline serum 5-S-CD and lactate dehydrogenase levels in patients with unresectable stage IIIC and IV malignant melanoma treated with nivolumab (n = 21) were analyzed to determine their utility as predictive markers for survival. We also analyzed the prognostic value of these markers among patients with only stage IV malignant melanoma (n = 17).RESULTS: Our analysis showed that patients with baseline serum 5-S-CD levels >25.0 nmol/L had significantly poor prognosis. In contrast, serum lactate dehydrogenase levels at the upper limit of the normal range did not exhibit such changes.CONCLUSIONS: Serum 5-S-CD levels have the potential to be an excellent predictive marker for the efficacy of nivolumab therapy in patients with advanced malignant melanoma.
CANIT0002739	31652661	Clinical research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	N/A	N/A	N/A	We demonstrate the new T cell signature, named signature-H, that differs from other gene signatures since it shows higher sensitivity and better predictivity in the evaluation of T cell infiltration in healthy tissues as well as 32 cancers. Further, results from signature-H are highly concordant with the immunohistochemistry methods currently used for assessing the prognosis of neuroblastoma, as demonstrated by the Kaplan-Meier curves of patients ranked by tumor T cell infiltration. Moreover, T cell infiltration levels calculated using signature-H correlate with the risk groups determined by the staging of the neuroblastoma. Finally, multiparametric analysis of tumor-infiltrating T cells based on signature-H let us favorably predict the response of melanoma to the anti-PD-1 antibody nivolumab.These findings suggest that signature-H evaluates T cell infiltration levels of tissues and may be used as a prognostic tool in the precision medicine perspective after appropriate clinical validation.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Tumor infiltrate (NCIT:C12546); Immune responses (NCIT:C17930); 	Tumor-infiltrating T-cell based on signature-H	Tumor-infiltrating immune cell	 2019 Oct 22	Identification of 15 T Cell Restricted Genes Evaluates T Cell Infiltration of Human Healthy Tissues and Cancers and Shows Prognostic and Predictive Potential.	 Int J Mol Sci	T cell gene signatures are used to evaluate T cell infiltration of non-lymphoid tissues and cancers in both experimental and clinical settings. However, some genes included in the available T cell signatures are not T cell-restricted. Herein, we propose a new human T cell signature that has been developed via a six-step procedure and comprises 15 T cell restricted genes. We demonstrate the new T cell signature, named signature-H, that differs from other gene signatures since it shows higher sensitivity and better predictivity in the evaluation of T cell infiltration in healthy tissues as well as 32 cancers. Further, results from signature-H are highly concordant with the immunohistochemistry methods currently used for assessing the prognosis of neuroblastoma, as demonstrated by the Kaplan-Meier curves of patients ranked by tumor T cell infiltration. Moreover, T cell infiltration levels calculated using signature-H correlate with the risk groups determined by the staging of the neuroblastoma. Finally, multiparametric analysis of tumor-infiltrating T cells based on signature-H let us favorably predict the response of melanoma to the anti-PD-1 antibody nivolumab. These findings suggest that signature-H evaluates T cell infiltration levels of tissues and may be used as a prognostic tool in the precision medicine perspective after appropriate clinical validation.
CANIT0002740	31653633	Case report	Metastatic cutaneous melanoma	Cutaneous melanoma	EFO:0000389	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Case	We present the case of a 67-year-old man with acute kidney injury (AKI) after the second cycle of combination anti-CTLA-4 and anti-PD-1 antibodies for metastatic cutaneous melanoma. He presented with vomiting and diarrhoea, and AKI secondary to dehydration was treated with aggressive rehydration. After failing to recover biochemically, a renal biopsy was performed, which demonstrated severe acute interstitial nephritis. The culprit medications were held and he was treated with steroids. With immunosuppression, creatinine improved to pretreatment values.	Acute kidney injury	N/A	N/A	N/A	N/A	N/A	 2019 Oct 25	Acute kidney injury from immune checkpoint inhibitor use.	 BMJ Case Rep	Immune checkpoint inhibitors are novel oncological medications, current classes of which include monoclonal antibodies that target inhibitory receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 protein (PD-1) and programmed death-ligand 1. While they are novel in their ability to treat cancer, they also have a unique spectrum of immune-related adverse events. Renal-related immune adverse events, though rare, are an increasingly recognised clinical entity. We present the case of a 67-year-old man with acute kidney injury (AKI) after the second cycle of combination anti-CTLA-4 and anti-PD-1 antibodies for metastatic cutaneous melanoma. He presented with vomiting and diarrhoea, and AKI secondary to dehydration was treated with aggressive rehydration. After failing to recover biochemically, a renal biopsy was performed, which demonstrated severe acute interstitial nephritis. The culprit medications were held and he was treated with steroids. With immunosuppression, creatinine improved to pretreatment values.
CANIT0002741	31661001	Basic research	Colon cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); CXCR4 (P70658); 	PD-1; CXCR4	Nivolumab plus Pep R	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Oct 28	Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1.	 J Exp Clin Cancer Res	BACKGROUND: Inefficient T-cell access to the tumor microenvironment (TME) is among the causes of tumor immune-resistance. Previous evidence demonstrated that targeting CXCR4 improves anti-PD-1/PD-L1 efficacy reshaping TME. To evaluate the role of newly developed CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/US2013/0079292A1) in potentiating anti-PD-1 efficacy two syngeneic murine models, the MC38 colon cancer and the B16 melanoma-human CXCR4-transduced, were employed.METHODS: Mice were subcutaneously injected with MC38 (1 ¡Á 106) or B16-hCXCR4 (5 ¡Á 105). After two weeks, tumors bearing mice were intraperitoneally (ip) treated with murine anti-PD-1 [RMP1-14] (5 mg/kg, twice week for 2 weeks), Pep R (2 mg/kg, 5 days per week for 2 weeks), or both agents. The TME was evaluated through immunohistochemistry and flow-cytometry. In addition, the effects of the human-anti-PD-1 nivolumab and/or Peptide-R54 (Pep R54), were evaluated on human melanoma PES43 cells and xenografts treated.RESULTS: The combined treatment, Pep R plus anti-PD-1, reduced the MC38 Relative Tumor Volume (RTV) by 2.67 fold (p = 0.038) while nor anti-PD-1, neither Pep R significantly impacted on tumor growth. Significant higher number of Granzyme B (GZMB) positive cells was detected in MC38 tumors from mice treated with the combined treatment (p = 0.016) while anti-PD-1 determined a modest but significant increase of tumor-infiltrating GZMB positive cells (p = 0.035). Also, a lower number of FoxP3 positive cells was detected (p = 0.022). In the B16-hCXCR4 tumors, two weeks of combined treatment reduced tumor volume by 2.27 fold while nor anti-PD-1 neither Pep R significantly impacted on tumor growth. A significant higher number of GRZB positive cells was observed in B16-hCXCR4 tumors treated with combined treatment (p = 0,0015) as compared to anti-PD-1 (p = 0.028). The combined treatment reduced CXCR4, CXCL12 and PD-L1 expression in MC38 tumors. In addition, flow cytometry on fresh B16-hCXCR4 tumors showed significantly higher Tregs number following anti-PD-1 partially reversed by the combined treatment Pep R and anti-PD-1. Combined treatment determined an increase of CD8/Tregs and CD8/MDSC ratio. To dissect the effect of anti-PD-1 and CXCR4 targeting on PD-1 expressed by human cancer cells, PES43 human melanoma xenograft model was employed. In vitro human anti-PD-1 nivolumab or pembrolizumab (10 ¦ÌM) reduced PES43 cells growth while nivolumab (10 ¦ÌM) inhibited pERK1/2, P38 MAPK, pAKT and p4EBP. PES43 xenograft mice were treated with Pep R54, a newly developed Pep R derivative (AcHN-Arg-Ala-[DCys-Arg- Nal(2')-His-Pen]- COOH), plus nivolumab. After 3 weeks of combined treatment a significant reduction in tumor growth was shown (p = 0.038). PES43 lung disseminated tumor cells (DTC) were detected in fresh lung tissues as melanoma positive MCSP-APC+ cells. Although not statistically significant, DTC-PES43 cells were reduced in mice lungs treated with combined treatment while nivolumab or Pep R54 did not affect DTC number.CONCLUSION: Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.
CANIT0002742	31661001	Basic research	Colon cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); CXCR4 (P70658); 	PD-1; CXCR4	Nivolumab plus Peptide-R54	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Oct 28	Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1.	 J Exp Clin Cancer Res	BACKGROUND: Inefficient T-cell access to the tumor microenvironment (TME) is among the causes of tumor immune-resistance. Previous evidence demonstrated that targeting CXCR4 improves anti-PD-1/PD-L1 efficacy reshaping TME. To evaluate the role of newly developed CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/US2013/0079292A1) in potentiating anti-PD-1 efficacy two syngeneic murine models, the MC38 colon cancer and the B16 melanoma-human CXCR4-transduced, were employed.METHODS: Mice were subcutaneously injected with MC38 (1 ¡Á 106) or B16-hCXCR4 (5 ¡Á 105). After two weeks, tumors bearing mice were intraperitoneally (ip) treated with murine anti-PD-1 [RMP1-14] (5 mg/kg, twice week for 2 weeks), Pep R (2 mg/kg, 5 days per week for 2 weeks), or both agents. The TME was evaluated through immunohistochemistry and flow-cytometry. In addition, the effects of the human-anti-PD-1 nivolumab and/or Peptide-R54 (Pep R54), were evaluated on human melanoma PES43 cells and xenografts treated.RESULTS: The combined treatment, Pep R plus anti-PD-1, reduced the MC38 Relative Tumor Volume (RTV) by 2.67 fold (p = 0.038) while nor anti-PD-1, neither Pep R significantly impacted on tumor growth. Significant higher number of Granzyme B (GZMB) positive cells was detected in MC38 tumors from mice treated with the combined treatment (p = 0.016) while anti-PD-1 determined a modest but significant increase of tumor-infiltrating GZMB positive cells (p = 0.035). Also, a lower number of FoxP3 positive cells was detected (p = 0.022). In the B16-hCXCR4 tumors, two weeks of combined treatment reduced tumor volume by 2.27 fold while nor anti-PD-1 neither Pep R significantly impacted on tumor growth. A significant higher number of GRZB positive cells was observed in B16-hCXCR4 tumors treated with combined treatment (p = 0,0015) as compared to anti-PD-1 (p = 0.028). The combined treatment reduced CXCR4, CXCL12 and PD-L1 expression in MC38 tumors. In addition, flow cytometry on fresh B16-hCXCR4 tumors showed significantly higher Tregs number following anti-PD-1 partially reversed by the combined treatment Pep R and anti-PD-1. Combined treatment determined an increase of CD8/Tregs and CD8/MDSC ratio. To dissect the effect of anti-PD-1 and CXCR4 targeting on PD-1 expressed by human cancer cells, PES43 human melanoma xenograft model was employed. In vitro human anti-PD-1 nivolumab or pembrolizumab (10 ¦ÌM) reduced PES43 cells growth while nivolumab (10 ¦ÌM) inhibited pERK1/2, P38 MAPK, pAKT and p4EBP. PES43 xenograft mice were treated with Pep R54, a newly developed Pep R derivative (AcHN-Arg-Ala-[DCys-Arg- Nal(2')-His-Pen]- COOH), plus nivolumab. After 3 weeks of combined treatment a significant reduction in tumor growth was shown (p = 0.038). PES43 lung disseminated tumor cells (DTC) were detected in fresh lung tissues as melanoma positive MCSP-APC+ cells. Although not statistically significant, DTC-PES43 cells were reduced in mice lungs treated with combined treatment while nivolumab or Pep R54 did not affect DTC number.CONCLUSION: Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.
CANIT0002743	31661001	Basic research	Colon cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	Placebo	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Oct 28	Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1.	 J Exp Clin Cancer Res	BACKGROUND: Inefficient T-cell access to the tumor microenvironment (TME) is among the causes of tumor immune-resistance. Previous evidence demonstrated that targeting CXCR4 improves anti-PD-1/PD-L1 efficacy reshaping TME. To evaluate the role of newly developed CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/US2013/0079292A1) in potentiating anti-PD-1 efficacy two syngeneic murine models, the MC38 colon cancer and the B16 melanoma-human CXCR4-transduced, were employed.METHODS: Mice were subcutaneously injected with MC38 (1 ¡Á 106) or B16-hCXCR4 (5 ¡Á 105). After two weeks, tumors bearing mice were intraperitoneally (ip) treated with murine anti-PD-1 [RMP1-14] (5 mg/kg, twice week for 2 weeks), Pep R (2 mg/kg, 5 days per week for 2 weeks), or both agents. The TME was evaluated through immunohistochemistry and flow-cytometry. In addition, the effects of the human-anti-PD-1 nivolumab and/or Peptide-R54 (Pep R54), were evaluated on human melanoma PES43 cells and xenografts treated.RESULTS: The combined treatment, Pep R plus anti-PD-1, reduced the MC38 Relative Tumor Volume (RTV) by 2.67 fold (p = 0.038) while nor anti-PD-1, neither Pep R significantly impacted on tumor growth. Significant higher number of Granzyme B (GZMB) positive cells was detected in MC38 tumors from mice treated with the combined treatment (p = 0.016) while anti-PD-1 determined a modest but significant increase of tumor-infiltrating GZMB positive cells (p = 0.035). Also, a lower number of FoxP3 positive cells was detected (p = 0.022). In the B16-hCXCR4 tumors, two weeks of combined treatment reduced tumor volume by 2.27 fold while nor anti-PD-1 neither Pep R significantly impacted on tumor growth. A significant higher number of GRZB positive cells was observed in B16-hCXCR4 tumors treated with combined treatment (p = 0,0015) as compared to anti-PD-1 (p = 0.028). The combined treatment reduced CXCR4, CXCL12 and PD-L1 expression in MC38 tumors. In addition, flow cytometry on fresh B16-hCXCR4 tumors showed significantly higher Tregs number following anti-PD-1 partially reversed by the combined treatment Pep R and anti-PD-1. Combined treatment determined an increase of CD8/Tregs and CD8/MDSC ratio. To dissect the effect of anti-PD-1 and CXCR4 targeting on PD-1 expressed by human cancer cells, PES43 human melanoma xenograft model was employed. In vitro human anti-PD-1 nivolumab or pembrolizumab (10 ¦ÌM) reduced PES43 cells growth while nivolumab (10 ¦ÌM) inhibited pERK1/2, P38 MAPK, pAKT and p4EBP. PES43 xenograft mice were treated with Pep R54, a newly developed Pep R derivative (AcHN-Arg-Ala-[DCys-Arg- Nal(2')-His-Pen]- COOH), plus nivolumab. After 3 weeks of combined treatment a significant reduction in tumor growth was shown (p = 0.038). PES43 lung disseminated tumor cells (DTC) were detected in fresh lung tissues as melanoma positive MCSP-APC+ cells. Although not statistically significant, DTC-PES43 cells were reduced in mice lungs treated with combined treatment while nivolumab or Pep R54 did not affect DTC number.CONCLUSION: Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.
CANIT0002744	31661001	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); CXCR4 (P70658); 	PD-1; CXCR4	Nivolumab plus Pep R	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Oct 28	Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1.	 J Exp Clin Cancer Res	BACKGROUND: Inefficient T-cell access to the tumor microenvironment (TME) is among the causes of tumor immune-resistance. Previous evidence demonstrated that targeting CXCR4 improves anti-PD-1/PD-L1 efficacy reshaping TME. To evaluate the role of newly developed CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/US2013/0079292A1) in potentiating anti-PD-1 efficacy two syngeneic murine models, the MC38 colon cancer and the B16 melanoma-human CXCR4-transduced, were employed.METHODS: Mice were subcutaneously injected with MC38 (1 ¡Á 106) or B16-hCXCR4 (5 ¡Á 105). After two weeks, tumors bearing mice were intraperitoneally (ip) treated with murine anti-PD-1 [RMP1-14] (5 mg/kg, twice week for 2 weeks), Pep R (2 mg/kg, 5 days per week for 2 weeks), or both agents. The TME was evaluated through immunohistochemistry and flow-cytometry. In addition, the effects of the human-anti-PD-1 nivolumab and/or Peptide-R54 (Pep R54), were evaluated on human melanoma PES43 cells and xenografts treated.RESULTS: The combined treatment, Pep R plus anti-PD-1, reduced the MC38 Relative Tumor Volume (RTV) by 2.67 fold (p = 0.038) while nor anti-PD-1, neither Pep R significantly impacted on tumor growth. Significant higher number of Granzyme B (GZMB) positive cells was detected in MC38 tumors from mice treated with the combined treatment (p = 0.016) while anti-PD-1 determined a modest but significant increase of tumor-infiltrating GZMB positive cells (p = 0.035). Also, a lower number of FoxP3 positive cells was detected (p = 0.022). In the B16-hCXCR4 tumors, two weeks of combined treatment reduced tumor volume by 2.27 fold while nor anti-PD-1 neither Pep R significantly impacted on tumor growth. A significant higher number of GRZB positive cells was observed in B16-hCXCR4 tumors treated with combined treatment (p = 0,0015) as compared to anti-PD-1 (p = 0.028). The combined treatment reduced CXCR4, CXCL12 and PD-L1 expression in MC38 tumors. In addition, flow cytometry on fresh B16-hCXCR4 tumors showed significantly higher Tregs number following anti-PD-1 partially reversed by the combined treatment Pep R and anti-PD-1. Combined treatment determined an increase of CD8/Tregs and CD8/MDSC ratio. To dissect the effect of anti-PD-1 and CXCR4 targeting on PD-1 expressed by human cancer cells, PES43 human melanoma xenograft model was employed. In vitro human anti-PD-1 nivolumab or pembrolizumab (10 ¦ÌM) reduced PES43 cells growth while nivolumab (10 ¦ÌM) inhibited pERK1/2, P38 MAPK, pAKT and p4EBP. PES43 xenograft mice were treated with Pep R54, a newly developed Pep R derivative (AcHN-Arg-Ala-[DCys-Arg- Nal(2')-His-Pen]- COOH), plus nivolumab. After 3 weeks of combined treatment a significant reduction in tumor growth was shown (p = 0.038). PES43 lung disseminated tumor cells (DTC) were detected in fresh lung tissues as melanoma positive MCSP-APC+ cells. Although not statistically significant, DTC-PES43 cells were reduced in mice lungs treated with combined treatment while nivolumab or Pep R54 did not affect DTC number.CONCLUSION: Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.
CANIT0002745	31661001	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); CXCR4 (P70658); 	PD-1; CXCR4	Nivolumab plus Peptide-R54	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Oct 28	Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1.	 J Exp Clin Cancer Res	BACKGROUND: Inefficient T-cell access to the tumor microenvironment (TME) is among the causes of tumor immune-resistance. Previous evidence demonstrated that targeting CXCR4 improves anti-PD-1/PD-L1 efficacy reshaping TME. To evaluate the role of newly developed CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/US2013/0079292A1) in potentiating anti-PD-1 efficacy two syngeneic murine models, the MC38 colon cancer and the B16 melanoma-human CXCR4-transduced, were employed.METHODS: Mice were subcutaneously injected with MC38 (1 ¡Á 106) or B16-hCXCR4 (5 ¡Á 105). After two weeks, tumors bearing mice were intraperitoneally (ip) treated with murine anti-PD-1 [RMP1-14] (5 mg/kg, twice week for 2 weeks), Pep R (2 mg/kg, 5 days per week for 2 weeks), or both agents. The TME was evaluated through immunohistochemistry and flow-cytometry. In addition, the effects of the human-anti-PD-1 nivolumab and/or Peptide-R54 (Pep R54), were evaluated on human melanoma PES43 cells and xenografts treated.RESULTS: The combined treatment, Pep R plus anti-PD-1, reduced the MC38 Relative Tumor Volume (RTV) by 2.67 fold (p = 0.038) while nor anti-PD-1, neither Pep R significantly impacted on tumor growth. Significant higher number of Granzyme B (GZMB) positive cells was detected in MC38 tumors from mice treated with the combined treatment (p = 0.016) while anti-PD-1 determined a modest but significant increase of tumor-infiltrating GZMB positive cells (p = 0.035). Also, a lower number of FoxP3 positive cells was detected (p = 0.022). In the B16-hCXCR4 tumors, two weeks of combined treatment reduced tumor volume by 2.27 fold while nor anti-PD-1 neither Pep R significantly impacted on tumor growth. A significant higher number of GRZB positive cells was observed in B16-hCXCR4 tumors treated with combined treatment (p = 0,0015) as compared to anti-PD-1 (p = 0.028). The combined treatment reduced CXCR4, CXCL12 and PD-L1 expression in MC38 tumors. In addition, flow cytometry on fresh B16-hCXCR4 tumors showed significantly higher Tregs number following anti-PD-1 partially reversed by the combined treatment Pep R and anti-PD-1. Combined treatment determined an increase of CD8/Tregs and CD8/MDSC ratio. To dissect the effect of anti-PD-1 and CXCR4 targeting on PD-1 expressed by human cancer cells, PES43 human melanoma xenograft model was employed. In vitro human anti-PD-1 nivolumab or pembrolizumab (10 ¦ÌM) reduced PES43 cells growth while nivolumab (10 ¦ÌM) inhibited pERK1/2, P38 MAPK, pAKT and p4EBP. PES43 xenograft mice were treated with Pep R54, a newly developed Pep R derivative (AcHN-Arg-Ala-[DCys-Arg- Nal(2')-His-Pen]- COOH), plus nivolumab. After 3 weeks of combined treatment a significant reduction in tumor growth was shown (p = 0.038). PES43 lung disseminated tumor cells (DTC) were detected in fresh lung tissues as melanoma positive MCSP-APC+ cells. Although not statistically significant, DTC-PES43 cells were reduced in mice lungs treated with combined treatment while nivolumab or Pep R54 did not affect DTC number.CONCLUSION: Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.
CANIT0002746	31661001	Basic research	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	Placebo	Immune checkpoint therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Oct 28	Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD-1.	 J Exp Clin Cancer Res	BACKGROUND: Inefficient T-cell access to the tumor microenvironment (TME) is among the causes of tumor immune-resistance. Previous evidence demonstrated that targeting CXCR4 improves anti-PD-1/PD-L1 efficacy reshaping TME. To evaluate the role of newly developed CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/US2013/0079292A1) in potentiating anti-PD-1 efficacy two syngeneic murine models, the MC38 colon cancer and the B16 melanoma-human CXCR4-transduced, were employed.METHODS: Mice were subcutaneously injected with MC38 (1 ¡Á 106) or B16-hCXCR4 (5 ¡Á 105). After two weeks, tumors bearing mice were intraperitoneally (ip) treated with murine anti-PD-1 [RMP1-14] (5 mg/kg, twice week for 2 weeks), Pep R (2 mg/kg, 5 days per week for 2 weeks), or both agents. The TME was evaluated through immunohistochemistry and flow-cytometry. In addition, the effects of the human-anti-PD-1 nivolumab and/or Peptide-R54 (Pep R54), were evaluated on human melanoma PES43 cells and xenografts treated.RESULTS: The combined treatment, Pep R plus anti-PD-1, reduced the MC38 Relative Tumor Volume (RTV) by 2.67 fold (p = 0.038) while nor anti-PD-1, neither Pep R significantly impacted on tumor growth. Significant higher number of Granzyme B (GZMB) positive cells was detected in MC38 tumors from mice treated with the combined treatment (p = 0.016) while anti-PD-1 determined a modest but significant increase of tumor-infiltrating GZMB positive cells (p = 0.035). Also, a lower number of FoxP3 positive cells was detected (p = 0.022). In the B16-hCXCR4 tumors, two weeks of combined treatment reduced tumor volume by 2.27 fold while nor anti-PD-1 neither Pep R significantly impacted on tumor growth. A significant higher number of GRZB positive cells was observed in B16-hCXCR4 tumors treated with combined treatment (p = 0,0015) as compared to anti-PD-1 (p = 0.028). The combined treatment reduced CXCR4, CXCL12 and PD-L1 expression in MC38 tumors. In addition, flow cytometry on fresh B16-hCXCR4 tumors showed significantly higher Tregs number following anti-PD-1 partially reversed by the combined treatment Pep R and anti-PD-1. Combined treatment determined an increase of CD8/Tregs and CD8/MDSC ratio. To dissect the effect of anti-PD-1 and CXCR4 targeting on PD-1 expressed by human cancer cells, PES43 human melanoma xenograft model was employed. In vitro human anti-PD-1 nivolumab or pembrolizumab (10 ¦ÌM) reduced PES43 cells growth while nivolumab (10 ¦ÌM) inhibited pERK1/2, P38 MAPK, pAKT and p4EBP. PES43 xenograft mice were treated with Pep R54, a newly developed Pep R derivative (AcHN-Arg-Ala-[DCys-Arg- Nal(2')-His-Pen]- COOH), plus nivolumab. After 3 weeks of combined treatment a significant reduction in tumor growth was shown (p = 0.038). PES43 lung disseminated tumor cells (DTC) were detected in fresh lung tissues as melanoma positive MCSP-APC+ cells. Although not statistically significant, DTC-PES43 cells were reduced in mice lungs treated with combined treatment while nivolumab or Pep R54 did not affect DTC number.CONCLUSION: Combined treatment with the new developed CXCR4 antagonist, Pep R, plus anti-PD-1, reduced tumor-growth in two syngeneic murine models, anti-PD-1 sensitive and resistant, potentiating Granzyme and reducing Foxp3 cells infiltration. In addition, the human specific CXCR4 antagonist, Pep R54, cooperated with nivolumab in inhibiting the growth of the PD-1 expressing human PES43 melanoma xenograft. This evidence sheds light on PD-1 targeting mechanisms and paves the way for CXCR4/PD-1 targeting combination therapy.
CANIT0002747	31666667	Clinical research	Primary chordoma	Chordoma	Orphanet:178	Nervous system	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	N/A	The more sensitive antibody, E1L3N (ROC = 0.896, p = 0.001), was associated with greater tumour diameters (p = 0.014) and detected both tumour cells and infiltrating lymphocytes in 54% of patients, but only 1-15% of their cells. Organoids generated from PD-L1-positive patients contained both tumour cells and PD-1/CD8-positive lymphocytes and responded to nivolumab treatment with marked dose-dependent diameter reductions of up to 50% and increased cell death in both PD-L1-positive and negative organoids. Patient-derived organoids may be valuable to predict individual responses to immunotherapy even in patients with low or no immunohistochemical PD-L1 expression.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	PD1(+)CD8(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Nov	Patient-derived organoids as a potential model to predict response to PD-1/PD-L1 checkpoint inhibitors.	 Br J Cancer	Selection of cancer patients for treatment with immune checkpoint inhibitors remains a challenge due to tumour heterogeneity and variable biomarker detection. PD-L1 expression in 24 surgical chordoma specimen was determined immunohistochemically with antibodies 28-8 and E1L3N. The ability of patient-derived organoids to detect treatment effects of nivolumab was explored by quantitative and qualitative immunofluorescence and FACS analysis. The more sensitive antibody, E1L3N (ROC = 0.896, p = 0.001), was associated with greater tumour diameters (p = 0.014) and detected both tumour cells and infiltrating lymphocytes in 54% of patients, but only 1-15% of their cells. Organoids generated from PD-L1-positive patients contained both tumour cells and PD-1/CD8-positive lymphocytes and responded to nivolumab treatment with marked dose-dependent diameter reductions of up to 50% and increased cell death in both PD-L1-positive and negative organoids. Patient-derived organoids may be valuable to predict individual responses to immunotherapy even in patients with low or no immunohistochemical PD-L1 expression.
CANIT0002748	31666667	Clinical research	Primary chordoma	Chordoma	Orphanet:178	Nervous system	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	24	N/A	N/A	The more sensitive antibody, E1L3N (ROC = 0.896, p = 0.001), was associated with greater tumour diameters (p = 0.014) and detected both tumour cells and infiltrating lymphocytes in 54% of patients, but only 1-15% of their cells. Organoids generated from PD-L1-positive patients contained both tumour cells and PD-1/CD8-positive lymphocytes and responded to nivolumab treatment with marked dose-dependent diameter reductions of up to 50% and increased cell death in both PD-L1-positive and negative organoids. Patient-derived organoids may be valuable to predict individual responses to immunotherapy even in patients with low or no immunohistochemical PD-L1 expression.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Nov	Patient-derived organoids as a potential model to predict response to PD-1/PD-L1 checkpoint inhibitors.	 Br J Cancer	Selection of cancer patients for treatment with immune checkpoint inhibitors remains a challenge due to tumour heterogeneity and variable biomarker detection. PD-L1 expression in 24 surgical chordoma specimen was determined immunohistochemically with antibodies 28-8 and E1L3N. The ability of patient-derived organoids to detect treatment effects of nivolumab was explored by quantitative and qualitative immunofluorescence and FACS analysis. The more sensitive antibody, E1L3N (ROC = 0.896, p = 0.001), was associated with greater tumour diameters (p = 0.014) and detected both tumour cells and infiltrating lymphocytes in 54% of patients, but only 1-15% of their cells. Organoids generated from PD-L1-positive patients contained both tumour cells and PD-1/CD8-positive lymphocytes and responded to nivolumab treatment with marked dose-dependent diameter reductions of up to 50% and increased cell death in both PD-L1-positive and negative organoids. Patient-derived organoids may be valuable to predict individual responses to immunotherapy even in patients with low or no immunohistochemical PD-L1 expression.
CANIT0002749	31670077	Clinical research	28 phase III RCTs involving 14,376 patients	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	Dabrafenib plus trametinib	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	14,376	14,376	Meta-analysis	For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec	A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma.	 Eur J Cancer	BACKGROUND: Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety.METHODS: A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments.RESULTS: The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57).CONCLUSIONS: Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.
CANIT0002750	31670077	Clinical research	28 phase III RCTs involving 14,376 patients	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); BRAF (P15056); 	CTLA-4; BRAF	Tremelimumab	Dabrafenib plus trametinib	Immune checkpoint therapy	Tremelimumab (DB11771); 	14,376	14,376	Meta-analysis	For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec	A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma.	 Eur J Cancer	BACKGROUND: Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety.METHODS: A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments.RESULTS: The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57).CONCLUSIONS: Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.
CANIT0002751	31670077	Clinical research	28 phase III RCTs involving 14,376 patients	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Dabrafenib plus trametinib	Immune checkpoint therapy	Pembrolizumab (DB09037); dacarbazine (DB00851); trametinib (DB08911); 	14,376	14,376	Meta-analysis	For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec	A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma.	 Eur J Cancer	BACKGROUND: Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety.METHODS: A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments.RESULTS: The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57).CONCLUSIONS: Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.
CANIT0002752	31674068	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We herein report a patient with non-small-cell lung cancer (NSCLC) treated with pembrolizumab who developed systemic bullous pemphigoid (BP) during the therapy.	Bullous pemphigoid	N/A	N/A	N/A	N/A	N/A	 2020 Jan	Bullous pemphigoid induced by pembrolizumab in a patient with non-small-cell lung cancer who achieved durable complete response despite treatment cessation and long-term corticosteroid administration: A case report.	 J Dermatol	Unable to provide
CANIT0002753	31677253	Clinical research	Advanced BRAF V600 mutant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	BRAF or MEK inhibition	Immune checkpoint therapy	Ipilimumab (DB06186); 	108	297	Real-world retrospective analysis	Patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2019 Dec	Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.	 Cancer Med	BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi.METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival.RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses.CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.
CANIT0002754	31677253	Clinical research	Advanced BRAF V600 mutant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	BRAF or MEK inhibition	Immune checkpoint therapy	Ipilimumab (DB06186); 	108	297	Real-world retrospective analysis	Patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Dec	Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.	 Cancer Med	BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi.METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival.RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses.CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.
CANIT0002755	31677253	Clinical research	Advanced BRAF V600 mutant melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	BRAF or MEK inhibition	Immune checkpoint therapy	Ipilimumab (DB06186); 	108	297	Real-world retrospective analysis	Patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Dec	Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.	 Cancer Med	BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi.METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival.RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses.CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.
CANIT0002756	31677253	Clinical research	Advanced BRAF V600 mutant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	BRAF or MEK inhibition	Immune checkpoint therapy	Nivolumab (DB09035); 	171	297	Real-world retrospective analysis	Patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2019 Dec	Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.	 Cancer Med	BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi.METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival.RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses.CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.
CANIT0002757	31677253	Clinical research	Advanced BRAF V600 mutant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	BRAF or MEK inhibition	Immune checkpoint therapy	Nivolumab (DB09035); 	171	297	Real-world retrospective analysis	Patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Dec	Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.	 Cancer Med	BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi.METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival.RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses.CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.
CANIT0002758	31677253	Clinical research	Advanced BRAF V600 mutant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	BRAF or MEK inhibition	Immune checkpoint therapy	Nivolumab (DB09035); 	171	297	Real-world retrospective analysis	Patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Dec	Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.	 Cancer Med	BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi.METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival.RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses.CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.
CANIT0002759	31677253	Clinical research	Advanced BRAF V600 mutant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	BRAF or MEK inhibition	Immune checkpoint therapy	Pembrolizumab (DB09037); 	93	297	Real-world retrospective analysis	Patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2019 Dec	Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.	 Cancer Med	BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi.METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival.RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses.CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.
CANIT0002760	31677253	Clinical research	Advanced BRAF V600 mutant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	BRAF or MEK inhibition	Immune checkpoint therapy	Pembrolizumab (DB09037); 	93	297	Real-world retrospective analysis	Patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Dec	Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.	 Cancer Med	BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi.METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival.RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses.CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.
CANIT0002761	31677253	Clinical research	Advanced BRAF V600 mutant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	BRAF or MEK inhibition	Immune checkpoint therapy	Pembrolizumab (DB09037); 	93	297	Real-world retrospective analysis	Patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Dec	Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab.	 Cancer Med	BACKGROUND: The optimal treatment sequence for patients with advanced BRAF V600 mutant melanoma is unknown. BRAF/MEK inhibition (BRAF/MEKi), single agent anti-PD-1 (aPD-1) antibodies and combination immune checkpoint inhibition with nivolumab and ipilimumab (niv/ipi) are all approved; however, they have not been prospectively compared. Therefore, we sought to compare overall survival of patients with advanced BRAF mutant melanoma treated with either front-line BRAF/MEKi, aPD-1, or niv/ipi.METHODS: Patients with advanced BRAF mutant melanoma who had received BRAF/MEKi, niv/ipi, or aPD-1 in the front-line setting were identified from a nationwide database comprising de-identified patient-level structured and unstructured data derived from electronic health records. Survival was compared using Kaplan-Meier curves and log-rank analysis. Univariate and multivariate Cox regression models were used to measure the effect of front-line treatment, age (>64 or not), LDH (elevated or not), and Eastern Cooperative Oncology Group (ECOG) performance status (>1 or not) on survival.RESULTS: Five hundred and sixty seven patients with advanced disease and treated with front-line aPD-1 (n = 162), BRAF/MEKi (n = 297) or niv/ipi (n = 108) were identified. With a median follow-up of 22.4 months, median overall survival (OS) for patients treated with front-line niv/ipi was not reached (NR) while median OS for patients treated with aPD-1 or BRAF/MEKi was 39.5 months and 13.2 months, respectively. Front-line treatment with PD-1 and niv/ipi were associated with statistically longer survival than BRAF/MEKi in multivariate analyses.CONCLUSIONS: In our real-world retrospective analysis, patients with advanced BRAF mutant melanoma treated with front-line niv/ipi or aPD-1 had longer survival compared to those treated with front-line BRAF/MEKi.
CANIT0002762	31679185	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	83	N/A	Retrospective analysis	Several baseline clinical factors were associated with survival, including Eastern Cooperative Oncology Group performance status (ECOG PS) , PD-L1 expression, and treatment line.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2019 Dec	Comparisons between tumor burden and other prognostic factors that influence survival of patients with non-small cell lung cancer treated with immune checkpoint inhibitors.	 Thorac Cancer	BACKGROUND: The use of baseline tumor burden (TB) as a prognostic factor for non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) and associations between TB and other prognostic biomarkers remain unclear. In this study, we investigated the association between TB and survival in NSCLC patients treated with ICIs in comparison with other biomarkers.METHODS: We retrospectively evaluated 83 NSCLC patients with ICIs administered between February 2016 and December 2018. TB was measured as the sum of the unidimensional diameters of up to five target lesions.RESULTS: The median observation period was 14.2 months. A total of 42 patients died during the follow-up. Univariate Cox regression analysis showed that baseline TB was associated with OS. Cox regression analysis adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) alone or with addition of programmed cell death ligand 1 expression and treatment line showed that TB was a prognostic factor for OS. Using time-dependent receiver operating characteristic curve analysis, the optimal TB cutoff for predicting OS was 12 cm, and patients were divided into a high TB group (n = 21) and a low TB group (n = 62). The low TB group achieved significantly longer OS than the high TB group (median OS: 18.5 months, [95% CI = 11.7-not reached] vs. 2.3 months [95% CI = 1.3-2.9], P < 0.001).CONCLUSION: TB is a useful, clinically measurable prognostic factor of survival in NSCLC patients treated with ICIs.
CANIT0002763	31679185	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	83	N/A	Retrospective analysis	Several baseline clinical factors were associated with survival, including ECOG PS, PD-L1 expression, and treatment line.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance Status	Disease status	 2019 Dec	Comparisons between tumor burden and other prognostic factors that influence survival of patients with non-small cell lung cancer treated with immune checkpoint inhibitors.	 Thorac Cancer	BACKGROUND: The use of baseline tumor burden (TB) as a prognostic factor for non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) and associations between TB and other prognostic biomarkers remain unclear. In this study, we investigated the association between TB and survival in NSCLC patients treated with ICIs in comparison with other biomarkers.METHODS: We retrospectively evaluated 83 NSCLC patients with ICIs administered between February 2016 and December 2018. TB was measured as the sum of the unidimensional diameters of up to five target lesions.RESULTS: The median observation period was 14.2 months. A total of 42 patients died during the follow-up. Univariate Cox regression analysis showed that baseline TB was associated with OS. Cox regression analysis adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) alone or with addition of programmed cell death ligand 1 expression and treatment line showed that TB was a prognostic factor for OS. Using time-dependent receiver operating characteristic curve analysis, the optimal TB cutoff for predicting OS was 12 cm, and patients were divided into a high TB group (n = 21) and a low TB group (n = 62). The low TB group achieved significantly longer OS than the high TB group (median OS: 18.5 months, [95% CI = 11.7-not reached] vs. 2.3 months [95% CI = 1.3-2.9], P < 0.001).CONCLUSION: TB is a useful, clinically measurable prognostic factor of survival in NSCLC patients treated with ICIs.
CANIT0002764	31679185	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	83	N/A	Retrospective analysis	Several baseline clinical factors were associated with survival, including ECOG PS, PD-L1 expression, and treatment line.	N/A	N/A	N/A	Therapy line (); 	Therapy line	Exposure factors/status	 2019 Dec	Comparisons between tumor burden and other prognostic factors that influence survival of patients with non-small cell lung cancer treated with immune checkpoint inhibitors.	 Thorac Cancer	BACKGROUND: The use of baseline tumor burden (TB) as a prognostic factor for non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) and associations between TB and other prognostic biomarkers remain unclear. In this study, we investigated the association between TB and survival in NSCLC patients treated with ICIs in comparison with other biomarkers.METHODS: We retrospectively evaluated 83 NSCLC patients with ICIs administered between February 2016 and December 2018. TB was measured as the sum of the unidimensional diameters of up to five target lesions.RESULTS: The median observation period was 14.2 months. A total of 42 patients died during the follow-up. Univariate Cox regression analysis showed that baseline TB was associated with OS. Cox regression analysis adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) alone or with addition of programmed cell death ligand 1 expression and treatment line showed that TB was a prognostic factor for OS. Using time-dependent receiver operating characteristic curve analysis, the optimal TB cutoff for predicting OS was 12 cm, and patients were divided into a high TB group (n = 21) and a low TB group (n = 62). The low TB group achieved significantly longer OS than the high TB group (median OS: 18.5 months, [95% CI = 11.7-not reached] vs. 2.3 months [95% CI = 1.3-2.9], P < 0.001).CONCLUSION: TB is a useful, clinically measurable prognostic factor of survival in NSCLC patients treated with ICIs.
CANIT0002765	31679185	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	83	N/A	Retrospective analysis	Baseline tumor burden (TB)  is a useful, clinically measurable prognostic factor of survival in NSCLC patients treated with immune checkpoint inhibitors (ICIs). Univariate Cox regression analysis showed that baseline TB was associated with OS. Cox regression analysis adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) alone or with addition of programmed cell death ligand 1 expression and treatment line showed that TB was a prognostic factor for OS. Using time-dependent receiver operating characteristic curve analysis, the optimal TB cutoff for predicting OS was 12 cm, and patients were divided into a high TB group (n = 21) and a low TB group (n = 62). The low TB group achieved significantly longer OS than the high TB group (median OS: 18.5 months, [95% CI = 11.7-not reached] vs. 2.3 months [95% CI = 1.3-2.9], P < 0.001).	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	Tumor burden	Disease status	 2019 Dec	Comparisons between tumor burden and other prognostic factors that influence survival of patients with non-small cell lung cancer treated with immune checkpoint inhibitors.	 Thorac Cancer	BACKGROUND: The use of baseline tumor burden (TB) as a prognostic factor for non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) and associations between TB and other prognostic biomarkers remain unclear. In this study, we investigated the association between TB and survival in NSCLC patients treated with ICIs in comparison with other biomarkers.METHODS: We retrospectively evaluated 83 NSCLC patients with ICIs administered between February 2016 and December 2018. TB was measured as the sum of the unidimensional diameters of up to five target lesions.RESULTS: The median observation period was 14.2 months. A total of 42 patients died during the follow-up. Univariate Cox regression analysis showed that baseline TB was associated with OS. Cox regression analysis adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) alone or with addition of programmed cell death ligand 1 expression and treatment line showed that TB was a prognostic factor for OS. Using time-dependent receiver operating characteristic curve analysis, the optimal TB cutoff for predicting OS was 12 cm, and patients were divided into a high TB group (n = 21) and a low TB group (n = 62). The low TB group achieved significantly longer OS than the high TB group (median OS: 18.5 months, [95% CI = 11.7-not reached] vs. 2.3 months [95% CI = 1.3-2.9], P < 0.001).CONCLUSION: TB is a useful, clinically measurable prognostic factor of survival in NSCLC patients treated with ICIs.
CANIT0002766	31682550	Clinical research	233 enrolled patients, 27 tumor types	Adrenocortical carcinoma	MONDO:0008734	Adrenal gland	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002767	31682550	Clinical research	233 enrolled patients, 27 tumor types	Anal cancer	EFO:1000081	Anus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002768	31682550	Clinical research	233 enrolled patients, 27 tumor types	Brain cancer	MONDO:0001657	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	13	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002769	31682550	Clinical research	233 enrolled patients, 27 tumor types	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002770	31682550	Clinical research	233 enrolled patients, 27 tumor types	Cervical carcinoma	EFO:0001416	Cervix	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002771	31682550	Clinical research	233 enrolled patients, 27 tumor types	Cholangiocarcinoma	EFO:0005221	Bilie duct	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	22	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002772	31682550	Clinical research	233 enrolled patients, 27 tumor types	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	19	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002773	31682550	Clinical research	233 enrolled patients, 27 tumor types	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	49	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002774	31682550	Clinical research	233 enrolled patients, 27 tumor types	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002775	31682550	Clinical research	233 enrolled patients, 27 tumor types	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002776	31682550	Clinical research	233 enrolled patients, 27 tumor types	Mesothelioma	EFO:0000588	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002777	31682550	Clinical research	233 enrolled patients, 27 tumor types	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002778	31682550	Clinical research	233 enrolled patients, 27 tumor types	Neuroendocrine carcinoma	MONDO:0002120	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	7	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002779	31682550	Clinical research	233 enrolled patients, 27 tumor types	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	15	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002780	31682550	Clinical research	233 enrolled patients, 27 tumor types	Pancreatic carcinoma	EFO:0002618	Pancreas	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	22	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002781	31682550	Clinical research	233 enrolled patients, 27 tumor types	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002782	31682550	Clinical research	233 enrolled patients, 27 tumor types	Renal carcinoma	EFO:0002890	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002783	31682550	Clinical research	233 enrolled patients, 27 tumor types	Retroperitoneal cancer	EFO:0007466	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002784	31682550	Clinical research	233 enrolled patients, 27 tumor types	Salivary gland carcinoma	MONDO:0004669	Salivary gland	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002785	31682550	Clinical research	233 enrolled patients, 27 tumor types	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	9	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002786	31682550	Clinical research	233 enrolled patients, 27 tumor types	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002787	31682550	Clinical research	233 enrolled patients, 27 tumor types	Testicular cancer	DOID:2998	Testis	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002788	31682550	Clinical research	233 enrolled patients, 27 tumor types	Thyroid cancer	MONDO:0002108	Thyroid	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002789	31682550	Clinical research	233 enrolled patients, 27 tumor types	Tonsil cancer	EFO:1001214	Tonsil	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002790	31682550	Clinical research	233 enrolled patients, 27 tumor types	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002791	31682550	Clinical research	233 enrolled patients, 27 tumor types	Vaginal cancer	MONDO:0001402	Vaginal	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002792	31682550	Clinical research	233 enrolled patients, 27 tumor types	Vulvar cancer	EFO:1000624	Vulvar	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Phase II KEYNOTE-158 study	The durable clinical benefit of pembrolizumab treatment in patients with metastatic or unresectable high microsatellite instability(MSI-H)/DNA mismatch repair(dMMR) noncolorectal cancer who have experienced progression on or been intolerant to earlier treatment. Moreover, the results observed in this study support the tumoragnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer, regardless of anatomic tumor location.	Hypothyroidism,hyperthyroidism, colitis, and pneumonitis	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.	 J Clin Oncol	PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.
CANIT0002793	31686036	Clinical research	Muscle-invasive urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Cystectomy followed by atezolizumab	N/A	Cystectomy followed by Immune checkpoint therapy	Atezolizumab (DB11595); 	95	N/A	Single-arm phase 2 study	The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-beta and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.	N/A	N/A	N/A	FAP (Q12884); 	Fibroblast activation protein	Gene expression signature on/in tumor cell	 2019 Nov	Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.	 Nat Med	Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-¦Â and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
CANIT0002794	31686036	Clinical research	Muscle-invasive urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Cystectomy followed by atezolizumab	N/A	Cystectomy followed by Immune checkpoint therapy	Atezolizumab (DB11595); 	95	N/A	Single-arm phase 2 study	The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-beta and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.	N/A	N/A	N/A	TGFB (P01137); 	TGFB1 expression on tumor cells	Gene expression signature on/in tumor cell	 2019 Nov	Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.	 Nat Med	Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-¦Â and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
CANIT0002795	31686036	Clinical research	Muscle-invasive urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Cystectomy followed by atezolizumab	N/A	Cystectomy followed by Immune checkpoint therapy	Atezolizumab (DB11595); 	95	N/A	Single-arm phase 2 study	The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-beta and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.	N/A	N/A	N/A	T-Lymphocyte (NCIT:C12476); 	Preexisting activated T-cell 	Immune response	 2019 Nov	Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.	 Nat Med	Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-¦Â and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
CANIT0002796	31686036	Clinical research	Muscle-invasive urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Cystectomy followed by atezolizumab	N/A	Cystectomy followed by Immune checkpoint therapy	Atezolizumab (DB11595); 	95	N/A	Single-arm phase 2 study	The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-beta and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Predominant expression of genes related to tissue repair after treatment	Gene expression signature on/in tumor cell	 2019 Nov	Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.	 Nat Med	Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-¦Â and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
CANIT0002797	31686036	Clinical research	Muscle-invasive urothelial cancer	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Cystectomy followed by atezolizumab	N/A	Cystectomy followed by Immune checkpoint therapy	Atezolizumab (DB11595); 	95	N/A	Single-arm phase 2 study	The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-beta and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Nov	Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.	 Nat Med	Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-¦Â and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.
CANIT0002798	31686247	Clinical research	Negative or < 1% PD-L1-expressing metastatic non-small-cell lung cancers	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); 	N/A	N/A	Meta-analysis	IMpower (atezolizumab + chemotherapy (CT)), Keynote (pembrolizumab + CT) and CheckMate (nivolumab + CT) trials included 2037 NSCLCs (1246 PD-L1-negative; 791 < 1% PD-L1 expression). Anti-PD-1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.75 [0.63-0.89]; p = 0.0008) and PFS (0.72 [0.65-0.80]; p < 0.0001), and higher ORR (odds ratio 2.06 [1.50-2.83]; p < 0.0001). First-line anti-PD-1/PD-L1 + CT combination appears superior to CT alone for advanced, < 1% PD-L3-expressing NSCLCs for OS, PFS and ORR.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Feb	First-line PD-1/PD-L1 inhibitor plus chemotherapy vs chemotherapy alone for negative or < 1% PD-L1-expressing metastatic non-small-cell lung cancers.	 J Cancer Res Clin Oncol	AIMS: Single-agent anti-PD-1/PD-L1 clinical efficacy against < 1% PD-L1-expressing non-small-cell lung cancers (NSCLCs) is controversial.METHODS: This meta-analysis examined randomized-trial data comparing first-line PD-1/PD-L1-inhibitor + chemotherapy (CT) vs CT alone for advanced < 1% PD-L1 NSCLCs. Outcome measures included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR).RESULTS: IMpower (atezolizumab + CT), Keynote (pembrolizumab + CT) and CheckMate (nivolumab + CT) trials included 2037 NSCLCs (1246 PD-L1-negative; 791 < 1% PD-L1 expression). Anti-PD-1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.75 [0.63-0.89]; p = 0.0008) and PFS (0.72 [0.65-0.80]; p < 0.0001), and higher ORR (odds ratio 2.06 [1.50-2.83]; p < 0.0001).CONCLUSIONS: First-line anti-PD-1/PD-L1 + CT combination appears superior to CT alone for advanced, < 1% PD-L1-expressing NSCLCs for OS, PFS and ORR.
CANIT0002799	31686247	Clinical research	Negative or < 1% PD-L1-expressing metastatic non-small-cell lung cancers	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Atezolizumab (DB11595); 	N/A	N/A	Meta-analysis	IMpower (atezolizumab + chemotherapy (CT)), Keynote (pembrolizumab + CT) and CheckMate (nivolumab + CT) trials included 2037 NSCLCs (1246 PD-L1-negative; 791 < 1% PD-L1 expression). Anti-PD-1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.75 [0.63-0.89]; p = 0.0008) and PFS (0.72 [0.65-0.80]; p < 0.0001), and higher ORR (odds ratio 2.06 [1.50-2.83]; p < 0.0001). First-line anti-PD-1/PD-L1 + CT combination appears superior to CT alone for advanced, < 1% PD-L2-expressing NSCLCs for OS, PFS and ORR.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Feb	First-line PD-1/PD-L1 inhibitor plus chemotherapy vs chemotherapy alone for negative or < 1% PD-L1-expressing metastatic non-small-cell lung cancers.	 J Cancer Res Clin Oncol	AIMS: Single-agent anti-PD-1/PD-L1 clinical efficacy against < 1% PD-L1-expressing non-small-cell lung cancers (NSCLCs) is controversial.METHODS: This meta-analysis examined randomized-trial data comparing first-line PD-1/PD-L1-inhibitor + chemotherapy (CT) vs CT alone for advanced < 1% PD-L1 NSCLCs. Outcome measures included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR).RESULTS: IMpower (atezolizumab + CT), Keynote (pembrolizumab + CT) and CheckMate (nivolumab + CT) trials included 2037 NSCLCs (1246 PD-L1-negative; 791 < 1% PD-L1 expression). Anti-PD-1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.75 [0.63-0.89]; p = 0.0008) and PFS (0.72 [0.65-0.80]; p < 0.0001), and higher ORR (odds ratio 2.06 [1.50-2.83]; p < 0.0001).CONCLUSIONS: First-line anti-PD-1/PD-L1 + CT combination appears superior to CT alone for advanced, < 1% PD-L1-expressing NSCLCs for OS, PFS and ORR.
CANIT0002800	31686247	Clinical research	Negative or < 1% PD-L1-expressing metastatic non-small-cell lung cancers	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Atezolizumab (DB11595); 	N/A	N/A	Meta-analysis	IMpower (atezolizumab + chemotherapy (CT)), Keynote (pembrolizumab + CT) and CheckMate (nivolumab + CT) trials included 2037 NSCLCs (1246 PD-L1-negative; 791 < 1% PD-L1 expression). Anti-PD-1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.75 [0.63-0.89]; p = 0.0008) and PFS (0.72 [0.65-0.80]; p < 0.0001), and higher ORR (odds ratio 2.06 [1.50-2.83]; p < 0.0001). First-line anti-PD-1/PD-L1 + CT combination appears superior to CT alone for advanced, < 1% PD-L1-expressing NSCLCs for OS, PFS and ORR.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Feb	First-line PD-1/PD-L1 inhibitor plus chemotherapy vs chemotherapy alone for negative or < 1% PD-L1-expressing metastatic non-small-cell lung cancers.	 J Cancer Res Clin Oncol	AIMS: Single-agent anti-PD-1/PD-L1 clinical efficacy against < 1% PD-L1-expressing non-small-cell lung cancers (NSCLCs) is controversial.METHODS: This meta-analysis examined randomized-trial data comparing first-line PD-1/PD-L1-inhibitor + chemotherapy (CT) vs CT alone for advanced < 1% PD-L1 NSCLCs. Outcome measures included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR).RESULTS: IMpower (atezolizumab + CT), Keynote (pembrolizumab + CT) and CheckMate (nivolumab + CT) trials included 2037 NSCLCs (1246 PD-L1-negative; 791 < 1% PD-L1 expression). Anti-PD-1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.75 [0.63-0.89]; p = 0.0008) and PFS (0.72 [0.65-0.80]; p < 0.0001), and higher ORR (odds ratio 2.06 [1.50-2.83]; p < 0.0001).CONCLUSIONS: First-line anti-PD-1/PD-L1 + CT combination appears superior to CT alone for advanced, < 1% PD-L1-expressing NSCLCs for OS, PFS and ORR.
CANIT0002801	31686799	Clinical research	A total of 137 patients with NSCLC were initially enrolled, and subsequently 95 patients (41 COPD and 54 non-COPD) receiving 4 cycles of nivolumab administration were included	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	95	N/A	Prospective study	Anti-PD-1 therapy changed FeNO levels and pulmonary function in NSCLC patients. This therapy does not worsen chronic obstructive pulmonary disease in terms of symptoms, pulmonary function, or acute exacerbation	N/A	N/A	N/A	FeNO (Q6PQK2); 	Serum FeNO levels	Gene expression signature in serum	 2019 Aug 21	Effect of PD-1 inhibitor on exhaled nitric oxide and pulmonary function in non-small cell lung cancer patients with and without COPD.	 Int J Chron Obstruct Pulmon Dis	BACKGROUND: Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, has been shown to improve survival in non-small cell lung cancer (NSCLC). The possible involvement of PD-1 axis in the pathogenesis of inflammatory lung disease, such as chronic obstructive pulmonary disease (COPD) has also been reported. However, effects of PD-1 blockade on the respiratory system remain unknown.OBJECTIVES: This prospective study aimed to investigate whether inhibition of the PD-1 axis altered lung inflammation and pulmonary function in NSCLC patients with and without COPD.METHOD: This was a prospective multi-center study. Measurements of fractioned exhaled nitric oxide (FeNO) and pulmonary function were performed before and after 4 cycles of nivolumab therapy.RESULTS: A total of 137 patients with NSCLC were initially enrolled, and subsequently 95 patients (41 COPD and 54 non-COPD) receiving 4 cycles of nivolumab administration were included. After anti-PD-1 therapy, FeNO levels were significantly elevated together with increase in peripheral eosinophils. Interestingly, significant FeNO elevation was only found in COPD patients without increased peripheral eosinophils, but this was not the case in non-COPD patients. Additionally, COPD patients exhibited significant increases in FVC and FEV1 but no changes in dyspnea scales, and acute exacerbation did not occur during the therapy.CONCLUSION: Our observations suggest that anti-PD-1 therapy changed FeNO levels and pulmonary function in NSCLC patients. This therapy does not worsen COPD in terms of symptoms, pulmonary function, or acute exacerbation.
CANIT0002802	31689840	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); KIT (P10721); 	PD-1; KIT	Pembrolizumab followed by pembrolizumab plus imatinib	N/A	Immune checkpoint therapy followed by Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); imatinib (DB00619); 	1	N/A	Case	A patient with double KIT mutant melanoma was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression.	Patient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. 	N/A	N/A	KIT (P10721); 	KIT mutational status	Mutational status	 2019 Nov	Combination of pembrolizumab and imatinib in a patient with double KIT mutant melanoma: A case report.	 Medicine (Baltimore)	RATIONALE: The treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies. Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone. To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients. Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations.PATIENT CONCERNS AND DIAGNOSIS: We report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I.INTERVENTIONS: She was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy.OUTCOMES: Patient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression.LESSONS: Treatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations. This novel combination can cause additional toxicities which seem to be overall manageable.
CANIT0002803	31690713	Case report	Metaplastic breast cancer 	Breast cancer	MONDO:0007254	Breast	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab plus paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Durvalumab (DB11714); paclitaxel (DB01229); 	1	N/A	Case	This is the first case reporting the successful use of durvalumab and paclitaxel combination for treatment of triple negative breast cancer in general, and in metastatic breast cancer (MPBC) in specific	Increase in serum cholesterol and she was given a statin with favorable response.	N/A	N/A	N/A	N/A	N/A	 2019 Nov 6	Complete Response of Chemo-Refractory Metastatic Metaplastic Breast Cancer to Paclitaxel-Immunotherapy Combination.	 Am J Case Rep	BACKGROUND Metaplastic breast cancer (MPBC) is a rare subtype of breast cancer that is difficult to manage and is resistant to therapy. Immunotherapy is becoming a promising option for care of several types of cancers including triple negative breast cancer. CASE REPORT We present a case of a patient with chemo-refractory metastatic metaplastic-type of breast cancer with failures to 3 active lines of chemotherapy. The patient achieved a complete and sustained response to chemo-immunotherapy combination with acceptable tolerability and minimal adverse events. The treatment was a combination of anti-PD-L1 antibody (durvalumab) immunotherapy in combination with the chemotherapeutic agent, paclitaxel. CONCLUSIONS This is the first case reporting the successful use of durvalumab and paclitaxel combination for treatment of triple negative breast cancer in general, and in metastatic MPBC in specific.
CANIT0002804	31694582	Clinical research	48 were obtained from pancreatic ductal adenocarcinoma (PDAC) patients (23 female and 25 male patients with a median age of 62 years; age range, 41¨C76 years), and 40 were obtained from healthy donors (20 female and 20 male patients with a median age of 60 years; age range, 40¨C79 years) 	Pancreatic carcinoma	EFO:0002618	Pancreas	PD-1 (Q15116); 	PD-1; 	Nivolumab plus IFNG	Nivolumab	Immune checkpoint therapy plus Immune cytokine	Nivolumab (DB09035); 	48	40	N/A	PD-1 protein expression is increased on peripheral CD8+ T cells in patients with pancreatic ductal adenocarcinoma compared with that in health donor. PD-1 expression on CD8+ T-lymphocytes was decreased by nivolumab in a concentration-dependent manner in vitro. IFNG could directly down-regulate expression of PD-1 in vitro. Furthermore, the combination therapy of nivolumab and IFNG resulted in greatest effect of PD-1-blockde (1.73 +/- 0.78), compared with IFNG along (18.63 +/- 0.82) and nivolumab along (13.65 +/- 1.22). Moreover, the effects of nivolumab plus IFNG largest promoted the T-lymphocytes function of proliferations, cytokine secretions and cytotoxic activities. Most importantly, T-lymphocytes induced by nivolumab plus IFNG presented the best repression of tumor growth.CONCLUSIONS: IFNG plus a PD-1-blockading agent could enhance the immunologic function and might play a crucial role in effective adoptive transfer treatments of pancreatic cancer.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	PD-1 expression on CD8(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Nov 6	IFN-¦Ã down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer.	 BMC Cancer	BACKGROUND: Pancreatic cancer is characterized by a highly immunosuppressive tumor microenvironment and evasion of immune surveillance. Although programmed cell death 1 receptor (PD-1) blockade has achieved certain success in immunogenic cancers, the responses to the PD-1 antibody are not effective or sustained in patients with pancreatic cancer.METHODS: Firstly, PD-1 expressions on peripheral CD8+ T-lymphocytes of patients with pancreatic cancer and healthy donors were measured. In in vitro study, peripheral T-lymphocytes were isolated and treated with nivolumab and/or interferon-¦Ã, and next, PD-1-blockade effects, proliferations, cytokine secretions and cytotoxic activities were tested after different treatments. In in vivo study, mice bearing subcutaneous pancreatic cancer cell lines were treated with induced T-lymphocytes and tumor sizes were measured.RESULTS: PD-1 protein expression is increased on peripheral CD8+ T cells in patients with pancreatic ductal adenocarcinoma compared with that in health donor. PD-1 expression on CD8+ T-lymphocytes was decreased by nivolumab in a concentration-dependent manner in vitro. IFN-¦Ã could directly down-regulate expression of PD-1 in vitro. Furthermore, the combination therapy of nivolumab and IFN-¦Ã resulted in greatest effect of PD-1-blockde (1.73 +/- 0.78), compared with IFN-¦Ã along (18.63 +/- 0.82) and nivolumab along (13.65 +/- 1.22). Moreover, the effects of nivolumab plus IFN-¦Ã largest promoted the T-lymphocytes function of proliferations, cytokine secretions and cytotoxic activities. Most importantly, T-lymphocytes induced by nivolumab plus IFN-¦Ã presented the best repression of tumor growth.CONCLUSIONS: IFN-¦Ã plus a PD-1-blockading agent could enhance the immunologic function and might play a crucial role in effective adoptive transfer treatments of pancreatic cancer.
CANIT0002805	31694832	Clinical research	Pancreatic ductal adenocarcinoma	Pancreatic ductal adenocarcinoma	EFO:1000044	Pancreas	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus Pelareorep plus Chemotherapy	N/A	Immune checkpoint therapy plus Oncolytic virus plus Chemotherapy	Pembrolizumab (DB09037); 	11	N/A	Phase Ib single-arm study	Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of pelareorep and anti-PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pretreatment and on-treatment biomarkers for pelareorep therapy warranting further investigation. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. T-cell receptor sequencing from peripheral blood revealed the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit.	Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies.	N/A	N/A	N/A	N/A	N/A	 2020 Jan 1	Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study.	 Clin Cancer Res	PURPOSE: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Tumor tissues from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab and chemotherapy in patients with PDAC would be safe and effective.PATIENTS AND METHODS: A phase Ib single-arm study enrolled patients with PDAC who progressed after first-line treatment. Patients received pelareorep, pembrolizumab, and either 5-fluorouracil, gemcitabine, or irinotecan until disease progression or unacceptable toxicity. Study objectives included safety and dose-limiting toxicities, tumor response, evaluation for reovirus replication, and immune analysis in peripheral blood and tumor biopsies.RESULTS: Eleven patients were enrolled. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit.CONCLUSIONS: Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of pelareorep and anti-PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pretreatment and on-treatment biomarkers for pelareorep therapy warranting further investigation.
CANIT0002806	31697878	Case report	Mucinous tubular and spindle cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Axitinib followed by Nivolumab	N/A	Target therapy followed by Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We report a case of metastatic mucinous tubular and spindle cell carcinoma (MTSCC) in a patient who showed a favorable response to nivolumab treatment. This is the first report to describe successful treatment of metastatic MTSCC with anti-programmed cell death 1 antibody	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Sep	[METASTATIC Mucinous Tubular and Spindle Cell Carcinoma Treated with Nivolumab Successfully : A Case Report].	 Hinyokika Kiyo	A 68-year-old man was referred to our hospital with a right-sided renal tumor identified by ultrasonography at the time of his medical check-up. Computed tomography revealed a well-circumscribed but distorted mass measuring 64¡Á45¡Á57 mm in the right kidney with para-aortic lymph node swelling. Laparoscopic right nephrectomy with para-aortic lymphadenectomy was performed. Histopathological diagnosis was mucinous tubular and spindle cell carcinoma (MTSCC) (pT3a) without lymph node metastasis (pN0). Postoperatively, metastases were identified in the lungs, and the vertebral and iliac bones. The patient was treated with axitinib. The lung nodule progressed and left sacrum metastases appeared even after treatment with axitinib. Therefore, nivolumab was administered as second-line treatment. The metastases in the lungs, as well as vertebral and iliac bone showed complete response to this therapy. MTSCC of the kidney is a rare low-grade renal cell carcinoma without any established systemic therapy for metastatic or unresectable lesions. We report a case of metastatic MTSCC in a patient who showed a favorable response to nivolumab treatment. This is the first report to describe successful treatment of metastatic MTSCC with anti-programmed cell death 1 antibody.
CANIT0002807	31699149	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	246	N/A	N/A	While the use of immunotherapy for metastatic melanoma has increased over time, adoption varies widely across hospitals. Underinsured patients were more likely to receive treatment at low immunotherapy prescribing hospitals. The variation suggests inequity in access to these potentially life-saving drugs. Between 2011 and 2015, the proportion of hospitals treating at least 20% of melanoma patients with immunotherapy within 90 days of diagnosis increased from 14.5 to 37.7%. The mean proportion of patients receiving immunotherapy was 7.8% (95% Confidence Interval [CI] 7.47-8.08) and 50.9% (95%-CI 47.6-54.3) in low and high prescribing hospitals, respectively. Predictors of receiving care in a low prescribing hospital included underinsurance (no insurance: relative risk ratio [RRR] 2.44, 95%-CI 1.28-4.67, p = 0.007; Medicaid: RRR 2.10, 95%-CI 1.12-3.92, p = 0.020), care in urban areas (RRR 2.58, 95%-CI 1.34-4.96, p = 0.005) and care at non-academic facilities (RRR 5.18, 95%CI 1.69-15.88, p = 0.004).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov 7	Adoption of immunotherapy in the community for patients diagnosed with metastatic melanoma.	 J Immunother Cancer	BACKGROUND: The introduction of immune checkpoint inhibitors has led to a survival benefit in patients with advanced melanoma; however data on the adoption of immunotherapy in the community are scarce.METHODS: Using the National Cancer Database, we identified 4725 patients aged >=20 diagnosed with metastatic melanoma in the United States between 2011 and 2015. Multinomial regression was used to identify factors associated with the receipt of treatment at a low vs. high immunotherapy prescribing hospital, defined as the bottom and top quintile of hospitals according to their proportion of treating metastatic melanoma patients with immunotherapy.RESULTS: We identified 246 unique hospitals treating patients with metastatic melanoma. Between 2011 and 2015, the proportion of hospitals treating at least 20% of melanoma patients with immunotherapy within 90 days of diagnosis increased from 14.5 to 37.7%. The mean proportion of patients receiving immunotherapy was 7.8% (95% Confidence Interval [CI] 7.47-8.08) and 50.9% (95%-CI 47.6-54.3) in low and high prescribing hospitals, respectively. Predictors of receiving care in a low prescribing hospital included underinsurance (no insurance: relative risk ratio [RRR] 2.44, 95%-CI 1.28-4.67, p = 0.007; Medicaid: RRR 2.10, 95%-CI 1.12-3.92, p = 0.020), care in urban areas (RRR 2.58, 95%-CI 1.34-4.96, p = 0.005) and care at non-academic facilities (RRR 5.18, 95%CI 1.69-15.88, p = 0.004).CONCLUSION: While the use of immunotherapy for metastatic melanoma has increased over time, adoption varies widely across hospitals. Underinsured patients were more likely to receive treatment at low immunotherapy prescribing hospitals. The variation suggests inequity in access to these potentially life-saving drugs.
CANIT0002808	31699709	Clinical research	High-risk resected melanoma	Melanoma	EFO:0000756	Skin	TLR3 (O15455); MDA5 (Q9BYX4); CTG1B (P78358); 	TLR3 ;  MDA5 ;  CTG1B 	NY-ESO-1 plus Poly-ICLC	NY-ESO-1	Tumor vaccine	NY-ESO-1 vaccine (NCIT:C2657); poly-ICLC (NCIT:C1198); 	35	N/A	Phase I/II	NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4+ T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8+ T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8+ T-cell responses to NY-ESO-1.	The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12479); 	CD5(+) T-cell responses	Gene expression signature on/in immune cell	 2020 Jan	Combined Vaccination with NY-ESO-1 Protein, Poly-ICLC, and Montanide Improves Humoral and Cellular Immune Responses in Patients with High-Risk Melanoma.	 Cancer Immunol Res	Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results from early-phase clinical studies in patients with melanoma, NY-ESO-1 vaccine immunotherapy has not been widely investigated in larger trials; consequently, many questions remain as to the optimal vaccine formulation, predictive biomarkers, and sequencing and timing of vaccines in melanoma treatment. We conducted an adjuvant phase I/II clinical trial in high-risk resected melanoma to optimize the delivery of poly-ICLC, a TLR-3/MDA-5 agonist, as a component of vaccine formulation. A phase I dose-escalation part was undertaken to identify the MTD of poly-ICLC administered in combination with NY-ESO-1 and montanide. This was followed by a randomized phase II part investigating the MTD of poly-ICLC with NY-ESO-1 with or without montanide. The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events. Both regimens induced integrated NY-ESO-1-specific CD4+ T-cell and humoral responses. CD8+ T-cell responses were mainly detected in patients receiving montanide. T-cell avidity toward NY-ESO-1 peptides was higher in patients vaccinated with montanide. In conclusion, NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4+ T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8+ T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8+ T-cell responses to NY-ESO-1.
CANIT0002809	31699709	Clinical research	High-risk resected melanoma	Melanoma	EFO:0000756	Skin	TLR3 (O15455); MDA5 (Q9BYX4); CTG1B (P78358); 	TLR3 ;  MDA5 ;  CTG1B 	NY-ESO-1 plus Poly-ICLC plus Montanide	NY-ESO-1 Protein plus Poly-ICLC	Tumor vaccine	NY-ESO-1 vaccine (NCIT:C2657); poly-ICLC (NCIT:C1198); Montanide ISA 51 VG (NCIT:C84843); 	35	N/A	Phase I/II	NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4+ T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8+ T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8+ T-cell responses to NY-ESO-1.	The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8(+) T-cell responses	Gene expression signature on/in immune cell	 2020 Jan	Combined Vaccination with NY-ESO-1 Protein, Poly-ICLC, and Montanide Improves Humoral and Cellular Immune Responses in Patients with High-Risk Melanoma.	 Cancer Immunol Res	Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results from early-phase clinical studies in patients with melanoma, NY-ESO-1 vaccine immunotherapy has not been widely investigated in larger trials; consequently, many questions remain as to the optimal vaccine formulation, predictive biomarkers, and sequencing and timing of vaccines in melanoma treatment. We conducted an adjuvant phase I/II clinical trial in high-risk resected melanoma to optimize the delivery of poly-ICLC, a TLR-3/MDA-5 agonist, as a component of vaccine formulation. A phase I dose-escalation part was undertaken to identify the MTD of poly-ICLC administered in combination with NY-ESO-1 and montanide. This was followed by a randomized phase II part investigating the MTD of poly-ICLC with NY-ESO-1 with or without montanide. The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events. Both regimens induced integrated NY-ESO-1-specific CD4+ T-cell and humoral responses. CD8+ T-cell responses were mainly detected in patients receiving montanide. T-cell avidity toward NY-ESO-1 peptides was higher in patients vaccinated with montanide. In conclusion, NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4+ T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8+ T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8+ T-cell responses to NY-ESO-1.
CANIT0002810	31699709	Clinical research	High-risk resected melanoma	Melanoma	EFO:0000756	Skin	TLR3 (O15455); MDA5 (Q9BYX4); CTG1B (P78358); 	TLR3 ;  MDA5 ;  CTG1B 	NY-ESO-1 plus Poly-ICLC	Poly-ICLC	Tumor vaccine	NY-ESO-1 vaccine (NCIT:C2657); poly-ICLC (NCIT:C1198); 	35	N/A	Phase I/II	NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4+ T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8+ T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8+ T-cell responses to NY-ESO-1.	The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12478); 	CD4(+) T-cell responses	Gene expression signature on/in immune cell	 2020 Jan	Combined Vaccination with NY-ESO-1 Protein, Poly-ICLC, and Montanide Improves Humoral and Cellular Immune Responses in Patients with High-Risk Melanoma.	 Cancer Immunol Res	Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results from early-phase clinical studies in patients with melanoma, NY-ESO-1 vaccine immunotherapy has not been widely investigated in larger trials; consequently, many questions remain as to the optimal vaccine formulation, predictive biomarkers, and sequencing and timing of vaccines in melanoma treatment. We conducted an adjuvant phase I/II clinical trial in high-risk resected melanoma to optimize the delivery of poly-ICLC, a TLR-3/MDA-5 agonist, as a component of vaccine formulation. A phase I dose-escalation part was undertaken to identify the MTD of poly-ICLC administered in combination with NY-ESO-1 and montanide. This was followed by a randomized phase II part investigating the MTD of poly-ICLC with NY-ESO-1 with or without montanide. The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events. Both regimens induced integrated NY-ESO-1-specific CD4+ T-cell and humoral responses. CD8+ T-cell responses were mainly detected in patients receiving montanide. T-cell avidity toward NY-ESO-1 peptides was higher in patients vaccinated with montanide. In conclusion, NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4+ T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8+ T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8+ T-cell responses to NY-ESO-1.
CANIT0002811	31700181	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	N/A	In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient's genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex-peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	HLAB (P01889); 	HLA-I evolutionary divergence	Mutational status	 2019 Nov	Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy.	 Nat Med	Functional diversity of the highly polymorphic human leukocyte antigen class I (HLA-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele advantage hypothesis dictates that an HLA-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes1-3. However, the effect of sequence divergence between HLA-I alleles-a quantifiable measure of HLA-I evolution-on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient's genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex-peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.
CANIT0002812	31701575	Case report	Desmoplastic malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Desmoplastic malignant melanoma (DM) is a rare variant of malignant melanoma (MM), and immune checkpoint inhibitors are effective in treating this condition. We report a case of DM treated with nivolumab	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	Nivolumab for adjuvant treatment of desmoplastic malignant melanoma: A case report.	 J Dermatol	Unable to provide
CANIT0002813	31703571	Case report	 A 63-year-old man	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); VEGFR2 (P35968); 	PD-1; VEGFR2	Pembrolizumab plus lenvatinib	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); lenvatinib (DB09078); 	1	N/A	Case	HCC is a potentially lethal malignant tumor and the combination of immunotherapy plus anti-angiogenic inhibitors shows promising outcome for advanced diseases.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov 8	Complete response to the combination of Lenvatinib and Pembrolizumab in an advanced hepatocellular carcinoma patient: a case report.	 BMC Cancer	BACKGROUND: The majority of patients diagnosed with hepatocellular carcinoma (HCC) have advanced diseases and many are not eligible for curative therapies.CASE PRESENTATION: We report a rare case of HCC from a patient who had a complete response (CR) with the use of combination of Lenvatinib and Pembrolizumab. A 63-year-old man presented at the hospital with serious abdominal pain and was found to have a mass with heterogeneous enhancement and with hemorrhage in segment III of the liver after the examination of abdominal computerized tomography (CT) scan. The patient's history of viral hepatitis B infection, liver cirrhosis and the ¨»-fetoprotein (AFP) level of 14,429.3 ng/ml supported the clinical diagnosis of HCC and laboratory results demonstrated liver function damage status (Child-Pugh class B, Score 8). The patient first received hepatic arterial embolization treatment on 28th November 2017. At this stage supportive care was recommended for poor liver function. In February 2018, combined immunotherapy of Pembrolizumab (2 mg/kg, q3w) and Lenvatinib (8 mg-4 mg, qd) were performed. Nine months following the treatment he had a CR and now, 22 months since the initial treatment, there is no clinical evidence of disease progression. The current overall survival is 22 months.CONCLUSIONS: HCC is a potentially lethal malignant tumor and the combination of immunotherapy plus anti-angiogenic inhibitors shows promising outcome for advanced diseases.
CANIT0002814	31704852	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	29	N/A	N/A	Serum IFNG levels could be a biomarker for  for Non-small-cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.	ICI-induced interstitial pneumonitis	N/A	N/A	IFNG (P01579); 	Serum IFNG expression levels	Gene expression signature in serum	 2019 Nov	The Levels of Interferon-gamma Release as a Biomarker for Non-small-cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.	 Anticancer Res	BACKGROUND/AIM: The present study aimed to prospectively examine the usefulness of interferonG (IFN-¦Ã) release (IGR) as a biomarker in non-small-cell lung cancer patients receiving immune checkpoint inhibitor treatment (ICI-Tx).PATIENTS AND METHODS: IGR was measured using enzyme-linked immunosorbent assay at four time points: within 14 days before ICI-Tx (T1), and 8+/-3 (T2), 22+/-7 (T3), and 43+/-7 (T4) days after ICI-Tx.RESULTS: Twenty-nine patients were divided into three groups based on IFN-¦Ã levels in the IGR-positive control: Group-1 (n=8) with <10 IU/ml at T1, Group-2 (n=12) with a decrease in IFN-¦Ã levels to <10 IU/ml at T3 and/or T4, and Group-3 (n=9) without changes in IFN-¦Ã levels. Early progression and ICI-induced interstitial pneumonitis were frequently observed in Group-1 and Group-2, respectively. Group-3 exhibited more treatment cycles than the other groups. All three groups showed clear differences in clinical outcomes.CONCLUSION: IFN-¦Ã levels could be a biomarker for ICI-Tx.
CANIT0002815	31704856	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Antibiotics followd by Nivolumab	Nivolumab	Immune checkpoint therapy	Nivolumab (DB09035); 	5	26	Retrospective analysis	In multivariate analyses, Antibiotics (AB) use (p=0.0377) and presence of immune related adverse events (p=0.0042) were independent prognostic factors for PFS in association with ICIs therapy.The use of AB before ICIs treatment was a predictor of poor immune check point inhibitors response in metastatic renal cell carcinoma.	N/A	N/A	N/A	Antibiotics (NCIT:C258); 	Antibiotics use	Exposure factors/status	 2019 Nov	The Impact of Antibiotics on Prognosis of Metastatic Renal Cell Carcinoma in Japanese Patients Treated With Immune Checkpoint Inhibitors.	 Anticancer Res	BACKGROUND/AIM: The present study aimed to examine the influence of antibiotics (AB) on the clinical outcomes of Japanese patients treated with immune check point inhibitors (ICIs) for metastatic renal cell carcinoma (RCC) patients.PATIENTS AND METHODS: A total of 31 patients with metastatic RCC treated with ICIs from November 2016 to April 2019 were retrospectively reviewed and analyzed.RESULTS: Five patients were treated with AB prior to ICIs treatment. Median progression free survival (PFS) of patients treated with AB vs. patients not treated with AB was 2.8 months and 18.4 months, respectively. The difference between PFS was statistically significant (p=0.0004). In multivariate analyses, AB use (p=0.0377) and presence of immune related adverse events (p=0.0042) were independent prognostic factors for PFS in association with ICIs therapy.CONCLUSION: The use of AB before ICIs treatment was a predictor of poor ICIs response in metastatic RCC.
CANIT0002816	31704856	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	31	N/A	Retrospective analysis	Five patients were treated with Antibiotics (AB) prior to immune check point inhibitors (ICIs) treatment. Median progression free survival (PFS) of patients treated with AB vs. patients not treated with AB was 2.8 months and 18.4 months, respectively. The difference between PFS was statistically significant (p=0.0004). In multivariate analyses, antibiotics (AB) use (p=0.0377) and presence of immune related adverse events (p=0.0042) were independent prognostic factors for PFS in association with ICIs therapy.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2019 Nov	The Impact of Antibiotics on Prognosis of Metastatic Renal Cell Carcinoma in Japanese Patients Treated With Immune Checkpoint Inhibitors.	 Anticancer Res	BACKGROUND/AIM: The present study aimed to examine the influence of antibiotics (AB) on the clinical outcomes of Japanese patients treated with immune check point inhibitors (ICIs) for metastatic renal cell carcinoma (RCC) patients.PATIENTS AND METHODS: A total of 31 patients with metastatic RCC treated with ICIs from November 2016 to April 2019 were retrospectively reviewed and analyzed.RESULTS: Five patients were treated with AB prior to ICIs treatment. Median progression free survival (PFS) of patients treated with AB vs. patients not treated with AB was 2.8 months and 18.4 months, respectively. The difference between PFS was statistically significant (p=0.0004). In multivariate analyses, AB use (p=0.0377) and presence of immune related adverse events (p=0.0042) were independent prognostic factors for PFS in association with ICIs therapy.CONCLUSION: The use of AB before ICIs treatment was a predictor of poor ICIs response in metastatic RCC.
CANIT0002817	31713453	Clinical research	Squamous non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	Chemotherapy	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	3112	N/A	Meta-analysis	PD-1/PD-L1 inhibitors significantly improved OS and PFS in advanced squamous NSCLC patients when compared with chemotherapy. A total of 11 trials (3112 patients) were included. PD-1/PD-L1 inhibitors demonstrated significant superiority to chemotherapy in overall survival (OS) (hazard ratio [HR]: 0.74; p < 0.001) and progression-free survival (PFS) (HR: 0.66; p < 0.001) for squamous NSCLC. The OS and PFS benefits of PD-1/PD-L1 inhibitors for squamous NSCLC were similar in subgroup analyses of line settings, PD-L1 expression and different study methodologies. No advantage in OS was found in advanced squamous NSCLC patients treated with atezolizumab (HR: 0.87; p = 0.087).	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec	The efficacy of PD-1/PD-L1 inhibitors in advanced squamous-cell lung cancer: a meta-analysis of 3112 patients.	 Immunotherapy	Aim: We performed a meta-analysis to explore the efficacy of immunotherapy for patients with squamous non-small-cell lung cancer (NSCLC). Materials & methods: Randomized clinical trials comparing immunotherapy with chemotherapy for advanced NSCLC patients were included. Results: A total of 11 trials (3112 patients) were included. PD-1/PD-L1 inhibitors demonstrated significant superiority to chemotherapy in overall survival (OS) (hazard ratio [HR]: 0.74; p < 0.001) and progression-free survival (PFS) (HR: 0.66; p < 0.001) for squamous NSCLC. The OS and PFS benefits of PD-1/PD-L1 inhibitors for squamous NSCLC were similar in subgroup analyses of line settings, PD-L1 expression and different study methodologies. No advantage in OS was found in advanced squamous NSCLC patients treated with atezolizumab (HR: 0.87; p = 0.087). Conclusion: PD-1/PD-L1 inhibitors significantly improved OS and PFS in advanced squamous NSCLC patients when compared with chemotherapy.
CANIT0002818	31719058	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	139	N/A	Retrospective analysis	The results show that changes (delta) in the radiomic texture (DelRADx) of CT patterns could be used to identify early functional responses in patients with NSCLC. It is found that DelRADx could predict response to ICI therapy and overall survival (OS) for patients with NSCLC. We retrospectively analyzed data acquired from 139 patients with NSCLC at two institutions, who were divided into a discovery set (D1 = 50) and two independent validation sets (D2 = 62, D3 = 27). Intranodular and perinodular texture descriptors were extracted, and the relative differences were computed. A linear discriminant analysis (LDA) classifier was trained with 8 DelRADx features to predict RECIST-derived response. Association of delta-radiomic risk score (DRS) with OS was determined. The association of DelRADx features with tumor-infiltrating lymphocyte (TIL) density on the diagnostic biopsies (n = 36) was also evaluated. The LDA classifier yielded an AUC of 0.88 +/- 0.08 in distinguishing responders from nonresponders in D1, and 0.85 and 0.81 in D2 and D3 DRS was associated with OS [HR: 1.64; 95% confidence interval (CI), 1.22-2.21; P = 0.0011; C-index = 0.72). Peritumoral Gabor features were associated with the density of TILs on diagnostic biopsy samples.	N/A	N/A	N/A	Lymphocyte (NCIT:C12535); 	CT Radiomic Features Associated with Lymphocyte Distribution	Cell percentage/counts in blood	 2020 Jan	Changes in CT Radiomic Features Associated with Lymphocyte Distribution Predict Overall Survival and Response to Immunotherapy in Non-Small Cell Lung Cancer.	 Cancer Immunol Res	No predictive biomarkers can robustly identify patients with non-small cell lung cancer (NSCLC) who will benefit from immune checkpoint inhibitor (ICI) therapies. Here, in a machine learning setting, we compared changes (delta) in the radiomic texture (DelRADx) of CT patterns both within and outside tumor nodules before and after two to three cycles of ICI therapy. We found that DelRADx patterns could predict response to ICI therapy and overall survival (OS) for patients with NSCLC. We retrospectively analyzed data acquired from 139 patients with NSCLC at two institutions, who were divided into a discovery set (D1 = 50) and two independent validation sets (D2 = 62, D3 = 27). Intranodular and perinodular texture descriptors were extracted, and the relative differences were computed. A linear discriminant analysis (LDA) classifier was trained with 8 DelRADx features to predict RECIST-derived response. Association of delta-radiomic risk score (DRS) with OS was determined. The association of DelRADx features with tumor-infiltrating lymphocyte (TIL) density on the diagnostic biopsies (n = 36) was also evaluated. The LDA classifier yielded an AUC of 0.88 +/- 0.08 in distinguishing responders from nonresponders in D1, and 0.85 and 0.81 in D2 and D3 DRS was associated with OS [HR: 1.64; 95% confidence interval (CI), 1.22-2.21; P = 0.0011; C-index = 0.72). Peritumoral Gabor features were associated with the density of TILs on diagnostic biopsy samples. Our results show that DelRADx could be used to identify early functional responses in patients with NSCLC.
CANIT0002819	31720993	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	Chemotherapy	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	48	105	Retrospective analysis	Anticancer treatment-related Acute exacerbation (AE) of interstitial lung disease (ILD) occurred in 12 patients (11.4%) in the chemotherapy cohort and seven patients (14.5%) in the ICI cohort. In the multivariate logistic regression analysis, ground-glass attenuation (GGA) score was the only factor significantly associated with the development of AE of ILD in both cohorts (P = 0.037 and 0.01 in the chemotherapy and ICI cohorts, respectively).	N/A	N/A	N/A	Ground-glass attenuation score ()	Ground-glass attenuation score	Disease status	 2020 Feb	The utility of ground-glass attenuation score for anticancer treatment-related acute exacerbation of interstitial lung disease among lung cancer patients with interstitial lung disease.	 Int J Clin Oncol	BACKGROUND: Acute exacerbation (AE) of interstitial lung disease (ILD) is a fatal adverse event in the treatment of lung cancer patients with ILD. The value of pre-treatment radiological findings obtained by high-resolution computed tomography for the detection of anticancer treatment-related AE of ILD has not been established.METHODS: Two medical record-based retrospective studies were performed. The chemotherapy cohort included 105 lung cancer patients with ILD who received chemotherapy at Tokyo Medical and Dental University between October 2008 and December 2017. The immune checkpoint inhibitor (ICI) cohort included 48 advanced non-small cell lung cancer patients with ILD treated with ICIs at nine institutions between January 2016 and September 2018. Variables were compared between AE-positive and -negative groups. Candidate variables were analyzed by multivariate logistic regression. A P value < 0.05 was considered statistically significant.RESULTS: Anticancer treatment-related AE of ILD occurred in 12 patients (11.4%) in the chemotherapy cohort and seven patients (14.5%) in the ICI cohort. In the multivariate logistic regression analysis, ground-glass attenuation (GGA) score was the only factor significantly associated with the development of AE of ILD in both cohorts (P = 0.037 and 0.01 in the chemotherapy and ICI cohorts, respectively).CONCLUSION: Evaluation of GGA may help predict anticancer treatment-related AE of ILD.
CANIT0002820	31721643	Clinical research	Sixty patients	Renal cell carcinoma	EFO:0000681	Kidney	PD-L1 (Q9NZQ7); VEGF (P15692); 	PD-L1; VEGF	Atezolizumab plus bevacizumab	N/A	Immune checkpoint therapy plus Target therapy	Atezolizumab (DB11595); bevacizumab (DB00112); 	60	N/A	Phase II 	Atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology advanced renal cell carcinoma (RCC) or RCC with >= 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1-positive tumors	Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan 1	Results of a Multicenter Phase II Study of Atezolizumab and Bevacizumab for Patients With Metastatic Renal Cell Carcinoma With Variant Histology and/or Sarcomatoid Features.	 J Clin Oncol	PURPOSE: In this multicenter phase II trial, we evaluated atezolizumab combined with bevacizumab in patients with advanced renal cell carcinoma (RCC) with variant histology or any RCC histology with >= 20% sarcomatoid differentiation.PATIENTS AND METHODS: Eligible patients may have received previous systemic therapy, excluding prior bevacizumab or checkpoint inhibitors. Patients underwent a baseline biopsy and received atezolizumab 1,200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. The primary end point was overall response rate (ORR) by RECIST version 1.1. Additional end points were progression-free survival (PFS), toxicity, biomarkers of response as determined by programmed death-ligand 1 (PD-L1) status, and on-therapy quality-of-life (QOL) metrics using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 and the Brief Fatigue Inventory.RESULTS: Sixty patients received at least 1 dose of either study agent; the majority (65%) were treatment na ve. The ORR for the overall population was 33% and 50% in patients with clear cell RCC with sarcomatoid differentiation and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7 to 10.9 months). PD-L1 status was available for 36 patients; 15 (42%) had >= 1% expression on tumor cells. ORR in PD-L1-positive patients was 60% (n = 9) v 19% (n = 4) in PD-L1-negative patients. Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities. QOL was maintained throughout therapy.CONCLUSION: In this study, atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology RCC or RCC with >= 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1-positive tumors.
CANIT0002821	31722735	Clinical research	64 (100%) patients with metastatic UM	Uveal melanoma	EFO:1000616	Eye	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	59	N/A	Retrospective analysis	Combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic uveal melanoma available outside of clinical trials. In univariate Cox regression, ECOG status (p =0.000096), the presence of bone metastasis (p = 0.011), and the best response to checkpoint blockade (p = 0.002) were significantly associated with OS.	Colitis,hepatitis,thyreoiditis,hypophysitis,fever,myalgia with myositis	N/A	N/A	Metastasis (NCIT:C19151); 	Bone metastasis	Disease status	 2019 Nov 13	Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study.	 J Immunother Cancer	BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
CANIT0002822	31722735	Clinical research	64 (100%) patients with metastatic UM	Uveal melanoma	EFO:1000616	Eye	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	59	N/A	Retrospective analysis	Combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic uveal melanoma available outside of clinical trials. In univariate Cox regression, ECOG status (p =0.000096), the presence of bone metastasis (p = 0.011), and the best response to checkpoint blockade (p = 0.002) were significantly associated with OS.	Colitis,hepatitis,thyreoiditis,hypophysitis,fever,myalgia with myositis	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Nov 13	Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study.	 J Immunother Cancer	BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
CANIT0002823	31722735	Clinical research	64 (100%) patients with metastatic UM	Uveal melanoma	EFO:1000616	Eye	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); 	5	N/A	Retrospective analysis	Combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic uveal melanoma available outside of clinical trials. In univariate Cox regression, ECOG status (p =0.000096), the presence of bone metastasis (p = 0.011), and the best response to checkpoint blockade (p = 0.002) were significantly associated with OS.	Colitis,hepatitis,thyreoiditis,hypophysitis,fever,myalgia with myositis	N/A	N/A	Metastasis (NCIT:C19151); 	Bone metastasis	Disease status	 2019 Nov 13	Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study.	 J Immunother Cancer	BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
CANIT0002824	31722735	Clinical research	64 (100%) patients with metastatic UM	Uveal melanoma	EFO:1000616	Eye	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); 	5	N/A	Retrospective analysis	Combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic uveal melanoma available outside of clinical trials. In univariate Cox regression, ECOG status (p =0.000096), the presence of bone metastasis (p = 0.011), and the best response to checkpoint blockade (p = 0.002) were significantly associated with OS.	Colitis,hepatitis,thyreoiditis,hypophysitis,fever,myalgia with myositis	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Nov 13	Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study.	 J Immunother Cancer	BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
CANIT0002825	31725351	Clinical research	Previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	124	N/A	Phase II open-label study	Pembrolizumab is effective with a manageable safety profile in patients with previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC). A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached).	Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in >= 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A.	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 Jan 1	Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164.	 J Clin Oncol	PURPOSE: KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC).METHODS: This phase II open-label study involved 128 centers worldwide. Eligible patients were age >= 18 years and had metastatic MSI-H/dMMR CRC treated with >= 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or >= 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability.RESULTS: A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in >= 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A.CONCLUSION: Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.
CANIT0002826	31727009	Case report	A 67 year old Caucasian male that was initially treated with BRAF inhibitors followed by anti-CTLA4 and then anti-PD1 immunotherapy for metastatic melanoma but later developed colorectal cancer.	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Using cancer-specific mutational targets, we report here for the first time the efficacy of ctDNA to accurately provide a comprehensive outlook of the tumour status of two different cancers within one patient. Thus, ctDNA analysis has a potential clinical utility to delineate clinical information in patients with multiple cancer types.	N/A	N/A	N/A	Circulating tumour DNA	CtDNA levels	Metabolite	 2019 Nov 14	Circulating tumour DNA (ctDNA) as a biomarker in metachronous melanoma and colorectal cancer- a case report.	 BMC Cancer	BACKGROUND: Circulating tumour DNA (ctDNA) has emerged as a promising blood-based biomarker for monitoring disease status of patients with advanced cancers. The presence of ctDNA in the blood is a result of biological processes, namely tumour cell apoptosis and/or necrosis, and can be used to monitor different cancers by targeting cancer-specific mutation.CASE PRESENTATION: We present the case of a 67 year old Caucasian male that was initially treated with BRAF inhibitors followed by anti-CTLA4 and then anti-PD1 immunotherapy for metastatic melanoma but later developed colorectal cancer. The kinetics of ctDNA derived from each cancer type were monitored targeting BRAF V600R (melanoma) and KRAS G13D (colon cancer), specifically reflected the status of the patient's tumours. In fact, the discordant pattern of BRAF and KRAS ctDNA was significantly correlated with the clinical response of melanoma to pembrolizumab treatment and progression of colorectal cancer noted by PET and/or CT scan. Based on these results, ctDNA can be used to specifically clarify disease status of patients with metachronous cancers.CONCLUSIONS: Using cancer-specific mutational targets, we report here for the first time the efficacy of ctDNA to accurately provide a comprehensive outlook of the tumour status of two different cancers within one patient. Thus, ctDNA analysis has a potential clinical utility to delineate clinical information in patients with multiple cancer types.
CANIT0002827	31727009	Case report	A 67 year old Caucasian male that was initially treated with BRAF inhibitors followed by anti-CTLA4 and then anti-PD1 immunotherapy for metastatic melanoma but later developed colorectal cancer.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Using cancer-specific mutational targets, we report here for the first time the efficacy of ctDNA to accurately provide a comprehensive outlook of the tumour status of two different cancers within one patient. Thus, ctDNA analysis has a potential clinical utility to delineate clinical information in patients with multiple cancer types.	N/A	N/A	N/A	Circulating tumour DNA	CtDNA levels	Metabolite	 2019 Nov 14	Circulating tumour DNA (ctDNA) as a biomarker in metachronous melanoma and colorectal cancer- a case report.	 BMC Cancer	BACKGROUND: Circulating tumour DNA (ctDNA) has emerged as a promising blood-based biomarker for monitoring disease status of patients with advanced cancers. The presence of ctDNA in the blood is a result of biological processes, namely tumour cell apoptosis and/or necrosis, and can be used to monitor different cancers by targeting cancer-specific mutation.CASE PRESENTATION: We present the case of a 67 year old Caucasian male that was initially treated with BRAF inhibitors followed by anti-CTLA4 and then anti-PD1 immunotherapy for metastatic melanoma but later developed colorectal cancer. The kinetics of ctDNA derived from each cancer type were monitored targeting BRAF V600R (melanoma) and KRAS G13D (colon cancer), specifically reflected the status of the patient's tumours. In fact, the discordant pattern of BRAF and KRAS ctDNA was significantly correlated with the clinical response of melanoma to pembrolizumab treatment and progression of colorectal cancer noted by PET and/or CT scan. Based on these results, ctDNA can be used to specifically clarify disease status of patients with metachronous cancers.CONCLUSIONS: Using cancer-specific mutational targets, we report here for the first time the efficacy of ctDNA to accurately provide a comprehensive outlook of the tumour status of two different cancers within one patient. Thus, ctDNA analysis has a potential clinical utility to delineate clinical information in patients with multiple cancer types.
CANIT0002828	31735557	Clinical research	Bladder cancer	Bladder cancer	EFO:0000292	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	1934	N/A	Retrospective analysis	The results reveal an immunotherapeutic option for immune checkpoint inhibitor treatment of highly progressive non-muscle-invasive bladder cancer and muscle-invasive bladder cancer with poor prognosis.	N/A	N/A	N/A	Muscle-Invasive Bladder Carcinoma (NCIT:C150572)	Muscle-Invasive Bladder Carcinoma	Disease status	 2019 Dec	Identification of an immunotherapy-responsive molecular subtype of bladder cancer.	 EBioMedicine	BACKGROUND: Although various molecular subtypes of bladder cancer (BC) have been investigated, most of these studies have focused on muscle-invasive BC (MIBC). A few studies have investigated non-muscle-invasive BC (NMIBC) or NMIBC and MIBC together, but none has classified progressive NMIBC or immune checkpoint inhibitor (ICI)-based therapeutic responses in early-stage BC patients.METHODS: A total of 1,934 samples from seven patient cohorts were used. We performed unsupervised hierarchical clustering to stratify patients into distinct subgroups and constructed a classifier by applying SAM/PAM algorithms. We then investigated the association between molecular subtypes and immunotherapy responsiveness using various statistical methods.FINDINGS: We explored large-scale genomic datasets encompassing NMIBC and MIBC, redefining four distinct molecular subtypes, including a subgroup containing progressive NMIBC and MIBC with poor prognosis that would benefit from ICI treatment. This subgroup showed poor progression-free survival with the distinct features of high mutation load, activated cell cycle, and inhibited TGF¦Â signalling. Importantly, we verified that BC patients with this subtype were significantly responsive to an anti-PD-L1 agent in the IMvigor210 cohort.INTERPRETATION: Our results reveal an immunotherapeutic option for ICI treatment of highly progressive NMIBC and MIBC with poor prognosis.FUNDING: This research was supported by the National Research Foundation of Korea grant funded by the Korean government, a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea, and a grant from the KRIBB Research Initiative Program.
CANIT0002829	31745589	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	331	N/A	Retrospective analysis	Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting interstitial lung disease (ILD). A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3-2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2-14.6 months) for the patients without preexisting ILD.	Immune-related pneumonitis, interstitial lung disease	N/A	N/A	Interstitial lung disease (NCIT:C27006); 	Pre-existing interstitial lung disease	Disease status	 2020 Jan	Association of immune-related pneumonitis with the presence of preexisting interstitial lung disease in patients with non-small lung cancer receiving anti-programmed cell death 1 antibody.	 Cancer Immunol Immunother	The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3-2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2-14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.
CANIT0002830	31745593	Clinical research	Locally advanced, inoperable or metastatic, EGFR wildtype and ALK-negative non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Antibiotics followd by Immune checkpoint therapy	Immune checkpoint therapy	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	33	185	N/A	The results of this study suggest that antibiotics (ATB) may have a deleterious effect in patients with advanced NSCLC receiving immune checkpoint inhibitor (ICI) treatment, and more research seems to be justified to explore potential mechanisms. 33 out of 218 evaluable patients (15.1%) received ATB within 2 months prior to starting ICI treatment. The use of ATB prior to starting ICI was associated with a lower rate of radiological response (18.2 vs. 28.3%, respectively, P = 0.02). PFS was significantly shorter in patients receiving ATB within 2 months prior to ICI compared to those not receiving ATB (median PFS 1.4 vs. 5.5 months, HR = 2.22, P < 0.01). OS-ICI was significantly shorter in NSCLC patients receiving ATB within 2 months prior to ICI compared to those not receiving ATB (median OS-ICI 1.8 vs. 15.4 months, HR = 2.61, P < 0.01; adjusted HR = 3.73, P < 0.01).	N/A	N/A	N/A	Antibiotics (NCIT:C258); 	Antibiotics use	Exposure factors/status	 2020 Jan	Predictive impact of antibiotics in patients with advanced non small-cell lung cancer receiving immune checkpoint inhibitors : Antibiotics immune checkpoint inhibitors in advanced NSCLC.	 Cancer Chemother Pharmacol	PURPOSE: In this study, we test the hypothesis that the use of ATB reduces the efficacy of PD(L)1-targeting mAb.METHODS: We included patients with locally advanced, inoperable or metastatic, EGFR wildtype and ALK-negative non-small-cell lung cancer (NSCLC) who received a PD(L)1 targeting mAb (immune checkpoint inhibitor, ICI) between January 2013 and December 2017. The primary study objective was to assess the predictive impact of ATB use within 2 months prior to starting ICI treatment on overall survival from the time of starting ICI treatment (OS-ICI).RESULTS: 33 out of 218 evaluable patients (15.1%) received ATB within 2 months prior to starting ICI treatment. The use of ATB prior to starting ICI was associated with a lower rate of radiological response (18.2 vs. 28.3%, respectively, P = 0.02). PFS was significantly shorter in patients receiving ATB within 2 months prior to ICI compared to those not receiving ATB (median PFS 1.4 vs. 5.5 months, HR = 2.22, P < 0.01). OS-ICI was significantly shorter in NSCLC patients receiving ATB within 2 months prior to ICI compared to those not receiving ATB (median OS-ICI 1.8 vs. 15.4 months, HR = 2.61, P < 0.01; adjusted HR = 3.73, P < 0.01).CONCLUSION: The results of this study suggest that ATB may have a deleterious effect in patients with advanced NSCLC receiving ICI treatment, and more research seems to be justified to explore potential mechanisms.
CANIT0002831	31751163	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus carboplatin plus paclitaxel or nab-paclitaxel	Placebo plus carboplatin plus paclitaxel or nab-paclitaxel	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); carboplatin (DB00958); paclitaxel (DB01229); nab-paclitaxel (DB01229); 	278	281	Phase 3 KEYNOTE-407 study	Addition of pembrolizumab to chemotherapy maintained or improved health-related quality of life (HRQoL) measurements relative to baseline and improved HRQoL versus chemotherapy alone at weeks 9 and 18. These results support use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC. A total of 554 and 553 patients completed >= 1 QLQ-C30 or >= 1 QLQ-LC13 assessment, respectively. GHS/QoL score improved for the pembrolizumab-combination group (least squares [LS] mean [95% CI] change from baseline: week 9, 1.8 [-0.9 to 4.4]; week 18, 4.3 [1.7 to 6.9]) and deteriorated in the placebo-combination group (week 9, -1.8 [-4.4 to 0.7]; week 18, -0.57 [-3.3 to 2.2]). Between-group differences were improved for the pembrolizumab-combination group (difference in LS mean scores: week 9, 3.6 [95% CI, 0.3 to 6.9], nominal P = .0337; week 18, 4.9 [1.4 to 8.3], nominal P = .0060). Median time to deterioration in cough, chest pain, or dyspnea was not reached in either group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06]; nominal P = .125).	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan 20	Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non-Small-Cell Lung Cancer.	 J Clin Oncol	PURPOSE: In the phase 3 KEYNOTE-407 study, the addition of pembrolizumab to carboplatin-paclitaxel/nab-paclitaxel significantly improved overall survival, progression-free survival, and objective response rate in patients with previously untreated metastatic squamous non-small-cell lung cancer (NSCLC), with little impact on severe toxicity. We present patient-reported outcomes (PROs) from KEYNOTE-407.METHODS: Patients were randomly assigned to receive 4 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus carboplatin plus paclitaxel or nab-paclitaxel, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life (HRQoL) was evaluated using the European Organisation for Research and Treatment of Cancer Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Lung Cancer Module 13 (QLQ-LC13). Key PRO endpoints were change from baseline to weeks 9 and 18 (during and after platinum therapy) in the QLQ-C30 global health status/quality of life (GHS/QoL) score and time to deterioration in the composite endpoint of cough, chest pain, or dyspnea from the QLQ-C30 and QLQ-LC13. Two-sided, nominal P values are provided.RESULTS: A total of 554 and 553 patients completed >= 1 QLQ-C30 or >= 1 QLQ-LC13 assessment, respectively. GHS/QoL score improved for the pembrolizumab-combination group (least squares [LS] mean [95% CI] change from baseline: week 9, 1.8 [-0.9 to 4.4]; week 18, 4.3 [1.7 to 6.9]) and deteriorated in the placebo-combination group (week 9, -1.8 [-4.4 to 0.7]; week 18, -0.57 [-3.3 to 2.2]). Between-group differences were improved for the pembrolizumab-combination group (difference in LS mean scores: week 9, 3.6 [95% CI, 0.3 to 6.9], nominal P = .0337; week 18, 4.9 [1.4 to 8.3], nominal P = .0060). Median time to deterioration in cough, chest pain, or dyspnea was not reached in either group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06]; nominal P = .125).CONCLUSION: Addition of pembrolizumab to chemotherapy maintained or improved HRQoL measurements relative to baseline and improved HRQoL versus chemotherapy alone at weeks 9 and 18. These results support use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC.
CANIT0002832	31752049	Clinical research	135 patients treated with anti-programmed cell death-1 (PD-1) antibodies	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	135	N/A	Retrospective analysis	Non-alcoholic fatty liver disease (NAFLD) is a potential risk factor for PD-1 inhibitor-associated drug-induced liver injury (DILI) based on the DDW-J 2004 scale. The DDW-J 2004 scale might be useful for determining whether steroid treatment is required in patients with PD-1 inhibitor-associated DILI	Grade >= 2 hepatotoxic AEs during anti-PD-1 therapy, and PD-1 inhibitor-associated DILI 	N/A	N/A	Non-alcoholic fatty liver disease (NCIT:C84444); 	Preexisting non-alcoholic fatty liver disease	Disease status	 2020 Jun	Non-alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor.	 J Gastroenterol Hepatol	BACKGROUND AND AIM: Because of their survival benefits, immune checkpoint inhibitors (ICIs) are widely administered to patients with various advanced-stage malignancies. During ICI treatment, drug-induced liver injury (DILI) occasionally occurs. In particular, hepatic immune-related adverse events (irAEs) are rare but serious and fatal. In patients with hepatic irAEs, immediate steroid treatment is generally recommended; however, the risk factors for ICI-associated DILI remain unknown. In the present study, we identified a risk factor for ICI-associated DILI.METHODS: We retrospectively analyzed 135 patients treated with anti-programmed cell death-1 (PD-1) antibodies, such as nivolumab and pembrolizumab, at Asahikawa Medical University Hospital. We investigated grade >= 2 hepatotoxic AEs during anti-PD-1 therapy, and PD-1 inhibitor-associated DILI was then diagnosed according to the Digestive Disease Week Japan (DDW-J) 2004 scale. The risk factors for PD-1 inhibitor-associated DILI were identified by Cox hazard analysis.RESULTS: Thirty-six patients developed grade >= 2 hepatic AEs during anti-PD-1 therapy. Among them, eight patients were diagnosed with PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. Cox hazard analysis revealed that non-alcoholic fatty liver disease (NAFLD) was a risk factor for PD-1 inhibitor-associated DILI. In addition, we revealed that the outcomes of patients with the DDW-J 2004 score = 3 were improved without steroid treatment.CONCLUSIONS: NAFLD is a potential risk factor for PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. The DDW-J 2004 scale might be useful for determining whether steroid treatment is required in patients with PD-1 inhibitor-associated DILI.
CANIT0002833	31752994	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1959	N/A	Retrospective analysis	Bone metastases (BoM)  impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy. Cohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p < 0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p < 0.0001; Cohort B: 2.7 versus 5.2 months, p < 0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p < 0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78).	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Bone metastasis	Disease status	 2019 Nov 21	Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer.	 J Immunother Cancer	BACKGROUND: Bone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy.METHODS: Pretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM.RESULTS: Cohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p <  0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p <  0.0001; Cohort B: 2.7 versus 5.2 months, p <  0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p <  0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78).CONCLUSIONS: BoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy.
CANIT0002834	31753015	Clinical research	124 patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	124	N/A	Retrospective analysis	Some patients with previously treated, advanced NSCLC who discontinued nivolumab treatment for reasons other than tumor progression may have potential for a long-lasting treatment response, and irAE onset and a good ECOG PS at nivolumab initiation may be predictive markers of a long-lasting treatment response	Pneumonitis	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Nov 21	Long-lasting responses after discontinuation of nivolumab treatment for reasons other than tumor progression in patients with previously treated, advanced non-small cell lung cancer.	 Cancer Commun (Lond)	Unable to provide
CANIT0002835	31755463	Case report	A 60-year-old Caucasian female	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); 	1	N/A	Case	A case of recurrent orbito-conjunctival melanoma with metastasis that showed regression following systemic immune checkpoint inhibitor therapy	Hepatitis	N/A	N/A	BRAF (P15056); c-kit (P10721); NRAS (P01111); PD-L1 (Q9NZQ7); 	NRAS mutational status without BRAF or c-KIT mutations and without PD-L1 expression	Mutational status	 2019 Dec	Conjunctival melanoma with orbital invasion and liver metastasis managed with systemic immune checkpoint inhibitor therapy.	 Indian J Ophthalmol	A 60-year-old Caucasian female was referred for biopsy-proven amelanotic orbito-conjunctival melanoma. Map biopsies revealed residual invasive melanoma on the deep tarsal margin at the site of previous surgery. Repeat excisions were required after recurrence was detected following 3 months and 7 months. Positron emission tomography scan detected liver metastasis and additional orbito-conjunctival melanoma recurrence. Biomarker testing showed NRAS mutation without BRAF or c-KIT mutations and without PD-L1 expression. Systemic checkpoint inhibitor therapy was initiated with regression of both the orbito-conjunctival melanoma and liver metastasis. Invasive, non resectable orbito-conjunctival melanoma with liver metastasis can demonstrate a response to systemic checkpoint inhibitor therapy.
CANIT0002836	31757674	Basic research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-L1 (Q9NZQ7); 	CTLA-4; PD-L1	Atezolizumab plus ipilimumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); 	Cell lines	N/A	Basic research	PD-L1 exerts an immunostimulatory effect by repressing the CTLA-4 axis; this has implications to the synergy of anti-PD-L1 and anti-CTLA-4 combination therapy. 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression on antigen-presenting cells 	Gene expression signature on/in immune cell	 2019 Dec 17	PD-L1:CD80 Cis-Heterodimer Triggers the Co-stimulatory Receptor CD28 While Repressing the Inhibitory PD-1 and CTLA-4 Pathways.	 Immunity	Combined immunotherapy targeting the immune checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), or CTLA-4 and the PD-1 ligand (PD-L1) exhibits superior anti-tumor responses compared with single-agent therapy. Here, we examined the molecular basis for this synergy. Using reconstitution assays with fluorescence readouts, we found that PD-L1 and the CTLA-4 ligand CD80 heterodimerize in cis but not trans. Quantitative biochemistry and cell biology assays revealed that PD-L1:CD80 cis-heterodimerization inhibited both PD-L1:PD-1 and CD80:CTLA-4 interactions through distinct mechanisms but preserved the ability of CD80 to activate the T cell co-stimulatory receptor CD28. Furthermore, PD-L1 expression on antigen-presenting cells (APCs) prevented CTLA-4-mediated trans-endocytosis of CD80. Atezolizumab (anti-PD-L1), but not anti-PD-1, reduced cell surface expression of CD80 on APCs, and this effect was negated by co-blockade of CTLA-4 with ipilimumab (anti-CTLA-4). Thus, PD-L1 exerts an immunostimulatory effect by repressing the CTLA-4 axis; this has implications to the synergy of anti-PD-L1 and anti-CTLA-4 combination therapy.
CANIT0002837	31759780	Case report	Metastatic lung cancer	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We present a case of fulminant diabetes after only two cycles of pembrolizumab in a 53-year-old man with a history of metastatic lung cancer who presented to our emergency department with coma and acidosis revealing diabetic ketoacidosis. The patient was rehydrated and treated with insulin and recovered quickly. Lung toxicity was also suspected on CT-scan findings. This rare and life-threatening complication that developed unusually early during the treatment course may be challenging in a cancer patient. Therefore, emergency physicians should investigate symptoms in patients treated with checkpoint inhibitors and consider toxicity when they present to the ED with complaints compatible with an immune-related adverse event.	Fulminant diabetes	N/A	N/A	N/A	N/A	N/A	 2020 Feb	Fulminant diabetes due to immune checkpoint inhibitors in the emergency department.	 Am J Emerg Med	Immune checkpoint inhibitors (ICIs) are of growing importance in new cancer therapies, exposing patients to various and potentially severe immune-related adverse events and placing emergency physicians on the front line when they occur. If endocrine toxicity is a well-known complication of ICIs, fulminant diabetes with diabetic ketoacidosis is exceptional. We present a case of fulminant diabetes after only two cycles of pembrolizumab in a 53-year-old man with a history of metastatic lung cancer who presented to our emergency department with coma and acidosis revealing diabetic ketoacidosis. The patient was rehydrated and treated with insulin and recovered quickly. Lung toxicity was also suspected on CT-scan findings. This rare and life-threatening complication that developed unusually early during the treatment course may be challenging in a cancer patient. Therefore, emergency physicians should investigate symptoms in patients treated with checkpoint inhibitors and consider toxicity when they present to the ED with complaints compatible with an immune-related adverse event.
CANIT0002838	31761899	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	439	N/A	N/A	Median follow-up was 18.2 months (95% CI: 15.9-19.6). The overall survival of the iSEND (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR) Good (HR = 0.31, 95% CI: 0.22-0.43, p < 0.0001) was superior to the iSEND Poor. Time-dependent PPV for mortality of iSEND Poor was superior to PD-L1 = 0% group at 12 (75 vs. 53%, p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Prognostic model iSEND (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR)	Disease status	 2020 Feb	Association of the prognostic model iSEND with PD-1/L1 monotherapy outcome in non-small-cell lung cancer.	 Br J Cancer	BACKGROUND: Accessible biomarkers are needed for immunotherapy in advanced non-small-cell lung cancer (NSCLC). We previously described a multivariate risk prediction model, the iSEND, which categorises advanced NSCLC patients treated with nivolumab into Good, Intermediate or Poor groups. This model was developed by using only clinical and analytical variables (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR).METHODS: An international database of 439 patients who received post-platinum PD-1/L1 monotherapies was collected for validation. Performance of the iSEND to different PD-L1 groups was compared by using time-dependent positive predictive value (PPV) for their mortality events.RESULTS: Median follow-up was 18.2 months (95% CI: 15.9-19.6). The overall survival of the iSEND Good (HR = 0.31, 95% CI: 0.22-0.43, p < 0.0001) was superior to the iSEND Poor. Time-dependent PPV for mortality of iSEND Poor was superior to PD-L1 = 0% group at 12 (75 vs. 53%, p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort.CONCLUSION: The iSEND model is associated with the outcome of post-platinum PD-1/L1 monotherapy in advanced NSCLC patients. The iSEND Poor demonstrated a superior performance to PD-L1 = 0% in negative prognostication. Prospective investigation and modelling with other significant parameters in a larger cohort are warranted.
CANIT0002839	31755463	Case report	A 60-year-old Caucasian female	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Case	A case of recurrent orbito-conjunctival melanoma with metastasis that showed regression following systemic immune checkpoint inhibitor therapy	Hepatitis	N/A	N/A	BRAF (P15056); c-kit (P10721); NRAS (P01111); PD-L1 (Q9NZQ7); 	NRAS mutational status without BRAF or c-KIT mutations and without PD-L1 expression	Mutational status	 2019 Dec	Conjunctival melanoma with orbital invasion and liver metastasis managed with systemic immune checkpoint inhibitor therapy.	 Indian J Ophthalmol	A 60-year-old Caucasian female was referred for biopsy-proven amelanotic orbito-conjunctival melanoma. Map biopsies revealed residual invasive melanoma on the deep tarsal margin at the site of previous surgery. Repeat excisions were required after recurrence was detected following 3 months and 7 months. Positron emission tomography scan detected liver metastasis and additional orbito-conjunctival melanoma recurrence. Biomarker testing showed NRAS mutation without BRAF or c-KIT mutations and without PD-L1 expression. Systemic checkpoint inhibitor therapy was initiated with regression of both the orbito-conjunctival melanoma and liver metastasis. Invasive, non resectable orbito-conjunctival melanoma with liver metastasis can demonstrate a response to systemic checkpoint inhibitor therapy.
CANIT0002840	31773815	Clinical research	Cancers	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	N/A	N/A	N/A	These results demonstrated that the benefit-risk of nivolumab 240 mg every 2 weeks (Q2W) was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types.	Three exposure-response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune-mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types	N/A	N/A	N/A	N/A	N/A	 2020 Feb	Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers.	 Cancer Sci	Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit-risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure-response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune-mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure-response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune-mediated adverse events of grade 2 or higher. In addition, the predicted 1-year and 2-year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit-risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types.
CANIT0002841	31774363	Clinical research	25 metastatic melanoma 	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	Pembrolizumab	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); 	25	N/A	N/A	Unlike cutaneous ir-AEs that appear in patients on antiPD1 monotherapy, similar ir-AEs appear earlier and more rapidly in the combination therapy group. Hence, we recommend intense dermatological surveillance earlier in the treatment for patients who are on the combination therapy.	Cutaneous toxicities	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Outcomes of first-line pembrolizumab monotherapy for PD-L1-positive (TPS ¡Ý50%) metastatic NSCLC at US oncology practices.	 Immunotherapy	Aim: To determine real-world outcomes with first-line pembrolizumab monotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor expression >=50%. Methods: This retrospective study included adults with ECOG 0-1 initiating first-line pembrolizumab monotherapy on/after 24 October 2016 (EHR cohort) or from 1 December 2016 through 30 November 2017 (spotlight cohort) with >=6-month follow-up. We estimated Kaplan-Meier overall survival (OS, both cohorts), and, for spotlight, real-world progression-free survival (rwPFS) by Kaplan-Meier and real-world tumor response (rwTR). Results: For 423 patients in the EHR cohort and 188 in spotlight, median OS was 18.9 months (95% CI: 14.9-25.5) and 19.1 months (12.6-not reached), respectively. For spotlight, median rwPFS was 6.8 months (5.3-8.1); rwTR of complete/partial response was 48% (41-56%). Conclusion: Observed OS, rwPFS and rwTR were consistent with clinical trial findings.
CANIT0002842	31774688	Clinical research	Metastatic castration-resistant prostate cancer	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	258	N/A	Phase II KEYNOTE-199 study	Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to >= 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3.	Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%.	N/A	N/A	N/A	N/A	N/A	 2020 Feb 10	Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study.	 J Clin Oncol	PURPOSE: Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population.METHODS: The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety.RESULTS: Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to >= 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%.CONCLUSION: Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.
CANIT0002843	31779702	Clinical research	Hepatocellular carcinoma	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	15	N/A	Prospective study	The pilotmagnetic resonance elastography (MRE) data suggests early change in tumor stiffness may be an indicator of immunotherapy response in patients with advanced HCC. Nine patients were evaluable. Median age was 71 years (range, 54-78). Etiology of liver disease was HCV (n = 4), HBV (n = 1) and NASH (n = 4). Median overall survival (OS) and time to disease progression (TTP) were 44 weeks and 13 weeks, respectively. Average baseline HCC stiffness and change in HCC stiffness were 5.0 kPa and 0.12 kPa, respectively. In contrast, average non-tumor liver stiffness was 3.2 kPa, and did not significantly change at 6 weeks (p = 0.42). Average size of measured tumor and change in size were 4 cm and - 0.32 cm, respectively. Change in HCC stiffness at 6 weeks correlated significantly with OS (R = 0.81), and TTP (R = 0.88,p < 0.01). Abundance of intratumoral T lymphocytes on tumor biopsy correlated significantly with HCC stiffness (R = 0.79,p = 0.007).	N/A	N/A	N/A	Early change in tumor stiffness (); 	Early change in tumor stiffness	Disease status	 2019 Nov 28	Immunotherapy response evaluation with magnetic resonance elastography (MRE) in advanced HCC.	 J Immunother Cancer	BACKGROUND: Currently, there are no imaging predictors of immunotherapy outcome in hepatocellular carcinoma (HCC). The study aim was to determine if stiffness changes measured by magnetic resonance elastography (MRE) can be a predictor of immunotherapy response in patients with advanced HCC.MATERIALS AND METHODS: This was a prospective study of 15 patients with biopsy proven-advanced HCC treated with Pembrolizumab. All patients had liver MRE and liver biopsy at baseline and at 6 weeks of therapy. Change in HCC stiffness on MRE was compared with overall survival (OS), time to disease progression (TTP), and number of intratumoral CD3+ T lymphocytes. Analysis was performed using descriptive statistics and Spearman correlation (R); p-value < 0.05 was considered statistically significant.RESULTS: Nine patients were evaluable. Median age was 71 years (range, 54-78). Etiology of liver disease was HCV (n = 4), HBV (n = 1) and NASH (n = 4). Median OS and TTP were 44 weeks and 13 weeks, respectively. Average baseline HCC stiffness and change in HCC stiffness were 5.0 kPa and 0.12 kPa, respectively. In contrast, average non-tumor liver stiffness was 3.2 kPa, and did not significantly change at 6 weeks (p = 0.42). Average size of measured tumor and change in size were 4 cm and - 0.32 cm, respectively. Change in HCC stiffness at 6 weeks correlated significantly with OS (R = 0.81), and TTP (R = 0.88,p < 0.01). Abundance of intratumoral T lymphocytes on tumor biopsy correlated significantly with HCC stiffness (R = 0.79,p = 0.007).CONCLUSION: Our pilot MRE data suggests early change in tumor stiffness may be an indicator of immunotherapy response in patients with advanced HCC.
CANIT0002844	31779710	Basic research	Tumor	Cancer	EFO:0000311	Other	PD-1 (Q15116); MDM2 (Q00987); 	PD-1; MDM2	APG-115 plus nivolumab	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	The results demonstrate that p53 activation mediated by APG-115 promotes antitumor immunity in the tumor microenvironment (TME) regardless of the Trp53 status of tumors per se. Instead, such an effect depends on p53 activation in Trp53 wild-type immune cells in the TME. Based on the data, a phase 1b clinical trial has been launched for the evaluation of APG-115 in combination with pembrolizumab in solid tumor patients including those with TP53mut tumors.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2019 Nov 28	MDM2 inhibitor APG-115 synergizes with PD-1 blockade through enhancing antitumor immunity in the tumor microenvironment.	 J Immunother Cancer	BACKGROUND: Programmed death-1 (PD-1) immune checkpoint blockade has achieved clinical successes in cancer therapy. However, the response rate of anti-PD-1 agents remains low. Additionally, a subpopulation of patients developed hyperprogressive disease upon PD-1 blockade therapy. Combination therapy with targeted agents may improve immunotherapy. Recent studies show that p53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization, and attenuates tumor development and invasion, leading to the hypothesis that p53 activation may augment antitumor immunity elicited by anti-PD-1 therapy.METHOD: Using APG-115 that is a MDM2 antagonist in clinical development as a pharmacological p53 activator, we investigated the role of p53 in immune modulation and combination therapy with PD-1 blockade.RESULTS: In vitro treatment of bone marrow-derived macrophages with APG-115 resulted in activation of p53 and p21, and a decrease in immunosuppressive M2 macrophage population through downregulation of c-Myc and c-Maf. Increased proinflammatory M1 macrophage polarization was observed in the spleen from mice treated with APG-115. Additionally, APG-115 has co-stimulatory activity in T cells and increases PD-L1 expression in tumor cells. In vivo, APG-115 plus anti-PD-1 combination therapy resulted in enhanced antitumor activity in Trp53wt, Trp53mut, and Trp53-deficient (Trp53-/-) syngeneic tumor models. Importantly, such enhanced activity was abolished in a syngeneic tumor model established in Trp53 knockout mice. Despite differential changes in tumor-infiltrating leukocytes (TILs), including the increases in infiltrated cytotoxic CD8+ T cells in Trp53wt tumors and M1 macrophages in Trp53mut tumors, a decrease in the proportion of M2 macrophages consistently occurred in both Trp53wt and Trp53mut tumors upon combination treatment.CONCLUSION: Our results demonstrate that p53 activation mediated by APG-115 promotes antitumor immunity in the tumor microenvironment (TME) regardless of the Trp53 status of tumors per se. Instead, such an effect depends on p53 activation in Trp53 wild-type immune cells in the TME. Based on the data, a phase 1b clinical trial has been launched for the evaluation of APG-115 in combination with pembrolizumab in solid tumor patients including those with TP53mut tumors.
CANIT0002845	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Atypical teratoid rhabdoid tumour	EFO:1002008	Brain	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	3	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002846	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Cancer	EFO:0000311	Other	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	4	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002847	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Ewing sarcoma	EFO:0000174	Soft tissue	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	11	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002848	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	9	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002849	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Malignant rhabdoid tumour	EFO:0005701	Brain	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	3	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002850	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Neuroblastoma	EFO:0000621	Nervous system	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	11	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002851	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Non-hodgkins lymphoma	EFO:0005952	Blood and lymph nodes	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	3	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002852	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Non-rhabdomyosarcoma soft-tissue sarcoma	EFO:0000691	Soft tissue	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	9	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002853	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Osteosarcoma	EFO:0000637	Bone	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002854	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Rhabdomyosarcoma	EFO:0000437	Soft tissue	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002855	31780255	Clinical research	90 patients, with a median age of 14 years (IQR 10-17), were enrolled.	Wilms' tumour	DOID:5191	Kidney	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	10	N/A	A multicentre, open-label, phase 1-2	Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. High PD-L1 expression (defined as >5% of PD-L1-positive cells) was observed in tumours from all patients who showed some level of response, while other patients with high PD-L1- expressing tumours did not respond to atezolizumab. 	The most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.	 Lancet Oncol	BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression.METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604.FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses).INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments.FUNDING: F Hoffmann-La Roche.
CANIT0002856	31800340	Clinical research	Cancer plus inflammatory bowel disease	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	102	N/A	Multicenter, retrospective study	Preexisting inflammatory bowel disease (IBD)  increases the risk of severe therapy-related GI adverse events in patients treated with immune checkpoint inhibitors.	Immune checkpoint inhibitor therapy-related GI adverse events	N/A	N/A	Inflammatory bowel disease (NCIT:C3138); 	Preexisting inflammatory bowel disease	Disease status	 2020 Feb 20	Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease.	 J Clin Oncol	PURPOSE: The risk of immune checkpoint inhibitor therapy-related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors.PATIENTS AND METHODS: We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events.RESULTS: Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn's disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event-related deaths were recorded. Anti-cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively).CONCLUSION: Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.
CANIT0002857	31803501	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	16	N/A	Retrospective analysis	The analyses provide clinical insights that stratification of the patients is important in managing ICI-pneumonitis. Along with ICI-pneumonitis grade, more factors associated with the outcome need to be unravelled in the future. ICI-pneumonitis developed in 16 patients (2.3%); nine grade 1, four grade 2 and three grade 3.  Initially, 10 patients were spared from corticosteroid administration; fourpatients eventually received corticosteroid after 4 weeks of pneumonitis diagnosis due to clinical, radiographical aggravation and/or clinicians' decision. The other sixpatients never received corticosteroid and improved or remained stable radiographically. When the four and sixpatients were compared, pneumonitis grade was similar, while the latter sixpatients had a later onset from initiation of ICIs (mean 37.48 weeksvs25.45 weeks), more prior lines of chemotherapy (median 2.5 vs 1.0 lines), higher proportion of current/ex-smokers (83.3% vs 50.0%), and fewer other accompanying immune-related adverse events (50% vs 75%). Time to improvement of pneumonitis was similar between the fourpatients who received delayed corticosteroid and fivepatients who received corticosteroid within 4 weeks(3.6 vs 2.5 weeks).	Immune checkpoint inhibitor (ICI)-induced pneumonitis	N/A	N/A	N/A	N/A	N/A	 2019 Nov 28	Clinical insights on outcomes of corticosteroid administration in immune checkpoint inhibitor-induced pneumonitis by retrospective case series analysis.	 ESMO Open	BACKGROUND: For the management of immune checkpoint inhibitor (ICI)-induced pneumonitis (ICI-pneumonitis), discontinuation of ICIs and high dose corticosteroid based on grade are generally recommended. The purpose of this study is to describe management and outcome of ICI-pneumonitis and explore what to consider when managing ICI-pneumonitis with or without corticosteroids in addition to grade.METHODS: We reviewed data of 706 cancer patients who were treated with ICIs and identified radiographically proven pneumonitis. The diagnosis of ICI-pneumonitis was established after excluding alternative aetiologies either by a bronchoscopy or a thorough examination of clinical features. The evaluation of the management and outcome of pneumonitis were evaluated according to the time of corticosteroid administration.RESULTS: ICI-pneumonitis developed in 16 patients (2.3%); nine grade 1, four grade 2 and three grade 3. Initially, 10 patients were spared from corticosteroid administration; fourpatients eventually received corticosteroid after 4 weeks of pneumonitis diagnosis due to clinical, radiographical aggravation and/or clinicians' decision. The other sixpatients never received corticosteroid and improved or remained stable radiographically. When the four and sixpatients were compared, pneumonitis grade was similar, while the latter sixpatients had a later onset from initiation of ICIs (mean 37.48 weeksvs25.45 weeks), more prior lines of chemotherapy (median 2.5 vs 1.0 lines), higher proportion of current/ex-smokers (83.3% vs 50.0%), and fewer other accompanying immune-related adverse events (50% vs 75%). Time to improvement of pneumonitis was similar between the fourpatients who received delayed corticosteroid and fivepatients who received corticosteroid within 4 weeks(3.6 vs 2.5 weeks).CONCLUSIONS: Our analyses provide clinical insights that stratification of the patients is important in managing ICI-pneumonitis. Along with ICI-pneumonitis grade, more factors associated with the outcome need to be unravelled in the future.
CANIT0002858	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CTLA-4 (P16410); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CTLA-4(+)CD4(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002859	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CTLA-4 (P16410); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CTLA-4(+)CD8(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002860	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	PD1(+)CD8(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002861	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	PD1(+)CD4(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002862	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CTLA-4 (P16410); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CTLA-4(+)CD4(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002863	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CTLA-4 (P16410); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CTLA-4(+)CD8(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002864	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	PD1(+)CD8(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002865	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	PD1(+)CD4(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002866	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CTLA-4 (P16410); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CTLA-4(+)CD4(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002867	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CTLA-4 (P16410); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CTLA-4(+)CD8(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002868	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	PD1(+)CD8(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002869	31810958	Clinical research	Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab.	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	19	N/A	N/A	The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	PD1(+)CD4(+) T-lymphocytes	Gene expression signature on/in immune cell	 2019 Dec	Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.	 Anticancer Res	BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy.PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor.RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood.CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.
CANIT0002870	31811095	Case report	An 81-year-old woman	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We present a case of life-threatening de novo autoimmune haemolytic anaemia (AIHA) complicated by immune cholangitis induced by pembrolizumab	Autoimmune haemolytic anaemia and cholangitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 5	Pembrolizumab-induced autoimmune haemolytic anaemia and cholangitis.	 BMJ Case Rep	Increasing numbers of patients are now offered immunotherapy as part of their cancer treatment. These treatments, while often very effective, have a wide range of adverse effects that are distinct from those of traditional chemotherapy regimens. Thyroid disease, dermatological disease, colitis and pneumonitis are some of the most commonly reported immune side effects. We present a case of life-threatening de novo autoimmune haemolytic anaemia (AIHA) complicated by immune cholangitis induced by pembrolizumab. An 81-year-old woman with metastatic melanoma completed a two-year course of pembrolizumab in August 2018 and six weeks later presented to hospital with jaundice. Admission haemoglobin (Hb) was 91 g/L, rapidly decreasing to 31 g/L, at which point she required admission to the intensive care unit. AIHA is a rare but potentially life-threatening complication of checkpoint inhibitors and should be considered in patients presenting with anaemia during or after immunotherapy treatment.
CANIT0002871	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Adenocarcinoma	EFO:0000228	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002872	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Adrenocortical carcinoma	MONDO:0008734	Adrenal gland	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002873	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Alveolar rhabdomyosarcoma	EFO:0000437	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002874	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Alveolar soft part sarcoma	EFO:0007143	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002875	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Angiosarcoma	EFO:0003968	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002876	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Atypical teratoid rhabdoid tumour	EFO:1002008	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002877	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Chordoma	Orphanet:178	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002878	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Clear cell soft tissue carcinoma	EFO:0000348	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002879	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Colloid carcinoma	EFO:0000197	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002880	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Colon adenocarcinoma	EFO:1001949	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002881	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Craniopharyngioma	EFO:1000209	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002882	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Diffuse large B cell lymphoma	EFO:0000403	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002883	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Embryonal rhabdomyosarcoma	EFO:0000437	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002884	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Embryonal rhabdomyosarcoma	EFO:0000437	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002885	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Ependymoma	EFO:1000028	Ovary	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002886	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Epithelioid sarcoma	MONDO:0017387	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002887	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Hepatoblastoma	EFO:1000292	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	5	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002888	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002889	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Hepatocellular carcinoma	EFO:0000182	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002890	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	High-grade glioma	MONDO:0021640	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	22	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002891	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	18	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002892	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Inflammatory myofibroblastic tumour	MONDO:0015798	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	4	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002893	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Low-grade astrocytoma	MONDO:0016685	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002894	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Lymphoepithelial carcinoma	DOID:5660	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002895	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Malignant histiocytosis	HP:0100727	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002896	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Malignant rhabdoid tumour	EFO:0005701	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002897	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Medulloblastoma	EFO:0002939	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002898	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	8	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002899	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Meningioma	Orphanet:2495	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002900	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Mesoblastic nephroma	EFO:0007365	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002901	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Mesothelioma	EFO:0000588	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002902	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Mixed acinar¨Cendocrine carcinoma	EFO:0000216	Salivary gland	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002903	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Myoepithelial carcinoma	DOID:4838	Thymus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002904	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002905	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Neuroblastoma	EFO:0000621	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	11	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002906	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Neuroendocrine tumour	N/A	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002907	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002908	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Osteosarcoma	EFO:0000637	Bone	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	10	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002909	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Paraganglioma	EFO:1000453	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002910	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Pilocytic astrocytoma	MONDO:0016691	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002911	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Precursor T lymphoblastic lymphoma	MONDO:0003537	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002912	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002913	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Renal medullary carcinoma	EFO:0002890	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002914	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	6	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002915	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Small cell carcinoma	EFO:0008524	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002916	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Spindle cell sarcoma	MONDO:0002927	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002917	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Squamous cell carcinoma	EFO:0000707	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002918	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Thymic cell carcinoma	EFO:1000579	Thymus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002919	31812554	Clinical research	Paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051)	Wilms' tumour	DOID:5191	Kidney	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	3	N/A	Open-label, single-arm, phase 1-2 trial	Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.	Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis).	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan	Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.METHODS: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.FINDINGS: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8.6 months (IQR 2.5-16.4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60.0%; 95% CI 32.3-83.7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5.9% (95% CI 2.6-11.3).INTERPRETATION: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
CANIT0002920	31815569	Case report	Stage IV lung adenocarcinoma	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab followed by prednisone plus tapering	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); prednisone (DB00635); 	1	N/A	Case	There is a case of cardiac tamponade in a patient with stage IV lung adenocarcinoma, with almost 100% expression of PD-L1, treated with pembrolizumab. The patient is a 62-year-old male who developed worsening shortness of breath after five cycles of pembrolizumab. He was diagnosed with large pericardial effusion on computed tomography chest. Echocardiogram confirmed tamponade physiology. He was treated with discontinuation of pembrolizumab and urgent pericardial window followed by high dose prednisone with tapering. The patient responded very well to the treatment.	Cardiac tamponade	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression on antigen-presenting cells 	Gene expression signature on/in immune cell	 2019 Dec	Cardiac tamponade in a patient with stage IV lung adenocarcinoma treated with pembrolizumab.	 Immunotherapy	Immunotherapy drugs are associated with a multitude of immune-related adverse events. We describe a case of cardiac tamponade in a patient with stage IV lung adenocarcinoma, with almost 100% expression of PDL-1, treated with pembrolizumab. The patient is a 62-year-old male who developed worsening shortness of breath after five cycles of pembrolizumab. He was diagnosed with large pericardial effusion on computed tomography chest. Echocardiogram confirmed tamponade physiology. He was treated with discontinuation of pembrolizumab and urgent pericardial window followed by high dose prednisone with tapering. The patient responded very well to the treatment. We have comprehensively reviewed cases of pericardial effusion secondary to either immune mediated mechanisms or pseudoprogression.
CANIT0002921	31836957	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116);  	CTLA-4; PD-1	Ipilimumab or nivolumab plus stereotactic radiosurgery	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of stereotactic radiosurgery was associated with better outcomes. In a multivariate Cox regression analysis an age > 65 was correlated with poorer prognosis. 	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2020 Jan	The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.	 J Neurooncol	BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS.METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018.RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels >= 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04).CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.
CANIT0002922	31836957	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab plus stereotactic radiosurgery	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of stereotactic radiosurgery was associated with better outcomes. Elevated serum LDH levels are predictors of poor outcome in these patients.	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2020 Jan	The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.	 J Neurooncol	BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS.METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018.RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels >= 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04).CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.
CANIT0002923	31836957	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab plus stereotactic radiosurgery	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of stereotactic radiosurgery was associated with better outcomes.In a multivariate Cox regression analysis > 2 metastatic sites was correlated with poorer prognosis.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Number of metastatic sites	Disease status	 2020 Jan	The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.	 J Neurooncol	BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS.METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018.RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels >= 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04).CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.
CANIT0002924	31836957	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab plus stereotactic radiosurgery	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of stereotactic radiosurgery was associated with better outcomes. In a multivariate Cox regression analysis > 4 brain metastases was correlated with poorer prognosis. 	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2020 Jan	The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.	 J Neurooncol	BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS.METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018.RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels >= 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04).CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.
CANIT0002925	31836957	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab plus stereotactic radiosurgery	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of stereotactic radiosurgery was associated with better outcomes. In a multivariate Cox regression analysis synchronous brain metastases was correlated with poorer prognosis. 	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2020 Jan	The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.	 J Neurooncol	BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS.METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018.RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels >= 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04).CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.
CANIT0002926	31836957	Clinical research	Melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab plus stereotactic radiosurgery	N/A	Immune checkpoint therapy plus Radiotherapy	Ipilimumab (DB06186); nivolumab (DB09035); 	84	N/A	Retrospective analysis	A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of stereotactic radiosurgery was associated with better outcomes. In a multivariate Cox regression analysis an ECOG > 1 was correlated with poorer prognosis. 	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2020 Jan	The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.	 J Neurooncol	BACKGROUND: Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9 weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS.METHODS: We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018.RESULTS: We included 84 patients. The median OS was 12 months (95% CI 9-20 months). The median follow-up was 30 months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9 weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5 months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7 months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9 weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels >= 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04).CONCLUSIONS: The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.
CANIT0002927	31838158	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	1615	N/A	Retrospective analysis	Isolated adrecocorticotrophic hormone deficiency  (IAD), a rare disease before the immunotherapy era, has become a predominant checkpoint related hypothalamic-pituitary-adrenal (HPA) axis autoimmune injury. Despite its life threatening potential, IAD may be missed due to its subtle presentation. Patients exposed to Ipilimumab and PD-1/PD-L1 in combination or sequentially and women have an increased risk for developing IAD.	Isolated adrecocorticotrophic hormone deficiency	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2020 Feb	Isolated autoimmune adrenocorticotropic hormone deficiency: From a rare disease to the dominant cause of adrenal insufficiency related to check point inhibitors.	 Autoimmun Rev	OBJECTIVE: Immune checkpoint inhibitors have introduced a new and heterogeneous class of immune-related adverse effects, with the endocrine system being a predominant target for autoimmunity. Autoimmune hypothalamic-pituitary-adrenal axis (HPA) diseases induced by checkpoint inhibitors are being increasingly recognized. We aimed to characterize the spectrum of checkpoint associated hypothalamic-pituitary-adrenal axis endocrinopathies.DESIGN: A retrospective cohort study of a tertiary cancer center.METHODS: Patients were characterized for HPA axis abnormalities based on clinical and pituitary axes evaluation. The risk for developing HPA endocrinopathies was compared by log- rank test, by the time since checkpoint inhibitors initiation. Additionally, the risk for developing HPA endocrinopathies after adjusting for covariates was assessed using multivariable logistic regression analysis.RESULTS: Among 1615 patients, fourteen (0.87%) patients developed isolated adrecocorticotrophic hormone deficiency (IAD), six (0.37%) - hypophysitis and no case of adrenalitis was identified. IAD presented with mild and non-specific symptoms, mainly asthenia. In multivariable analysis, exposure to both PD-1/PD-L1 and Ipilimumab and female gender were associated with an increased odds ratio (OR) for developing IAD (6.98 [95% CI 2.38-20.47, p < .001] and 3.67 [95% CI 1.13-11.84, p = .03]), respectively.CONCLUSIONS: IAD, a rare disease before the immunotherapy era, has become a predominant checkpoint related HPA axis autoimmune injury. Despite its life threatening potential, IAD may be missed due to its subtle presentation. Patients exposed to Ipilimumab and PD-1/PD-L1 in combination or sequentially and women have an increased risk for developing IAD.
CANIT0002928	31838158	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	1615	N/A	Retrospective analysis	Isolated adrecocorticotrophic hormone deficiency  (IAD), a rare disease before the immunotherapy era, has become a predominant checkpoint related hypothalamic-pituitary-adrenal (HPA) axis autoimmune injury. Despite its life threatening potential, IAD may be missed due to its subtle presentation. Patients exposed to Ipilimumab and PD-1/PD-L1 in combination or sequentially and women have an increased risk for developing IAD.	Isolated adrecocorticotrophic hormone deficiency	N/A	N/A	PD-L1 (Q9NZQ7); PD-1 (Q15116); 	Exposure to both PD-1/PD-L1 and Ipilimumab	Gene expression signature on/in tumor cell	 2020 Feb	Isolated autoimmune adrenocorticotropic hormone deficiency: From a rare disease to the dominant cause of adrenal insufficiency related to check point inhibitors.	 Autoimmun Rev	OBJECTIVE: Immune checkpoint inhibitors have introduced a new and heterogeneous class of immune-related adverse effects, with the endocrine system being a predominant target for autoimmunity. Autoimmune hypothalamic-pituitary-adrenal axis (HPA) diseases induced by checkpoint inhibitors are being increasingly recognized. We aimed to characterize the spectrum of checkpoint associated hypothalamic-pituitary-adrenal axis endocrinopathies.DESIGN: A retrospective cohort study of a tertiary cancer center.METHODS: Patients were characterized for HPA axis abnormalities based on clinical and pituitary axes evaluation. The risk for developing HPA endocrinopathies was compared by log- rank test, by the time since checkpoint inhibitors initiation. Additionally, the risk for developing HPA endocrinopathies after adjusting for covariates was assessed using multivariable logistic regression analysis.RESULTS: Among 1615 patients, fourteen (0.87%) patients developed isolated adrecocorticotrophic hormone deficiency (IAD), six (0.37%) - hypophysitis and no case of adrenalitis was identified. IAD presented with mild and non-specific symptoms, mainly asthenia. In multivariable analysis, exposure to both PD-1/PD-L1 and Ipilimumab and female gender were associated with an increased odds ratio (OR) for developing IAD (6.98 [95% CI 2.38-20.47, p < .001] and 3.67 [95% CI 1.13-11.84, p = .03]), respectively.CONCLUSIONS: IAD, a rare disease before the immunotherapy era, has become a predominant checkpoint related HPA axis autoimmune injury. Despite its life threatening potential, IAD may be missed due to its subtle presentation. Patients exposed to Ipilimumab and PD-1/PD-L1 in combination or sequentially and women have an increased risk for developing IAD.
CANIT0002929	31843780	Case report	Metastatic gastro-oesophageal junction cancer	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We present a case of a 71-year-old woman with metastatic gastro-oesophageal junction (GOJ) adenocarcinoma who developed delayed-onset chronic intestinal pseudo-obstruction (CIPO) while receiving second-line pembrolizumab. Repeated CT scans of the abdomen/pelvis found no small bowel obstruction, and evaluations for bowel inflammation, infection and paraneoplastic syndrome were negative. Bowel rest and glucocorticoids were associated with transient symptom resolution; however, symptoms recurred within 1 month. The patient was ultimately supported with total parenteral nutrition and intestinal motility agents. After 4 months, the GOJ cancer remained stable with no signs of progression. As immune checkpoint inhibitors use expands, the incidence of rare irAEs, such as CIPO, may increase.	Chronic intestinal pseudo-obstruction	N/A	N/A	N/A	N/A	N/A	 2019 Dec 15	Chronic intestinal pseudo-obstruction in a patient with metastatic gastro-oesophageal junction cancer receiving treatment with pembrolizumab.	 BMJ Case Rep	Acute gastrointestinal (GI) immune-related adverse events (irAE) are commonly reported by patients with cancer undergoing treatment with immune checkpoint inhibitors (CPI); however chronic irAEs are rare. We present a case of a 71-year-old woman with metastatic gastro-oesophageal junction (GOJ) adenocarcinoma who developed delayed-onset chronic intestinal pseudo-obstruction (CIPO) while receiving second-line pembrolizumab. Repeated CT scans of the abdomen/pelvis found no small bowel obstruction, and evaluations for bowel inflammation, infection and paraneoplastic syndrome were negative. Bowel rest and glucocorticoids were associated with transient symptom resolution; however, symptoms recurred within 1 month. The patient was ultimately supported with total parenteral nutrition and intestinal motility agents. After 4 months, the GOJ cancer remained stable with no signs of progression. As CPI use expands, the incidence of rare irAEs, such as CIPO, may increase.
CANIT0002930	31852068	Case report	Papillary renal cell carcinoma	Papillary renal cell carcinoma	EFO:0000640	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The patients underwent left radical nephrectomy and homolateral cervical and para-aortic lymphadenectomy, with histological diagnosis of PRCC, type II. After disease relapse, the inter-aortocaval lymph node was laparoscopically removed. Following the detection of further disease relapse in several lymph nodes and the lung, several lines of target-therapy were started; then disease progression and worsening of clinical and hematological status led us to start Nivolumab as last-line therapy. A heterogeneous response to therapies was documented with morphological and nuclear medicine imaging, however the concomitant deterioration of performance status and liver function led to discontinuation of Nivolumab; then the patient died, 30 months after diagnosis. Highlighting that 18F-FDG PET/CT shows greater adequacy in assessing the response to therapy, avoiding premature drug discontinuation, and ensuring better management of a patient with advanced PRCC.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec	Heterogeneous response to target therapy in metastatic papillary renal cell carcinoma evaluated by morphologic and metabolic multimodality imaging: A case report.	 Medicine (Baltimore)	RATIONALE: Papillary renal cell carcinoma (PRCC) accounts for about 15% to 20% of renal cell carcinoma and is histologically distinguished in type I and type II. The last one is associated with poorer prognosis.Treatment options for PRCC patients are surgery, immunotherapy, revolutionized by Nivolumab, and other target-therapy with an improvement in overall survival. Heterogenous response and a pseudo-progression may be observed in the initial phase of biological treatment that could induce premature discontinuation.PATIENT CONCERNS: We present the case of a 44-year-old woman with left cervical palpable mass increased in size and without concomitant disease or previous surgery.DIAGNOSIS: Neck ultrasonography, contrast-enhanced Computed Tomography, and 18F-FDG PET/CT were performed with the detection of lymph nodes involvement and a left renal lesion.INTERVENTIONS: The patients underwent left radical nephrectomy and homolateral cervical and para-aortic lymphadenectomy, with histological diagnosis of PRCC, type II. After disease relapse, the inter-aortocaval lymph node was laparoscopically removed. Following the detection of further disease relapse in several lymph nodes and the lung, several lines of target-therapy were started; then disease progression and worsening of clinical and hematological status led us to start Nivolumab as last-line therapy.OUTCOMES: A heterogeneous response to therapies was documented with morphological and nuclear medicine imaging, however the concomitant deterioration of performance status and liver function led to discontinuation of Nivolumab; then the patient died, 30 months after diagnosis.LESSONS: Here we describe the clinical case and radiological and nuclear medicine imaging investigations performed by our patient, highlighting that 18F-FDG PET/CT shows greater adequacy in assessing the response to therapy, avoiding premature drug discontinuation, and ensuring better management of a patient with advanced PRCC.
CANIT0002931	31852845	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	153	N/A	3 distinct patient cohorts and 1 mouse model of lung cancer	Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	Neutrophil antagonism (); 	Neutrophil antagonism	Cell percentage/counts in blood	 2019 Dec 19	Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC.	 JCI Insight	Immune checkpoint inhibitor (ICI) treatment has recently become a first-line therapy for many non-small cell lung cancer (NSCLC) patients. Unfortunately, most NSCLC patients are refractory to ICI monotherapy, and initial attempts to address this issue with secondary therapeutics have proven unsuccessful. To identify entities precluding CD8+ T cell accumulation in this process, we performed unbiased analyses on flow cytometry, gene expression, and multiplexed immunohistochemical data from a NSCLC patient cohort. The results revealed the presence of a myeloid-rich subgroup, which was devoid of CD4+ and CD8+ T cells. Of all myeloid cell types assessed, neutrophils were the most highly associated with the myeloid phenotype. Additionally, the ratio of CD8+ T cells to neutrophils (CD8/PMN) within the tumor mass optimally distinguished between active and myeloid cases. This ratio was also capable of showing the separation of patients responsive to ICI therapy from those with stable or progressive disease in 2 independent cohorts. Tumor-bearing mice treated with a combination of anti-PD1 and SX-682 (CXCR1/2 inhibitor) displayed relocation of lymphocytes from the tumor periphery into a malignant tumor, which was associated with induction of IFN-¦Ã-responsive genes. These results suggest that neutrophil antagonism may represent a viable secondary therapeutic strategy to enhance ICI treatment outcomes.
CANIT0002932	31853575	Case report	Myxofibrosarcoma	Myxofibrosarcoma	MONDO:0019202	Soft tissue	PD-1 (Q15116); 	PD-1; 	Nivolumab plus peptide vaccination	Peptide vaccination	Immune checkpoint therapy plus Tumor vaccine 	Nivolumab (DB09035); 	1	1	Case	Peptide vaccinations elicited strong immune responses that were reboosted by anti-PD1 therapy in a patient with myxofibrosarcoma.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Feb	Peptide vaccinations elicited strong immune responses that were reboosted by anti-PD1 therapy in a patient with myxofibrosarcoma.	 Cancer Immunol Immunother	Peptide-based immunotherapy does not usually elicit strong immunological and clinical responses in patients with end-stage cancer, including sarcoma. Here we report a myxofibrosarcoma patient who showed a strong clinical response to peptide vaccinations and whose immune responses were reboosted by anti-PD1 therapy combined with peptide vaccinations. The 46-year-old man showed a strong response to the peptide vaccinations (papillomavirus binding factor peptide, survivin-2B peptide, incomplete Freund's adjuvant, and polyethylene glycol-conjugated interferon-alpha 2a) and subsequent wide necrosis and massive infiltration of CD8+ T cells in a recurrent tumor. The patient's immune responses weakened after surgical resection; however, they were reboosted following the administration of nivolumab combined with peptide vaccinations. Thus, anti-PD1 therapy combined with peptide vaccinations might be beneficial, as suggested by the observations in this sarcoma patient.
CANIT0002933	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002934	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	40	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002935	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	11	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002936	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	7	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002937	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	13	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002938	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002939	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	17	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002940	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Pleural mesothelioma	EFO:1000485	Soft tissue	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002941	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	2	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002942	31857638	Clinical research	249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Retrospective analysis	The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.	Hypophysitis	N/A	N/A	N/A	N/A	N/A	 2019 Dec 19	Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.	 Sci Rep	Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.
CANIT0002943	31858306	Clinical research	Sixty-seven patients who received nivolumab after the failure of at least one molecular-targeted therapy were evaluated. The patients were divided into two groups based on the line of nivolumab: second-line and later-line groups. 	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	42	N/A	Retrospective analysis	There was no difference in PFS or ORR between second-line and later-line nivolumab therapy for previously-treated mRCC. Meanwhile,the OS after nivolumab initiation tended to be longer and the rate of subsequent therapy after nivolumab failure was significantly higher in second-line therapy.In addition, the OS after nivolumab failure tended to be longer with second-line therapy. Regarding safety, there was no difference in the incidences of immune-related adverse events between the second-line and later-line therapy.	Rash/ ruritus,Alanine/aspartate aminotransferase increased	N/A	N/A	N/A	N/A	N/A	 2020 Apr	Comparable efficacy and safety between second-line and later-line nivolumab therapy for metastatic renal cell carcinoma.	 Int J Clin Oncol	BACKGROUND: The aim of this study was to compare the efficacy and safety of nivolumab as second-line and later-line (third-line or thereafter) therapy in metastatic renal cell carcinoma (mRCC).METHODS: Sixty-seven patients who received nivolumab after the failure of at least one molecular-targeted therapy were evaluated. The patients were divided into two groups based on the line of nivolumab: second-line and later-line groups. Efficacy was assessed using progression-free survival and overall survival (OS) after nivolumab initiation, and objective response rate. Safety was assessed using the incidence of immune-related adverse events. These outcomes were compared between the second-line and later-line groups.RESULTS: Forty-two patients (62.7%) received nivolumab as second-line therapy. There was no significant difference in the progression-free survival (median: 5.06 vs. 6.28 months, p = 0.691) or objective response rate (35.7% vs. 32.0%, p = 0.757) between the second-line and later-line groups. The OS tended to be longer in the second-line group (not reached vs. 26.0 months, p = 0.118), and the rate of patients who received subsequent therapy after nivolumab failure was significantly higher in the second-line group (90.9% vs. 55.0%, p = 0.0025). There was no difference in the incidences of immune-related adverse events between the second-line and later-line groups (any grade: 54.8% vs. 48.0%, p = 0.592; grade >= 3: 19.1% vs. 20.0%, p = 0.924).CONCLUSIONS: The efficacy of nivolumab did not deteriorate and the tolerability was also maintained even in later-line therapy. However, a tendency of longer OS and a higher chance of subsequent therapy after nivolumab failure were observed with nivolumab as second-line therapy.
CANIT0002944	31864957	Clinical research	Head and neck squamous cell carcinoma	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus systemic therapy	N/A	Immune checkpoint therapy plus Systemic therapy	N/A	43	N/A	Retrospective analysis	In the cohort of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) patients, the  overall response rate (ORR) and  overall survival (OS) to systemic therapy after progression on  immune checkpoint inhibitors (ICI) were higher than historical controls for second-line or beyond. Further investigations are warranted to better characterize optimal sequencing and combination strategies. A total of 43 patients met criteria for inclusion. The majority were male (91%) and former smokers (60%). Most patients received ICI as first-line (58.14%); the vast majority was platinum exposed (90.7%). The ORR to ICI was 21%. The ORR to systemic therapy before ICI was 47%, and the ORR after ICI failure was 42%. After progression on ICI, the median PFS and OS on the subsequent line of therapy were 4.2 and 8.4 months respectively.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Feb	Response rates and survival to systemic therapy after immune checkpoint inhibitor failure in recurrent/metastatic head and neck squamous cell carcinoma.	 Oral Oncol	OBJECTIVES: Prior reports have demonstrated a potential enhancement in overall response rate (ORR) to chemotherapy after exposure to immunotherapy. The goal of this study was to evaluate the ORR and survival to chemotherapy and/or targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients who progressed on immune checkpoint inhibitors (ICI).MATERIALS AND METHODS: We retrospectively collected clinical and pathologic data from patients with recurrent/metastatic HNSCC who progressed on ICI and subsequently received chemotherapy or targeted therapy. ORR was assessed by RECIST version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.RESULTS: A total of 43 patients met criteria for inclusion. The majority were male (91%) and former smokers (60%). Most patients received ICI as first-line (58.14%); the vast majority was platinum exposed (90.7%). The ORR to ICI was 21%. The ORR to systemic therapy before ICI was 47%, and the ORR after ICI failure was 42%. After progression on ICI, the median PFS and OS on the subsequent line of therapy were 4.2 and 8.4 months respectively.CONCLUSION: In our cohort of recurrent/metastatic HNSCC patients, the ORR and OS to systemic therapy after progression on ICI were higher than historical controls for second-line or beyond. Further investigations are warranted to better characterize optimal sequencing and combination strategies.
CANIT0002945	31873875	Clinical research	44 patients with melanoma brain metastases	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Retrospective analysis	Lower perfusion parameters in pseudoprogression, suggesting that dynamic contrast enhanced T1 MRI derived capillary permeability (Ktrans) and plasma volume measurements can be helpful in the diagnosis of pseudoprogression in melanoma patients with brain metastases after being treated with immunotherapy	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	DCE-MRI perfusion predicts pseudoprogression in metastatic melanoma treated with immunotherapy.	 J Neurooncol	PURPOSE: It can be challenging to differentiate pseudoprogression from progression. We assessed the ability of dynamic contrast enhanced T1 MRI (DCE-MRI) perfusion to identify pseudoprogression in melanoma brain metastases.METHODS: Patients with melanoma brain metastases who underwent immunotherapy and DCE-MRI were identified. Enhancing lesions >=  5mm in diameter on DCE-MRI and that were new or increased in size between a week from beginning the treatment, and a month after completing the treatment were included in the analysis. The 90th percentiles of rVp and rKtrans and the presence or absence of hemorrhage were recorded. Histopathology served as the reference standard for pseudoprogression. If not available, pseudoprogression was defined as neurological and radiographic stability or improvement without any new treatment for >= 2 months.RESULTS: Forty-four patients were identified; 64% received ipilimumab monotherapy for a median duration of 9 weeks (range, 1-138). Sixty-four lesions in 44 patients were included in the study. Of these, nine lesions in eight patients were determined to be pseudoprogression and seven lesions were previously irradiated. Forty-four progression lesions and eight pseudoprogression lesions were hemorrhagic. Median lesion volume for pseudoprogression and progression were not significantly different, at 2.3 cm3 and 3.2 cm3, respectively (p = 0.82). The rVp90 was smaller in pseudoprogression versus progression, at 2.2 and 5.3, respectively (p = 0.02), and remained significant after false discovery rate adjustment (p = 0.04).CONCLUSIONS: Pseudoprogression exhibited significantly lower rVp90 on DCE-MRI compared with progression. This knowledge can be useful for managing growing lesions in patients with melanoma brain metastases who are receiving immunotherapy.
CANIT0002946	31873875	Clinical research	44 patients with melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); KIR2DL1(); KIR2DL2(); KIR2DL3 (); 	PD-1 ;  KIR2DL1;  KIR2DL2	Lirilumab plus nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); lirilumab (DB11754); 	1	N/A	Retrospective analysis	Lower perfusion parameters in pseudoprogression, suggesting that dynamic contrast enhanced T1 MRI derived capillary permeability (Ktrans) and plasma volume measurements can be helpful in the diagnosis of pseudoprogression in melanoma patients with brain metastases after being treated with immunotherapy	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	DCE-MRI perfusion predicts pseudoprogression in metastatic melanoma treated with immunotherapy.	 J Neurooncol	PURPOSE: It can be challenging to differentiate pseudoprogression from progression. We assessed the ability of dynamic contrast enhanced T1 MRI (DCE-MRI) perfusion to identify pseudoprogression in melanoma brain metastases.METHODS: Patients with melanoma brain metastases who underwent immunotherapy and DCE-MRI were identified. Enhancing lesions >=  5mm in diameter on DCE-MRI and that were new or increased in size between a week from beginning the treatment, and a month after completing the treatment were included in the analysis. The 90th percentiles of rVp and rKtrans and the presence or absence of hemorrhage were recorded. Histopathology served as the reference standard for pseudoprogression. If not available, pseudoprogression was defined as neurological and radiographic stability or improvement without any new treatment for >= 2 months.RESULTS: Forty-four patients were identified; 64% received ipilimumab monotherapy for a median duration of 9 weeks (range, 1-138). Sixty-four lesions in 44 patients were included in the study. Of these, nine lesions in eight patients were determined to be pseudoprogression and seven lesions were previously irradiated. Forty-four progression lesions and eight pseudoprogression lesions were hemorrhagic. Median lesion volume for pseudoprogression and progression were not significantly different, at 2.3 cm3 and 3.2 cm3, respectively (p = 0.82). The rVp90 was smaller in pseudoprogression versus progression, at 2.2 and 5.3, respectively (p = 0.02), and remained significant after false discovery rate adjustment (p = 0.04).CONCLUSIONS: Pseudoprogression exhibited significantly lower rVp90 on DCE-MRI compared with progression. This knowledge can be useful for managing growing lesions in patients with melanoma brain metastases who are receiving immunotherapy.
CANIT0002947	31873875	Clinical research	44 patients with melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pidilizumab 	N/A	Immune checkpoint therapy	Pidilizumab (DB15383); 	1	N/A	Retrospective analysis	Lower perfusion parameters in pseudoprogression, suggesting that dynamic contrast enhanced T1 MRI derived capillary permeability (Ktrans) and plasma volume measurements can be helpful in the diagnosis of pseudoprogression in melanoma patients with brain metastases after being treated with immunotherapy	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	DCE-MRI perfusion predicts pseudoprogression in metastatic melanoma treated with immunotherapy.	 J Neurooncol	PURPOSE: It can be challenging to differentiate pseudoprogression from progression. We assessed the ability of dynamic contrast enhanced T1 MRI (DCE-MRI) perfusion to identify pseudoprogression in melanoma brain metastases.METHODS: Patients with melanoma brain metastases who underwent immunotherapy and DCE-MRI were identified. Enhancing lesions >=  5mm in diameter on DCE-MRI and that were new or increased in size between a week from beginning the treatment, and a month after completing the treatment were included in the analysis. The 90th percentiles of rVp and rKtrans and the presence or absence of hemorrhage were recorded. Histopathology served as the reference standard for pseudoprogression. If not available, pseudoprogression was defined as neurological and radiographic stability or improvement without any new treatment for >= 2 months.RESULTS: Forty-four patients were identified; 64% received ipilimumab monotherapy for a median duration of 9 weeks (range, 1-138). Sixty-four lesions in 44 patients were included in the study. Of these, nine lesions in eight patients were determined to be pseudoprogression and seven lesions were previously irradiated. Forty-four progression lesions and eight pseudoprogression lesions were hemorrhagic. Median lesion volume for pseudoprogression and progression were not significantly different, at 2.3 cm3 and 3.2 cm3, respectively (p = 0.82). The rVp90 was smaller in pseudoprogression versus progression, at 2.2 and 5.3, respectively (p = 0.02), and remained significant after false discovery rate adjustment (p = 0.04).CONCLUSIONS: Pseudoprogression exhibited significantly lower rVp90 on DCE-MRI compared with progression. This knowledge can be useful for managing growing lesions in patients with melanoma brain metastases who are receiving immunotherapy.
CANIT0002948	31873875	Clinical research	44 patients with melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	28	N/A	Retrospective analysis	Lower perfusion parameters in pseudoprogression, suggesting that dynamic contrast enhanced T1 MRI derived capillary permeability (Ktrans) and plasma volume measurements can be helpful in the diagnosis of pseudoprogression in melanoma patients with brain metastases after being treated with immunotherapy	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	DCE-MRI perfusion predicts pseudoprogression in metastatic melanoma treated with immunotherapy.	 J Neurooncol	PURPOSE: It can be challenging to differentiate pseudoprogression from progression. We assessed the ability of dynamic contrast enhanced T1 MRI (DCE-MRI) perfusion to identify pseudoprogression in melanoma brain metastases.METHODS: Patients with melanoma brain metastases who underwent immunotherapy and DCE-MRI were identified. Enhancing lesions >=  5mm in diameter on DCE-MRI and that were new or increased in size between a week from beginning the treatment, and a month after completing the treatment were included in the analysis. The 90th percentiles of rVp and rKtrans and the presence or absence of hemorrhage were recorded. Histopathology served as the reference standard for pseudoprogression. If not available, pseudoprogression was defined as neurological and radiographic stability or improvement without any new treatment for >= 2 months.RESULTS: Forty-four patients were identified; 64% received ipilimumab monotherapy for a median duration of 9 weeks (range, 1-138). Sixty-four lesions in 44 patients were included in the study. Of these, nine lesions in eight patients were determined to be pseudoprogression and seven lesions were previously irradiated. Forty-four progression lesions and eight pseudoprogression lesions were hemorrhagic. Median lesion volume for pseudoprogression and progression were not significantly different, at 2.3 cm3 and 3.2 cm3, respectively (p = 0.82). The rVp90 was smaller in pseudoprogression versus progression, at 2.2 and 5.3, respectively (p = 0.02), and remained significant after false discovery rate adjustment (p = 0.04).CONCLUSIONS: Pseudoprogression exhibited significantly lower rVp90 on DCE-MRI compared with progression. This knowledge can be useful for managing growing lesions in patients with melanoma brain metastases who are receiving immunotherapy.
CANIT0002949	31873875	Clinical research	44 patients with melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	3	N/A	Retrospective analysis	Lower perfusion parameters in pseudoprogression, suggesting that dynamic contrast enhanced T3 MRI derived capillary permeability (Ktrans) and plasma volume measurements can be helpful in the diagnosis of pseudoprogression in melanoma patients with brain metastases after being treated with immunotherapy	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	DCE-MRI perfusion predicts pseudoprogression in metastatic melanoma treated with immunotherapy.	 J Neurooncol	PURPOSE: It can be challenging to differentiate pseudoprogression from progression. We assessed the ability of dynamic contrast enhanced T1 MRI (DCE-MRI) perfusion to identify pseudoprogression in melanoma brain metastases.METHODS: Patients with melanoma brain metastases who underwent immunotherapy and DCE-MRI were identified. Enhancing lesions >=  5mm in diameter on DCE-MRI and that were new or increased in size between a week from beginning the treatment, and a month after completing the treatment were included in the analysis. The 90th percentiles of rVp and rKtrans and the presence or absence of hemorrhage were recorded. Histopathology served as the reference standard for pseudoprogression. If not available, pseudoprogression was defined as neurological and radiographic stability or improvement without any new treatment for >= 2 months.RESULTS: Forty-four patients were identified; 64% received ipilimumab monotherapy for a median duration of 9 weeks (range, 1-138). Sixty-four lesions in 44 patients were included in the study. Of these, nine lesions in eight patients were determined to be pseudoprogression and seven lesions were previously irradiated. Forty-four progression lesions and eight pseudoprogression lesions were hemorrhagic. Median lesion volume for pseudoprogression and progression were not significantly different, at 2.3 cm3 and 3.2 cm3, respectively (p = 0.82). The rVp90 was smaller in pseudoprogression versus progression, at 2.2 and 5.3, respectively (p = 0.02), and remained significant after false discovery rate adjustment (p = 0.04).CONCLUSIONS: Pseudoprogression exhibited significantly lower rVp90 on DCE-MRI compared with progression. This knowledge can be useful for managing growing lesions in patients with melanoma brain metastases who are receiving immunotherapy.
CANIT0002950	31873875	Clinical research	44 patients with melanoma brain metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	9	N/A	Retrospective analysis	Lower perfusion parameters in pseudoprogression, suggesting that dynamic contrast enhanced dynamic contrast enhanced T2 derived capillary permeability (Ktrans) and plasma volume measurements can be helpful in the diagnosis of pseudoprogression in melanoma patients with brain metastases after being treated with immunotherapy	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan	DCE-MRI perfusion predicts pseudoprogression in metastatic melanoma treated with immunotherapy.	 J Neurooncol	PURPOSE: It can be challenging to differentiate pseudoprogression from progression. We assessed the ability of dynamic contrast enhanced T1 MRI (DCE-MRI) perfusion to identify pseudoprogression in melanoma brain metastases.METHODS: Patients with melanoma brain metastases who underwent immunotherapy and DCE-MRI were identified. Enhancing lesions >=  5mm in diameter on DCE-MRI and that were new or increased in size between a week from beginning the treatment, and a month after completing the treatment were included in the analysis. The 90th percentiles of rVp and rKtrans and the presence or absence of hemorrhage were recorded. Histopathology served as the reference standard for pseudoprogression. If not available, pseudoprogression was defined as neurological and radiographic stability or improvement without any new treatment for >= 2 months.RESULTS: Forty-four patients were identified; 64% received ipilimumab monotherapy for a median duration of 9 weeks (range, 1-138). Sixty-four lesions in 44 patients were included in the study. Of these, nine lesions in eight patients were determined to be pseudoprogression and seven lesions were previously irradiated. Forty-four progression lesions and eight pseudoprogression lesions were hemorrhagic. Median lesion volume for pseudoprogression and progression were not significantly different, at 2.3 cm3 and 3.2 cm3, respectively (p = 0.82). The rVp90 was smaller in pseudoprogression versus progression, at 2.2 and 5.3, respectively (p = 0.02), and remained significant after false discovery rate adjustment (p = 0.04).CONCLUSIONS: Pseudoprogression exhibited significantly lower rVp90 on DCE-MRI compared with progression. This knowledge can be useful for managing growing lesions in patients with melanoma brain metastases who are receiving immunotherapy.
CANIT0002951	31879407	Case report	Adrenocorticotropic hormone(ACTH)deficiency	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	His is the first report of isolated adrenocorticotropic hormone(ACTH) deficiency induced by nivolumab in a patient with gastric cancer metastasis of the peritoneum. 	Fatigue and appetite loss	N/A	N/A	N/A	N/A	N/A	 2019 Dec	[A Case of Isolated ACTH Deficiency Induced by Nivolumab in a Patient with Gastric Cancer Metastasis of the Peritoneum].	 Gan To Kagaku Ryoho	Nivolumab induces several immune-related adverse events. Isolated adrenocorticotropic hormone(ACTH)deficiency has low frequency. A 73-year-old woman with gastric cancer metastasis of the peritoneum was treated with nivolumab as the third-line chemotherapy. After 5 courses of nivolumab, she developed hypothyroidism. After completing 12 courses, peritoneal metastasis increased. We evaluated the metastasis as progression of disease, so treatment with nivolumab was discontinued. Two weeks after the last dosage of nivolumab, she developed general fatigue and appetite loss. At first, we considered that these symptoms were caused by peritoneal metastasis, but progression was not indicated in the CT. Blood levels of cortisol and ACTH were very low. We suspected secondary adrenocortical insufficiency induced by nivolumab. Endocrinological examinations and the results of brain MRIsuggested isolated ACTH deficiency. This is the first report of isolated ACTH deficiency induced by nivolumab in a patient with gastric cancer metastasis of the peritoneum. The symptoms of adrenocortical insufficiency induced by nivolumab overlap with those of peritoneal metastasis, and thus, it may be difficult to confirm a differential diagnosis. When adrenocortical insufficiency is suspected, we should check the blood levels of cortisol and ACTH.
CANIT0002952	31880964	Clinical research	1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511)	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	IFNA2B	Immune checkpoint therapy	Ipilimumab (DB06186); 	1034	636	Open-label, multicenter, multinational, 3-arm, phase III study	Adjuvant therapy with ipilimumab at 3 mg/kg (ipi3) benefits survival versus high-dose interferon alfa (HDI); for the first time to our knowledge in melanoma adjuvant therapy, E1609 (a phase III trial in patients with resected cutaneous melanoma) has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab at 10 mg/kg (ipi10) was more toxic and not superior in efficacy to HDI	Treatment-related adverse events grade >= 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively	N/A	N/A	N/A	N/A	N/A	 2020 Feb 20	Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609.	 J Clin Oncol	PURPOSE: Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI.PATIENTS AND METHODS: E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI.RESULTS: Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade >= 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti-programmed death 1 use in the HDI arm versus ipi3 and ipi10 (P <= .001).CONCLUSION: Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.
CANIT0002953	31892620	Case report	A 71-year-old male patient with adenocarcinoma of the lung and contralateral lung metastasis 	Adenocarcinoma	EFO:0000228	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	The first report of a case of acute cerebellar ataxia due to EBV under administration of an Pembrolizumab.	Cerebellar ataxia	N/A	N/A	EBV (NCIT:C14204); 	EBV-positive	Microbiota	 2019 Dec 30	Acute cerebellar ataxia due to Epstein-Barr virus under administration of an immune checkpoint inhibitor.	 BMJ Case Rep	A 71-year-old male patient with adenocarcinoma of the lung and contralateral lung metastasis under administration of pembrolizumab had symptoms of cerebellar ataxia. We suspected that the symptoms were immune-related adverse events (irAE), but the patient was subsequently diagnosed as cerebellitis due to Epstein-Barr virus (EBV) infection. After steroid pulse therapy, the symptoms of cerebellar ataxia improved immediately. Immune checkpoint inhibitors (ICI) can induce neurological adverse events and cause acute cerebellar ataxia. Initially, irAEs were suspected in this case. His clinical data suggested that reactivation of the virus had occurred because the ICI affected his immune system. This is the first report of a case of acute cerebellar ataxia due to EBV under administration of an ICI.
CANIT0002954	31907567	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	73	N/A	Retrospective analysis	The efficacy of nivolumab is comparable in patients with NSCLC presenting with and without brain metastases, but the results must be verified in large-scale prospective studies. Theobjective response rates (ORRs) of the brain metastases (BM) cohort and the non-brain metastasis (non-BM) cohort were 25.0% and 19.5% (p = 0.574), disease control rates (DCRs) were 53.1% and 56.1% (p = 0.800), respectively. Their median progression-free survival (PFS) were 2.8 and 4.9 months (p = 0.204), median DORs were 9.8 and 28.8 months (p = 0.003), and median overall survival (OS)  were 14.8 and 20.2 months (p = 0.114), respectively. According to the Cox multivariate regression analysis, BM was not an independent prognostic factor. The IORR and IDCR of the BM cohort were 28.1% and 46.9%, respectively, with a median iPFS of 2.2 months.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Brain metastasis	Disease status	 2020 Mar	Comparable outcomes of nivolumab in patients with advanced NSCLC presenting with or without brain metastases: a retrospective cohort study.	 Cancer Immunol Immunother	OBJECTIVE: This study aimed to determine whether there is a difference in the efficacy of nivolumab in patients with advanced non-small cell lung cancer (NSCLC) presenting with or without brain metastases.MATERIALS AND METHODS: Patients with advanced NSCLC treated with nivolumab monotherapy were retrospectively analyzed. They were divided into two cohorts according to the presence or absence of brain metastases. The differences between the two cohorts in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS) were investigated, and the intracranial efficacy, including intracerebral objective response rate (IORR), intracranial disease control rate (IDCR) and intracranial progression-free survival (iPFS), were examined in the brain metastasis (BM) cohort.RESULTS: Seventy-three patients (32 with brain metastases and 41 without) were included. The ORRs of the BM cohort and the non-brain metastasis (non-BM) cohort were 25.0% and 19.5% (p = 0.574), DCRs were 53.1% and 56.1% (p = 0.800), respectively. Their median PFS were 2.8 and 4.9 months (p = 0.204), median DORs were 9.8 and 28.8 months (p = 0.003), and median OS were 14.8 and 20.2 months (p = 0.114), respectively. According to the Cox multivariate regression analysis, BM was not an independent prognostic factor. The IORR and IDCR of the BM cohort were 28.1% and 46.9%, respectively, with a median iPFS of 2.2 months.CONCLUSIONS: The efficacy of nivolumab is comparable in patients with NSCLC presenting with and without brain metastases, but the results must be verified in large-scale prospective studies.
CANIT0002955	31910171	Clinical research	Metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	11	N/A	N/A	Considering the likely high dynamism of tumor-infiltrating lymphocytes, rebiopsy before therapy might be proposed to assess the utility of CD4(+)/CD8(+) tumor-infiltrating lymphocytes ratio for predictive purpose.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD4 (P01730); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	 CD4(+)/CD8(+) tumor-infiltrating lymphocytes ratio	Tumor-infiltrating immune cell	 2019 Dec 23	Correlations between tumor-infiltrating and circulating lymphocyte subpopulations in advanced renal cancer patients treated with nivolumab.	 Acta Biomed	BACKGROUND: In clinical trials with immunotherapy, histological features such as tumor-infiltrating lymphocytes (TILs) are investigated as potential predictive biomarkers, with the limit of an outdated parameter for a typically dynamic element.METHODS: This explorative study compared, in metastatic renal cell carcinoma (mRCC) patients, basal pathological data about TILs on diagnostic histological specimens with circulating lymphocyte subpopulations measured before and during therapy with nivolumab.RESULTS: Of 11 mRCC patients, 5 had low presence of TILs (L-TILs), 3 moderate amount (M-TILs) and 3 high number (H-TILs). Overall, 8 patients had low intratumoral pathological CD4+/CD8+ ratio (LIPR) <=1 and 3 cases high intratumoral pathological ratio (HIPR) >=2. Of 8 patients with LIPR, only 2 matched with low circulating CD4+/CD8+ ratio (LCR) <=1; 5 had high circulating ratio (HCR) >=2. All 3 cases with HIPR (>=2) conversely had LCR (<=1). Circulating CD4+/CD8+ ratio remained unchanged during therapy (mean -0.12 in 8 weeks). The respective percentage values of CD4+ and CD8+ circulating T cells also remained stable (variation 0%); the absolute value of CD4+ was more likely to increase (mean +46.3/mm3); the level of CD8+ tended to slightly decrease (mean -6.5/mm3). No correlation of lymphocyte subpopulations with treatment outcome was found. Of note, we did not evidence correspondence between histopathological and circulating findings in terms of T-lymphocyte subpopulations, also suggesting the inconsistency of circulating data in terms of relative variations.CONCLUSIONS: Considering the likely high dynamism of TILs, rebiopsy before therapy might be proposed to assess the utility of TILs characterization for predictive purpose. (www.actabiomedica.it).
CANIT0002956	31936762	Clinical research	Gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Avelumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); pembrolizumab (DB09037); nivolumab (DB09035); 	811	645	Meta-analysis	The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64-1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location.Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy.	N/A	N/A	N/A	Gastro-oesophageal junction cancer (MONDO:0001056); 	Gastro-oesophageal junction cancer	Disease status	 2020 Jan 10	Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis.	 Int J Mol Sci	Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomised controlled trials to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in metastatic gastric cancer. The main outcome was overall survival. Based on age (cut-off agreed at 65 years), tumour location (gastric vs. gastro-oesophageal junction), programmed death-ligand 1 (PD-L1) status, sex and Eastern Cooperative Oncology Group (ECOG) status (1 vs. 0), we scheduled a subgroup analysis for the overall survival. Three studies were included in the analysis for a total of 1456 cases (811 cases were in the experimental group and 645 cases in the control group). The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64-1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location. Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy.
CANIT0002957	31936762	Clinical research	Gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Avelumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); pembrolizumab (DB09037); nivolumab (DB09035); 	811	645	Meta-analysis	The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64-1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location.Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jan 10	Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis.	 Int J Mol Sci	Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomised controlled trials to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in metastatic gastric cancer. The main outcome was overall survival. Based on age (cut-off agreed at 65 years), tumour location (gastric vs. gastro-oesophageal junction), programmed death-ligand 1 (PD-L1) status, sex and Eastern Cooperative Oncology Group (ECOG) status (1 vs. 0), we scheduled a subgroup analysis for the overall survival. Three studies were included in the analysis for a total of 1456 cases (811 cases were in the experimental group and 645 cases in the control group). The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64-1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location. Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy.
CANIT0002958	31942077	Clinical research	Soft-tissue sarcoma	Sarcoma	EFO:0000691	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	608	N/A	N/A	We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial.Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	B-Lymphocyte (NCIT:C12474); 	B cells	Tumor-infiltrating immune cell	 2020 Jan	B cells are associated with survival and immunotherapy response in sarcoma.	 Nature	Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.
CANIT0002959	31959178	Clinical research	Carcinomas	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	Chemotherapy	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	Meta-analysis	Smokers benefit from either anti-PD-1/PD-L1 monotherapy or the combined regimen compared with chemotherapy. Considering cost-effectiveness, monotherapy was recommended to smokers. For non-smokers, only the combined regimen was feasible in non-small cell lung cancer.	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2020 Jan 20	Smokers or non-smokers: who benefits more from immune checkpoint inhibitors in treatment of malignancies  An up-to-date meta-analysis.	 World J Surg Oncol	BACKGROUND: Immune checkpoint inhibitors, which are a milestone in anti-cancer therapy, have been applied in the treatment of multiple malignancies. Real-world data have suggested that smoking status may be associated with the efficacy of anti-PD-1/PD-L1 therapy. Hereby, to evaluate smoking benefit or not, we included numerous high-quality randomized controlled clinical trials (RCTs) without any restriction on category.METHODS: A systematic search of online database was performed from July 2010 to July 2019. Eligible studies included phase II/III RCTs comparing PD-1/PD-L1 inhibitors with chemotherapy in the treatment of multiple carcinomas and contained subgroup analysis of smoking status. Then, related hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) were pooled.RESULTS: In the initial meta-analysis, compared with chemotherapy, the OS of non-smokers (HR, 0.81; 95% CI, 0.67-0.98) and smokers (HR, 0.77; 95% CI, 0.71-0.83) were significantly prolonged with PD-1/PD-L1 inhibitors. Outcomes from subgroup analysis showed that in anti-PD-1/PD-L1 monotherapy groups, non-smokers showed no significant improvement in OS (HR, 0.94; 95% CI, 0.83-1.06), while the OS of smokers was significantly prolonged (HR, 0.79; 95% CI, 0.74-0.85); in groups of PD-1/PD-L1 inhibitors combined with chemotherapy, the OS of non-smokers (HR, 0.45; 95% CI, 0.28-0.71) and smokers (HR, 0.72; 95% CI, 0.61-0.85) were significantly prolonged. Combined ipilimumab and chemotherapy showed no significance in both groups.CONCLUSION: Smokers benefit from either anti-PD-1/PD-L1 monotherapy or the combined regimen compared with chemotherapy. Considering cost-effectiveness, monotherapy was recommended to smokers. For non-smokers, only the combined regimen was feasible in non-small cell lung cancer.
CANIT0002960	31961685	Basic research	Cancer	Cancer	EFO:0000311	Other	IDO1 (P14902); 	IDO1; 	N-(4-chlorophenyl)-2-((5-phenylthiazolo[2 or 3-c][1 or 2 or 4]triazol-3-yl)thio)acetamide 1	N/A	Immune checkpoint therapy	N/A	Cell lines	N/A	Basic research	Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2020 Feb 27	Unique Sulfur-Aromatic Interactions Contribute to the Binding of Potent Imidazothiazole Indoleamine 2,3-Dioxygenase Inhibitors.	 J Med Chem	Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor N-(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-c][1,2,4]triazol-3-yl)thio)acetamide 1 through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.
CANIT0002961	31963646	Basic research	Tumor	Cancer	EFO:0000311	Other	TNF14 (Q80WM9); 	TNF14; 	TNF14 (14-39) peptide	N/A	Tumor vaccine	N/A	Cell lines	N/A	Basic research	This work was based on the crystal structure of the BTLA/HVEM complex showing that BTLA binds the N-terminal cysteine-rich domain of HVEM. We investigated the amino acid sequence of HVEM and used molecular modeling methods to develop inhibitors of the BTLA/HVEM interaction. We synthesized novel compounds and determined their ability to interact with the BTLA protein and inhibit the formation of the BTLA/HVEM complex. Our results suggest that the HVEM (14-39) peptide is a potent inhibitor of the formation of the BTLA/HVEM protein complex.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan 18	Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding.	 Int J Mol Sci	Immune checkpoints are crucial in the maintenance of antitumor immune responses. The activation or blockade of immune checkpoints is dependent on the interactions between receptors and ligands; such interactions can provide inhibitory or stimulatory signals, including the enhancement or suppression of T-cell proliferation, differentiation, and/or cytokine secretion. B-and T-lymphocyte attenuator (BTLA) is a lymphoid-specific cell surface receptor which is present on T-cells and interacts with herpes virus entry mediator (HVEM), which is present on tumor cells. The binding of HVEM to BTLA triggers an inhibitory signal which attenuates the immune response. This feature is interesting for studying the molecular interactions between HVEM and BTLA, as they may be targeted for novel immunotherapies. This work was based on the crystal structure of the BTLA/HVEM complex showing that BTLA binds the N-terminal cysteine-rich domain of HVEM. We investigated the amino acid sequence of HVEM and used molecular modeling methods to develop inhibitors of the BTLA/HVEM interaction. We synthesized novel compounds and determined their ability to interact with the BTLA protein and inhibit the formation of the BTLA/HVEM complex. Our results suggest that the HVEM (14-39) peptide is a potent inhibitor of the formation of the BTLA/HVEM protein complex.
CANIT0002962	31980560	Clinical research	Renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	322	N/A	N/A	PD-L1 protein expression was associated with an unfavourable prognosis in the study cohort. PD-L1 (E1L3N) expression was an independent prognostic indicator of clinical outcome in all renal cell carcinomas when using a 1% cut-off.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Aug	PD-L1 expression is an unfavourable prognostic indicator in Asian renal cell carcinomas.	 J Clin Pathol	BACKGROUND/AIMS: The programmed cell death receptor 1 (PD-1) checkpoint inhibitor, nivolumab, has been approved for the treatment of metastatic renal cell carcinoma (RCC). However, the understanding of the expression and distribution of PD ligand 1 (PD-L1) in the tumour immune microenvironment and its prognostic role in an Asian cohort is limited. Our group investigated PD-L1 protein expression in a cohort of Asian patients with RCC of mixed ethnicity, using two commercially available antibody clones.METHODS: E1L3N and SP263 anti-PD-L1 clones were used to categorise RCCs of various histological subtypes, diagnosed at our institution between 1995 and 2008, into PD-L1-positive or PD-L1-negative groups, based on a 1% Tumour Proportion Score (TPS) cut-off.RESULTS: In total, 267 (83%) clear cell (cc)RCC and 55 (17%) non-ccRCC cases were studied. Overall PD-L1 protein expression rates for the entire cohort were 13% and 8% for the E1L3N and SP263 clones, respectively. Patients bearing PD-L1-positive tumours experienced significantly decreased disease-free survival (DFS; E1L3N: p=0.01; SP263: p=0.03) but not overall survival, compared with those with PD-L1-negative tumours. Multivariate survival analysis further confirmed the results of the E1L3N clone (HR 1.85, 95% CI 1.10 to 3.13, p=0.02), but not SP263, after adjusting for pathological stage, histological subtype and grade. The addition of PD-L1 (E1L3N) TPS to clinicopathological features significantly increased the prognostic value for DFS ( LRx2=5.25; p=0.022), compared with clinicopathological features alone.CONCLUSIONS: PD-L1 protein expression was associated with an unfavourable prognosis in our study cohort. PD-L1 (E1L3N) expression was an independent prognostic indicator of clinical outcome in all RCCs when using a 1% cut-off.
CANIT0002963	31988143	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	38	N/A	N/A	Late cardiac adverse events (CAEs) could occur with immune checkpoint inhibitor therapy and were mainly revealed to be heart failure with left ventricular systolic dysfunction.	Immune checkpoint inhibitor (ICI)-associated late cardiac adverse events	N/A	N/A	N/A	N/A	N/A	 2020 Jan	Late cardiac adverse events in patients with cancer treated with immune checkpoint inhibitors.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitor (ICI)-associated early cardiac adverse events (CAEs), mostly acute and fulminant myocarditis, have been well characterized and mainly occur during the first 90 days after ICI therapy initiation. ICI-associated late CAEs (occurring after the first 90 days of treatment) have not yet been described.METHODS: First, we compared characteristics of a cohort involving early (defined as a CAE time to onset (TTO) of <90 days after ICI therapy initiation) and late (defined as a CAE TTO of >=90 days after ICI therapy initiation) ICI-associated CAE consecutive cases who were referred to three French cardio-oncology units. Second, ICI-associated CAE cases were searched in VigiBase, the WHO global individual case safety report database, and early and late ICI-associated CAEs were compared.RESULTS: In the cohort study, compared with early CAE cases (n=19, median TTO of 14 days), late ICI-associated CAE cases (n=19, median TTO of 304 days) exhibited significantly more left ventricular systolic dysfunction (LVSD) and heart failure (HF) and less frequent supraventricular arrhythmias. In VigiBase, compared with early cases (n=437, 73.3%, median TTO 21 days), the late ICI-associated CAE reports (n=159, 26.7%, median TTO 178 days) had significantly more frequent HF (21.1% vs 31.4%, respectively, p=0.01). Early and late ICI-associated CAE cases had similarly high mortality rates (40.0% vs 44.4% in the cohort and 30.0% vs 27.0% in VigiBase, respectively).CONCLUSIONS: Late CAEs could occur with ICI therapy and were mainly revealed to be HF with LVSD.TRIAL REGISTRATION NUMBERS: NCT03678337, NCT03882580, and NCT03492528.
CANIT0002964	31995619	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	Chemotherapy	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	N/A	N/A	N/A	For patients with stage IV NSCLC and varying comorbidity burden, first-line chemotherapy with pembrolizumab does not represent a cost-effective strategy compared to chemotherapy. Resources should be focused on collecting immunotherapy survival data for more representative NSCLC patient populations.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jan 29	Cost-effectiveness of pembrolizumab for advanced non-small cell lung cancer patients with varying comorbidity burden.	 PLoS One	OBJECTIVES: While previous cost-effectiveness studies on pembrolizumab in stage IV non-small cell lung cancer (NSCLC) have found these regimens to be cost-effective, their reliance on randomized controlled trial (RCT) data with strict inclusion criteria limits generalizability to patients with comorbidities. We estimated the cost-effectiveness of first-line pembrolizumab for patients with various comorbidities.MATERIALS AND METHODS: In our base case analysis, we studied pembrolizumab plus chemotherapy (pembrolizumab combination therapy) versus chemotherapy alone. In a secondary analysis, we considered only patients with PD-L1 expression of at least 50% (PD-L1-high) and evaluated pembrolizumab monotherapy, pembrolizumab combination therapy, and chemotherapy alone. Microsimulation models were developed for the base case and the PD-L1-high analyses. To estimate outcomes of patients with differing comorbidities, we combined survival data from patients with few or no comorbidities from the RCTs with estimates from the general population obtained from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Comorbidity burden level was divided into three groups based on the Charlson score (equal to 0, 1, or 2+); patients with various other specific comorbidities were also analyzed. Incremental cost-effectiveness ratios (ICER) were compared to a willingness-to-pay (WTP) threshold of $100,000/quality-adjusted life-year (QALY).RESULTS: In the Charlson 0, Charlson 1, and Charlson 2+ patient populations, estimated ICERs for pembrolizumab combination therapy in the base case model were $173,919/QALY, $175,165/QALY, and $181,777/QALY, respectively, compared to chemotherapy. In the PD-L1-high model, the Charlson 0, Charlson 1, and Charlson 2+ patients had ICERs of $147,406/QALY, $149,026/QALY, and $154,521/QALY with pembrolizumab combination therapy versus chemotherapy. Pembrolizumab monotherapy was weakly dominated for each comorbidity group in the PD-L1-high model.CONCLUSION: For patients with stage IV NSCLC and varying comorbidity burden, first-line treatment with pembrolizumab does not represent a cost-effective strategy compared to chemotherapy. Resources should be focused on collecting immunotherapy survival data for more representative NSCLC patient populations.
CANIT0002965	31998317	Clinical research	Langerhans Cell Histiocytosis	Langerhans cell histiocytosis	EFO:1000318	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	N/A	101	N/A	N/A	The results indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAF V600E protein are not presented by HLA class I molecules. Given that the BRAF V600E mutation is highly prevalent in chemotherapy refractory Langerhans Cell Histiocytosis (LCH)-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2020 Jan 10	Apparent Lack of BRAF (V600E) Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8(+) T Cells in Langerhans Cell Histiocytosis.	 Front Immunol	Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAF V600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAF V600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAF V600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAF V600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAF V600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAF V600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the HLA class I peptidomes of two distinct BRAF V600E transduced cell lines with confirmed expression of HLA-A*03:01 or HLA-A*11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAF V600E protein are not presented by HLA class I molecules. Given that the BRAF V600E mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.
CANIT0002966	32002809	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	187	N/A	Retrospective analysis	In this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Mar	Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study.	 Adv Ther	INTRODUCTION: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab.METHODS: This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging.RESULTS: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes.CONCLUSIONS: Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.
CANIT0002967	32002809	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	187	N/A	Retrospective analysis	Serum lactate dehydrogenase levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes. 	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2020 Mar	Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study.	 Adv Ther	INTRODUCTION: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab.METHODS: This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging.RESULTS: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes.CONCLUSIONS: Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.
CANIT0002968	32002809	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	187	N/A	Retrospective analysis	Neutrophil-to-lymphocyte ratios below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). 	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2020 Mar	Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study.	 Adv Ther	INTRODUCTION: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab.METHODS: This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging.RESULTS: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes.CONCLUSIONS: Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.
CANIT0002969	32002809	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	187	N/A	Retrospective analysis	Platelet-to-lymphocyte ratios levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). 	N/A	N/A	N/A	Platelet-to-lymphocyte ratios (EFO:0008446); 	Platelet-to-lymphocyte ratios	Cell percentage/counts in blood	 2020 Mar	Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study.	 Adv Ther	INTRODUCTION: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab.METHODS: This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging.RESULTS: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes.CONCLUSIONS: Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.
CANIT0002970	32008152	Clinical research	Advanced or metastatic renal cell carcinoma	Renal cell carcinoma	EFO:0000681	Kidney	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or Avelumab or pembrolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); avelumab (DB11945); pembrolizumab (DB09037); 	2662	N/A	Meta-analysis	A total of three RCTs covering 2662 patients were enrolled. In PFS analysis, the estimated HR for ITT subset was 0.74 with 95% CI of 0.65 to 0.84 and for PD-L1 subset was 0.65 with 95% CI of 0.56 to 0.76. And in OS analysis, the result was 0.74 with 95% CI of 0.53 to 1.03 in ITT subset and 0.74 with 95% CI of 0.56 to 0.96 in PD-L1 subset. As for ORR analysis, combination therapy showed advantage rather than monotherapy in ITT subset (RR 1.54; 95% CI 1.11 to 2.14), but conversely in PD-L1 positive subset (RR 1.64; 95% CI 0.94 to 2.84).	Additionally, combination therapy failed to show obvious safety in most immune-related adverse events, whatever in all-grade or high grade.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Feb 1	To be or not to be: whether anti-angiogenic agent combined with immune checkpoint inhibitoris necessary in the treatment of advanced or metastatic renal cell carcinoma.	 Med Oncol	Although it's widely known that targeted therapy against angiogenesis and immunotherapy agents showed survival benefit over chemoradiotherapy in advanced or metastatic renal cell carcinoma, some patients still cannot receive a satisfied prognosis. We performed a systematic review and meta-analysis to explore the efficacy and safety of anti-angiogenic agents combined with immune checkpoint inhibitors. We conducted a search for randomized controlled trials in Pubmed, Embase, Cochrane, and major conference. Enrolled eligible studies and extracted data were completed by two investigators to compare OS, PFS, and ORR both in PD-L1 and ITT subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. Besides, we assessed the heterogeneity through subgroup and sensitivity analysis. A total of three RCTs covering 2662 patients were enrolled. In PFS analysis, the estimated HR for ITT subset was 0.74 with 95% CI of 0.65 to 0.84 and for PD-L1 subset was 0.65 with 95% CI of 0.56 to 0.76. And in OS analysis, the result was 0.74 with 95% CI of 0.53 to 1.03 in ITT subset and 0.74 with 95% CI of 0.56 to 0.96 in PD-L1 subset. As for ORR analysis, combination therapy showed advantage rather than monotherapy in ITT subset (RR 1.54; 95% CI 1.11 to 2.14), but conversely in PD-L1 positive subset (RR 1.64; 95% CI 0.94 to 2.84). Additionally, combination therapy failed to show obvious safety in most immune-related adverse events, whatever in all-grade or high grade.
CANIT0002971	32009093	Case report	An elderly man with rheumatoid arthritis	Lung adenocarcinoma	EFO:0000571	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We herein report the case of a patient with pembrolizumab-induced HLH	Hemophagocytic lymphohistiocytosis (HLH)	N/A	N/A	N/A	N/A	N/A	 2020 Apr 15	Hemophagocytic Lymphohistiocytosis in a Patient with Rheumatoid Arthritis on Pembrolizumab for Lung Adenocarcinoma.	 Intern Med	Immune checkpoint inhibitors have changed the landscape of classic cancer treatment. However, their use is associated with the emergence of new adverse events. An elderly man with rheumatoid arthritis was started on pembrolizumab for newly diagnosed advanced lung cancer. He subsequently developed hemophagocytic lymphohistiocytosis (HLH), which is potentially fatal but has not been properly established as an immune checkpoint inhibition-induced event. We herein report the case of a patient with pembrolizumab-induced HLH.
CANIT0002972	32009094	Case report	A patient with epipharyngeal carcinoma and ulcerative colitis	Epipharyngeal carcinoma	MONDO:0000536	Head and neck	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	This is the first report of a patient with epipharyngeal carcinoma and ulcerative colitis who was confirmed to have been safely treated with nivolumab based on autopsy findings.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Apr 15	Safe Use of Nivolumab in a Patient with Epipharyngeal Carcinoma and Preexisting Ulcerative Colitis: A Histologically Proven Case Report.	 Intern Med	Nivolumab, an antibody against human programmed cell death 1 (PD-1), enhances pre-existing immune responses and has antitumor activity. However, it may also cause undesirable immune-related adverse events (irAEs), such as anti-PD-1-related colitis. In addition, Nivolumab can worsen pre-existing autoimmune diseases. Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Its exact cause is unknown, but it may involve the dysregulation of the mucosal immune response. Thus, it is of great interest whether nivolumab can affect UC activity. This is the first report of a patient with epipharyngeal carcinoma and ulcerative colitis who was confirmed to have been safely treated with nivolumab based on autopsy findings.
CANIT0002973	32011450	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	51	N/A	Retrospective, multicenter study	Fifty-one NSCLC patients (mean age, 58.0 years) were included from 20 French centers: 61% were never-smokers and 59% were women. Among them, 82% had EGFR-activating mutations, 16% ALK translocations, or 2% ROS1 translocations. Before ICI therapy, patients had received a median of 3 treatment lines (including tyrosine-kinase inhibitor). The median PFS was 2.1 (95% confidence interval [CI], 1.5-3.2) months for the entire cohort, 2.2 (95% CI, 1.4-3.2) for EGFR-mutated patients, and 2.4 (95% CI, 2.1-not reached) months for ALK-translocated patients. The median OS was 14.7 (95% CI, 12.1-19.2) months for the entire population and 13.9 (95% CI, 8.8-20.0) and 19.2 (95% CI, 13.1-not reached) months for EGFR-mutated and ALK-translocated patients, respectively. Seven (13.7%) patients were treated with ICI for >9 months.	Toxicities were reported in 22% (11/51), including 8% (4/51) grade >=3.	N/A	N/A	EGFR/ALK (P00533); 	EGFR/ALK mutational status	Mutational status	 2020 Jan	Efficacy and safety of programmed cell-death-protein-1 and its ligand inhibitors in pretreated patients with epidermal growth-factor receptor-mutated or anaplastic lymphoma kinase-translocated lung adenocarcinoma.	 Medicine (Baltimore)	Immune-checkpoint inhibitor (ICI) efficacy in patients with non-small cell lung cancer (NSCLC) harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against epidermal growth-factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1)-mutated NSCLC patients in the real-world setting.In this retrospective, multicenter study on adults with ICI-treated EGFR-mutated or ALK- or ROS1-translated NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, and progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS) from immunotherapy initiation.Fifty-one NSCLC patients (mean age, 58.0 years) were included from 20 French centers: 61% were never-smokers and 59% were women. Among them, 82% had EGFR-activating mutations, 16% ALK translocations, or 2% ROS1 translocations. Before ICI therapy, patients had received a median of 3 treatment lines (including tyrosine-kinase inhibitor). The median PFS was 2.1 (95% confidence interval [CI], 1.5-3.2) months for the entire cohort, 2.2 (95% CI, 1.4-3.2) for EGFR-mutated patients, and 2.4 (95% CI, 2.1-not reached) months for ALK-translocated patients. The median OS was 14.7 (95% CI, 12.1-19.2) months for the entire population and 13.9 (95% CI, 8.8-20.0) and 19.2 (95% CI, 13.1-not reached) months for EGFR-mutated and ALK-translocated patients, respectively. Seven (13.7%) patients were treated with ICI for >9 months. Toxicities were reported in 22% (11/51), including 8% (4/51) grade >=3.In this real-world setting, analysis of ICI PFS against EGFR-mutated or ALK-translocated NSCLC patients appeared close to that observed in pretreated unselected NSCLC patients. The more promising OS probably linked to post-ICI treatments. Large prospective studies on these patient subsets are needed.
CANIT0002974	32012411	Clinical research	Previously treated advanced recurrent ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Chemotherapy followed by Pembrolizumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	21	N/A	Two-cohort, phase 2 KEYNOTE-100 study (NCT02674061)	There were no treatment-related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with advanced recurrent ovarian cancer, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD-L1 expression among some patients with higher objective response rate.	A total of 13 (61.9%) patients had treatment-related adverse events (TRAE), and 5 (23.8%) had grade 3-4 TRAE. There were no treatment-related deaths in this subpopulation.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Apr	Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE-100.	 Cancer Sci	Interim results from the two-cohort, phase 2 KEYNOTE-100 study (NCT02674061) of 376 patients with previously treated advanced recurrent ovarian cancer (ROC) showed that pembrolizumab monotherapy was associated with an objective response rate (ORR) of 8.0% (95% CI, 5.4-11.2). We present outcomes for the Japanese patients (n = 21) enrolled in KEYNOTE-100. Patients with epithelial ROC had received either 1-3 prior chemotherapy lines and had platinum-free interval or treatment-free interval (PFI; TFI) of 3-12 months (cohort A) or 4-6 prior chemotherapy lines and had PFI/TFI of >=3 months (cohort B). All patients received pembrolizumab 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity or consent withdrawal. Primary objectives were ORR per RECIST v1.1 for each cohort and higher programmed death ligand-1 (PD-L1) tumor expression. The relationship between PD-L1 expression (measured as combined positive score [CPS]) and ORR was assessed. Twenty-one Japanese patients (cohort A, n = 19; cohort B, n = 2) were treated. The median (range) age was 57 (37-78) years; 19 (90.5%) patients had ECOG status of 0 and 16 (76.2%) patients had stage III-IV disease. ORR was 19.0% (95% CI, 5.4-41.9) and seemed to increase with increasing PD-L1 expression. A total of 13 (61.9%) patients had treatment-related adverse events (TRAE), and 5 (23.8%) had grade 3-4 TRAE. There were no treatment-related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with ROC, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD-L1 expression among some patients with higher ORR.
CANIT0002975	32014936	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Cytotoxic regimens	Immune checkpoint therapy	Nivolumab (DB09035); 	31	35	Retrospective analysis	Patients with squamous cell carcinoma who received ICIs had better overall survival (OS) than those who did not (9.7 versus 4.7 months, p=0.027). In multivariate analysis, treatment with ICIs [hazard ratio (HR)=0.54, 95% confidence interval (CI)=0.30-0.98, p=0.044], good performance status (HR=0.30, 95%CI=0.16-0.57, p=0.0003), and histology other than squamous cell carcinoma (HR=0.41, 95%CI=0.19-0.83, p=0.014) were significantly favorable factors for OS. ICIs may be effective for older patients with NSCLC, especially squamous cell carcinoma patients.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Performance Status	Disease status	 2020 Feb	Efficacy of PD-1 Inhibitors in Older Non-small Cell Lung Cancer Patients.	 Anticancer Res	BACKGROUND/AIM: We assessed the efficacy of immune checkpoint inhibitors (ICIs) in older patients because of the limited information regarding these patients.PATIENTS AND METHODS: We retrospectively analyzed 66 consecutive patients >=70 years old with advanced non-small cell lung cancer (NSCLC). A total of 31 patients received ICIs (ICIs group) and 35 patients received only cytotoxic regimens (No ICIs group).RESULTS: Patients with squamous cell carcinoma who received ICIs had better overall survival (OS) than those who did not (9.7 versus 4.7 months, p=0.027). In multivariate analysis, treatment with ICIs [hazard ratio (HR)=0.54, 95% confidence interval (CI)=0.30-0.98, p=0.044], good performance status (HR=0.30, 95%CI=0.16-0.57, p=0.0003), and histology other than squamous cell carcinoma (HR=0.41, 95%CI=0.19-0.83, p=0.014) were significantly favorable factors for OS.CONCLUSION: ICIs may be effective for older patients with NSCLC, especially squamous cell carcinoma patients.
CANIT0002976	32014936	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	Cytotoxic regimens	Immune checkpoint therapy	Nivolumab (DB09035); 	31	35	Retrospective analysis	Patients with squamous cell carcinoma who received ICIs had better overall survival (OS) than those who did not (9.7 versus 4.7 months, p=0.027). In multivariate analysis, treatment with ICIs [hazard ratio (HR)=0.54, 95% confidence interval (CI)=0.30-0.98, p=0.044], good performance status (HR=0.30, 95%CI=0.16-0.57, p=0.0003), and histology other than squamous cell carcinoma (HR=0.41, 95%CI=0.19-0.83, p=0.014) were significantly favorable factors for OS.ICIs may be effective for older patients with NSCLC, especially squamous cell carcinoma patients.	N/A	N/A	N/A	Squamous histology (NCIT:C19165); 	Squamous histology	Disease status	 2020 Feb	Efficacy of PD-1 Inhibitors in Older Non-small Cell Lung Cancer Patients.	 Anticancer Res	BACKGROUND/AIM: We assessed the efficacy of immune checkpoint inhibitors (ICIs) in older patients because of the limited information regarding these patients.PATIENTS AND METHODS: We retrospectively analyzed 66 consecutive patients >=70 years old with advanced non-small cell lung cancer (NSCLC). A total of 31 patients received ICIs (ICIs group) and 35 patients received only cytotoxic regimens (No ICIs group).RESULTS: Patients with squamous cell carcinoma who received ICIs had better overall survival (OS) than those who did not (9.7 versus 4.7 months, p=0.027). In multivariate analysis, treatment with ICIs [hazard ratio (HR)=0.54, 95% confidence interval (CI)=0.30-0.98, p=0.044], good performance status (HR=0.30, 95%CI=0.16-0.57, p=0.0003), and histology other than squamous cell carcinoma (HR=0.41, 95%CI=0.19-0.83, p=0.014) were significantly favorable factors for OS.CONCLUSION: ICIs may be effective for older patients with NSCLC, especially squamous cell carcinoma patients.
CANIT0002977	32016503	Basic research	Spontaneous prostate cancer	Spontaneous prostate cancer	MONDO:0008315	Prostate	PSCA (O43653); PAP1 (Q8TA86); PAP2 (O14494); SPAS1(Q496A3); 	PSCA ;  PAP1 ;  PAP2 	Bovine papillomavirus prostate cancer antigen virus-like particle vaccines	N/A	Tumor vaccine	N/A	Cell lines/ animal models	N/A	Basic research	All treatments significantly increased CD3 + and CD8 + T cell infiltration into tumor tissue compared to control mice, and combination therapy resulted in significantly greater CD3 + and CD8 + T cell infiltration than monotherapy. Reduction in tumor burden in vaccine-treated mice was inversely correlated with CD8 + T cell numbers in tumor tissue. No other immunotherapy has shown efficacy in this animal model of advanced prostate cancer, making bovine papillomavirus VLPs an attractive vaccine technology to test in patients with metastatic prostate cancer.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	CD4 (P01730); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	 CD3 (+)/CD8(+) T cell infiltration into tumor tissue	Tumor-infiltrating immune cell	 2020 Apr	Bovine papillomavirus prostate cancer antigen virus-like particle vaccines are efficacious in advanced cancers in the TRAMP mouse spontaneous prostate cancer model.	 Cancer Immunol Immunother	Prostate cancer is a candidate for immunotherapy because cancer cells express tissue-specific proteins that can be therapeutic targets. However, immune checkpoint inhibitors and active immunization have performed poorly in clinical trials. We developed a novel virus-like particle (VLP) vaccine composed of bovine papillomavirus L1 protein engineered to display surface docking sites. We decorated VLPs with peptides encoding T cell epitopes from two prostate cancer-associated tumor antigens, prostate stem cell antigen (PSCA), and prostatic acid phosphatase (PAP-1 and PAP-2), and a neo-antigen, stimulator of prostatic adenocarcinoma-specific T cells (SPAS-1). The VLP vaccines induced a mean frequency of antigen-specific IFN-¦Ã secreting CD8 + T cells of 2.9% to PSCA, 9.5% to SPAS-1, 0.03% to PAP-1, and 0.03% to PAP-2 in tumor-bearing TRAMP mice. We treated TRAMP mice at 19-20 weeks of age, when mice have advanced stages of carcinogenesis, with either VLP vaccine, anti-PD1 antibody, or combination immunotherapy. The VLP vaccine alone or in combination with anti-PD1 antibody significantly reduced tumor burden, while anti-PD1 antibody had a modest non-significant therapeutic effect. All treatments significantly increased CD3 + and CD8 + T cell infiltration into tumor tissue compared to control mice, and combination therapy resulted in significantly greater CD3 + and CD8 + T cell infiltration than monotherapy. Reduction in tumor burden in vaccine-treated mice was inversely correlated with CD8 + T cell numbers in tumor tissue. No other immunotherapy has shown efficacy in this animal model of advanced prostate cancer, making bovine papillomavirus VLPs an attractive vaccine technology to test in patients with metastatic prostate cancer.
CANIT0002978	32020472	Basic research	Glioblastoma	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Nivolumab plus rapamycin plus hydroxychloroquine	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); rapamycin (DB00877); hydroxychloroquine (DB01611); 	Cell lines/ animal models	N/A	Basic research	Rapamycin plus hydroxychloroquine (RQ) is a rationale for manipulating the macrophage phenotype and increased the therapeutic effect of immune checkpoint inhibitor. To re-educate and re-empower the tumor associated macrophage/microglia opens an interesting avenue for glioblastoma treatment. In vitro RQ treatment decreased the macrophages polarization of M2, increased the phagocytic ability, and increased the lipid droplets accumulation. RQ treatment decreased the expression levels of CD47 and SIRPA on tumor cells and macrophage cells in co-culture experiments. The combination of RQ and anti-PD1 treatment was synergistic in action. Enhanced the intra-tumoral M1/M2 ratio, the CD8/CD4 ratio in the intracranial GL261 tumor model after RQ treatment were evident.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2020 Feb	Rapamycin and hydroxychloroquine combination alters macrophage polarization and sensitizes glioblastoma to immune checkpoint inhibitors.	 J Neurooncol	INTRODUCTION: The failure of immune checkpoint inhibitor (ICPi) on glioblastoma (GBM) treatment underscores the need for improving therapeutic strategy. We aimed to change tumor associated macrophage (TAM) from M2 type (anti-inflammatory) to M1 (pro-inflammatory) type to increase the therapeutic response of ICPi. We proposed that combined rapamycin (R) and hydroxychloroquine (Q) preferentially induce M2 cells death, as fatty acid oxidation was their major source of energy.METHODS: Macrophage polarization was characterized on mice and human macrophage cell lines by specific cytokines stimulation with or without RQ treatment under single culture or co-culture with GBM cell lines. Tumor sizes were evaluated on subcutaneous and intracranial GL261 mice models with or without RQ, anti-PD1 mAb treatment. Tumor volumes assessed by MRI scan and proportions of tumor infiltrating immune cells analyzed by flow cytometry were compared.RESULTS: In vitro RQ treatment decreased the macrophages polarization of M2, increased the phagocytic ability, and increased the lipid droplets accumulation. RQ treatment decreased the expression levels of CD47 and SIRPa on tumor cells and macrophage cells in co-culture experiments. The combination of RQ and anti-PD1 treatment was synergistic in action. Enhanced the intra-tumoral M1/M2 ratio, the CD8/CD4 ratio in the intracranial GL261 tumor model after RQ treatment were evident.CONCLUSION: We provide a rationale for manipulating the macrophage phenotype and increased the therapeutic effect of ICPi. To re-educate and re-empower the TAM/microglia opens an interesting avenue for GBM treatment.
CANIT0002979	32023563	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus platinum-containing chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); platinum (DB12257); 	119	N/A	Retrospective analysis	In multivariate analysis, presence of bone metastases (HR: 2.08, 95% CI: 1.10-4.94, p = 0.030) was found to be independent negative prognostic factors for poor OS.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Bone metastasis	Disease status	 2020 Mar 16	Neutrophil to lymphocyte ratio as a potential predictive marker for treatment with pembrolizumab as a second line treatment in patients with non-small cell lung cancer.	 Biosci Trends	The aim of this multicentric retrospective study is to evaluate the predictive and prognostic performance of neutrophil to lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and their dynamics in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab as a second line. Patients with metastatic NSCLC (n = 119), whose tumors expressed programmed death-ligand 1 (PD-L1) >= 1%, were retrospectively analyzed between Apr 2017 and Apr 2019. All patients received platinum-containing chemotherapy as a first line treatment. Pre-treatment NLR was calculated by dividing the number of neutrophils by the number of lymphocytes in peripheral blood before the first pembrolizumab infusion. Progression free survival (PFS) and overall survival (OS) was compared by Kaplan-Meier method and Cox Proportional Hazard model. Patients with NLR > 5 before immunotherapy showed significantly shorter mean PFS of 6.86 months (95% CI: 5.81-7.90) as compared to those with NLR <= 5 of 18.82 months (95% CI: 15.87-21.78) (long rank test p < 0.001). Furthermore in the multivariate analysis, only NLR > 5 was an independent predictive factor for shorter PFS (HR: 4.47, 95% CI: 2.20-9.07, p < 0.001). In multivariate analysis, presence of bone metastases (HR: 2.08, 95% CI: 1.10-4.94, p = 0.030), NLR > 5 before chemotherapy (HR: 8.09, 95% CI: 2.35-27.81, p = 0.001) and high PLR before chemotherapy (HR: 2.81, 95% CI: 1.13-6.97, p = 0.025) were found to be independent negative prognostic factors for poor OS. Our data suggests that NLR <= 5 is a potential predictive marker, which may identify patients appropriate for immunotherapy as a second line treatment.
CANIT0002980	32023563	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus platinum-containing chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); platinum (DB12257); 	119	N/A	Retrospective analysis	Patients with Neutrophil-to-lymphocyte ratios (NLR) > 5 before immunotherapy showed significantly shorter mean PFS of 6.86 months (95% CI: 5.81-7.90) as compared to those with NLR <= 5 of 18.82 months (95% CI: 15.87-21.78) (long rank test p < 0.001). Furthermore in the multivariate analysis, only NLR > 5 was an independent predictive factor for shorter PFS (HR: 4.47, 95% CI: 2.20-9.07, p < 0.001). In multivariate analysis, presence of NLR > 5 before chemotherapy (HR: 8.09, 95% CI: 2.35-27.81, p = 0.001) was found to be independent negative prognostic factors for poor OS. The data suggests that NLR <= 5 is a potential predictive marker, which may identify patients appropriate for immunotherapy as a second line treatment.	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2020 Mar 16	Neutrophil to lymphocyte ratio as a potential predictive marker for treatment with pembrolizumab as a second line treatment in patients with non-small cell lung cancer.	 Biosci Trends	The aim of this multicentric retrospective study is to evaluate the predictive and prognostic performance of neutrophil to lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and their dynamics in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab as a second line. Patients with metastatic NSCLC (n = 119), whose tumors expressed programmed death-ligand 1 (PD-L1) >= 1%, were retrospectively analyzed between Apr 2017 and Apr 2019. All patients received platinum-containing chemotherapy as a first line treatment. Pre-treatment NLR was calculated by dividing the number of neutrophils by the number of lymphocytes in peripheral blood before the first pembrolizumab infusion. Progression free survival (PFS) and overall survival (OS) was compared by Kaplan-Meier method and Cox Proportional Hazard model. Patients with NLR > 5 before immunotherapy showed significantly shorter mean PFS of 6.86 months (95% CI: 5.81-7.90) as compared to those with NLR <= 5 of 18.82 months (95% CI: 15.87-21.78) (long rank test p < 0.001). Furthermore in the multivariate analysis, only NLR > 5 was an independent predictive factor for shorter PFS (HR: 4.47, 95% CI: 2.20-9.07, p < 0.001). In multivariate analysis, presence of bone metastases (HR: 2.08, 95% CI: 1.10-4.94, p = 0.030), NLR > 5 before chemotherapy (HR: 8.09, 95% CI: 2.35-27.81, p = 0.001) and high PLR before chemotherapy (HR: 2.81, 95% CI: 1.13-6.97, p = 0.025) were found to be independent negative prognostic factors for poor OS. Our data suggests that NLR <= 5 is a potential predictive marker, which may identify patients appropriate for immunotherapy as a second line treatment.
CANIT0002981	32023563	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus platinum-containing chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); platinum (DB12257); 	119	N/A	Retrospective analysis	In multivariate analysis, high Platelet-to-lymphocyte ratios before chemotherapy (HR: 2.81, 95% CI: 1.13-6.97, p = 0.025) was found to be independent negative prognostic factors for poor OS.	N/A	N/A	N/A	Platelet-to-lymphocyte ratios (EFO:0008446); 	Platelet-to-lymphocyte ratios	Cell percentage/counts in blood	 2020 Mar 16	Neutrophil to lymphocyte ratio as a potential predictive marker for treatment with pembrolizumab as a second line treatment in patients with non-small cell lung cancer.	 Biosci Trends	The aim of this multicentric retrospective study is to evaluate the predictive and prognostic performance of neutrophil to lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and their dynamics in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab as a second line. Patients with metastatic NSCLC (n = 119), whose tumors expressed programmed death-ligand 1 (PD-L1) >= 1%, were retrospectively analyzed between Apr 2017 and Apr 2019. All patients received platinum-containing chemotherapy as a first line treatment. Pre-treatment NLR was calculated by dividing the number of neutrophils by the number of lymphocytes in peripheral blood before the first pembrolizumab infusion. Progression free survival (PFS) and overall survival (OS) was compared by Kaplan-Meier method and Cox Proportional Hazard model. Patients with NLR > 5 before immunotherapy showed significantly shorter mean PFS of 6.86 months (95% CI: 5.81-7.90) as compared to those with NLR <= 5 of 18.82 months (95% CI: 15.87-21.78) (long rank test p < 0.001). Furthermore in the multivariate analysis, only NLR > 5 was an independent predictive factor for shorter PFS (HR: 4.47, 95% CI: 2.20-9.07, p < 0.001). In multivariate analysis, presence of bone metastases (HR: 2.08, 95% CI: 1.10-4.94, p = 0.030), NLR > 5 before chemotherapy (HR: 8.09, 95% CI: 2.35-27.81, p = 0.001) and high PLR before chemotherapy (HR: 2.81, 95% CI: 1.13-6.97, p = 0.025) were found to be independent negative prognostic factors for poor OS. Our data suggests that NLR <= 5 is a potential predictive marker, which may identify patients appropriate for immunotherapy as a second line treatment.
CANIT0002982	32023769	Clinical research	Malignant tumor	Live cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	112	N/A	N/A	The results of univariate and multivariate analyses showed that liver cancer was attributed to the immune checkpoint inhibitors (CPI) induced hepatitis (P<0.05). Patients with severe hepatic injury got almost complete resolution after receiving methlprednisolone for 4 to 6 weeks. Live cancer is the risk factor of CPI-related hepatic adverse events.	Immune treatment-related hepatic adverse events	N/A	N/A	N/A	N/A	N/A	 2020 Jan 23	[Retrospectively analysis of characteristics and risk factors of immune treatment-related hepatic adverse events in malignant tumor].	 Zhonghua Zhong Liu Za Zhi	Objective: To explore the clinical features and risk factors of hepatic injury due to immune checkpoint inhibitors (CPI) therapy in malignant tumor. Methods: Data of 112 patients (64 men and 48 women) who received CPI between January 2016 and March 2019 in Chinese Academy of Medical Sciences and Peking Union Medical College Shenzhen Hospital, and Huazhong University of Science and Techology Union Shenzhen Hospital were retrospectively collected. The median age of these patients was 60 years. Results: Hepatic adverse events were observed in 30 patients out of 112 patients (26.8%). Among them, the incidence of grade 3-5 hepatic adverse events were 7.14% (8/112). The median time of hepatic adverse event occurrence was 3 weeks (2-30) after undergoing therapy. The results of univariate and multivariate analyses showed that liver cancer was attributed to the CPI induced hepatitis (P<0.05). Patients with severe hepatic injury got almost complete resolution after receiving methlprednisolone for 4 to 6 weeks. Conclusion: Live cancer is the risk factor of CPI-related hepatic adverse events.
CANIT0002983	32028209	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	811	N/A	Open-label, multicentre, phase 2 trial	Median OS was similar in all treated patients and those aged >=70 and >=75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2. These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population.	Safety was similar across populations; the most frequent grade 3-4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%).	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2020 Mar	CheckMate 171: A phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS 2 and elderly populations.	 Eur J Cancer	BACKGROUND: CheckMate 171 (NCT02409368) is an open-label, multicentre, phase 2 trial of nivolumab in previously treated advanced squamous non-small cell lung cancer (NSCLC), conducted as part of a post-approval commitment to the European Medicines Agency (EMA). We report outcomes from this trial.METHODS: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and disease progression during/after >=1 systemic treatment (>=1 being platinum-based chemotherapy) for advanced or metastatic disease were treated with nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary end-point was incidence of grade 3-4 treatment-related select adverse events (AEs). Other end-points included overall survival (OS) and safety.RESULTS: Of 811 patients treated, 103 had ECOG PS 2; 278 were aged >=70 years and 125 were >=75 years of age. Minimum follow-up was ~18 months. Safety was similar across populations; the most frequent grade 3-4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%). Median OS was similar in all treated patients and those aged >=70 and >=75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2.CONCLUSION: These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population.CLINICAL TRIAL REGISTRATION: NCT02409368.
CANIT0002984	32029128	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	193	N/A	Retrospective analysis	Global longitudinal strain (GLS) decreases with immune checkpoint inhibitors (ICIs) myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced ejection fraction. Lower GLS was strongly associated with major adverse cardiac events in ICI myocarditis presenting with either a preserved or reduced ejection fraction.	Major adverse cardiac events in ICI myocarditis presenting with either a preserved or reduced ejection fraction	N/A	N/A	Global Longitudinal Strain (NCIT:C172266); 	Global longitudinal strain	Personal feature	 2020 Feb 11	Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis.	 J Am Coll Cardiol	BACKGROUND: There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis.OBJECTIVES: This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis.METHODS: This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death.RESULTS: Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 +/- 2.6% vs. 20.6 +/- 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 +/- 2.0% vs. 20.5 +/- 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 +/- 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 +/- 2.7%) or preserved EF (15.3 +/- 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8).CONCLUSIONS: GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.
CANIT0002985	32035514	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus pemetrexed-platinum	Pemetrexed-platinum plus placebo	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); pemetrexed (DB00642); 	405	202	Multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study	The addition of pembrolizumab to standard chemotherapy maintained global health status/quality of life (GHS/QOL), with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexed-platinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Mar	Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab plus pemetrexed-platinum led to superior overall survival and progression-free survival, and a higher proportion of patients with a confirmed complete or partial response over placebo plus pemetrexed-platinum in the KEYNOTE-189 study. We aimed to evaluate prespecified exploratory patient-reported outcomes (PROs) in patients in KEYNOTE-189.METHODS: In the multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study done at 126 cancer centres in 16 countries, eligible patients aged 18 years or older with histologically or cytologically confirmed metastatic non-squamous non-small-cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive intravenous pembrolizumab (200 mg) or saline placebo every 3 weeks for up to 2 years (35 cycles); all patients received four cycles of intravenous pemetrexed (500 mg/m2) with carboplatin (5 mg/mL per min) or cisplatin (75 mg/m2; investigator's choice) every 3 weeks for four cycles, followed by pemetrexed maintenance therapy every 3 weeks. Permuted block randomisation (block size six) was done with an interactive voice-response system and stratified by PD-L1 expression, choice of platinum, and smoking status. Patients, investigators, and other study personnel were unaware of treatment assignment. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13) were administered at cycles 1-5, every three cycles thereafter during year 1, and every four cycles during years 2-3. The primary endpoints (overall survival and progression-free survival) have been published previously. Key PRO endpoints were change from baseline to week 12 (during chemotherapy) and week 21 (following chemotherapy) in QLQ-C30 global health status/quality of life (GHS/QOL) score, and time to deterioration in cough, chest pain, or dyspnoea. PROs were analysed in all randomly assigned patients who received at least one dose of study medication and who completed at least one PRO assessment, and the results are provided with two-sided, nominal p values. This ongoing study is registered with ClinicalTrials.gov, number NCT02578680.FINDINGS: Between Feb 26, 2016, and March 6, 2017, 616 patients were enrolled; median follow-up was 10.5 months (range 0.2-20.4) as of data cutoff on Nov 8, 2017. 402 (99%) of 405 patients in the pembrolizumab plus pemetrexed-platinum group and 200 (99%) of 202 patients in the placebo plus pemetrexed-platinum-treated group completed at least one PRO assessment. At baseline, 359 (89%) of 402 patients in the pembrolizumab plus pemetrexed-platinum group and 180 (90%) of 200 in the placebo plus pemetrexed-platinum group were compliant with QLQ-C30; at week 12, 319 (90%) of 354 and 149 (89%) of 167 patients were compliant, respectively; and at week 21, 249 (76%) of 326 and 91 (64%) of 143 patients were compliant, respectively. From baseline to week 12, GHS/QOL scores were maintained with both pembrolizumab plus pemetrexed-platinum (least-squares mean change: 1.0 point [95% CI -1.3 to 3.2] increase) and placebo plus pemetrexed-platinum (-2.6 points [-5.8 to 0.5] decrease; between-group difference: 3.6 points [-0.1 to 7.2]; p=0.053). From baseline to week 21, GHS/QOL scores were better maintained with pembrolizumab plus pemetrexed-platinum (least-squares mean change: 1.3 points [95% CI -1.2 to 3.6] increase) than with placebo plus pemetrexed-platinum (-4.0 points [-7.7 to -0.3] decrease; between-group difference: 5.3 points [1.1 to 9.5]; p=0.014). Median time to deterioration in cough, chest pain, or dyspnoea was not reached (95% CI 10.2 months to not reached) with pembrolizumab plus pemetrexed-platinum, and was 7.0 months (4.8 months to not reached) with placebo plus pemetrexed-platinum (hazard ratio 0.81 [95% CI 0.60-1.09], p=0.16).INTERPRETATION: The addition of pembrolizumab to standard chemotherapy maintained GHS/QOL, with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexed-platinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer.FUNDING: Merck Sharp & Dohme.
CANIT0002986	32047958	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	30	N/A	Retrospective analysis	High tumor mutational load (TML) was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007).	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	Total CD8(+) T-cell infiltrate	Tumor-infiltrating immune cell	 2020 May	Tumor mutational load, CD8(+) T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients.	 Cancer Immunol Immunother	OBJECTIVES: A minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitors. A rational combination of biomarkers is needed. The objective was to determine the predictive value of tumor mutational load (TML), CD8+ T cell infiltration, HLA class-I and PD-L1 expression in the tumor.MATERIALS AND METHODS: Metastatic NSCLC patients were prospectively included in an immune-monitoring trial (NTR7015) between April 2016-August 2017, retrospectively analyzed in FFPE tissue for TML (NGS: 409 cancer-related-genes) and by IHC staining to score PD-L1, CD8+ T cell infiltration, HLA class-I. PFS (RECISTv1.1) and OS were analyzed by Kaplan-Meier methodology.RESULTS: 30 patients with adenocarcinoma (67%) or squamous cell carcinoma (33%) were included. High TML was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007).CONCLUSION: This proof-of-concept study suggests that a combination of PD-L1 expression, TML, CD8+ T cell infiltration and HLA class-I functions as a better predictive biomarker for response to anti-PD-1 immunotherapy. Consequently, refinement of this set of biomarkers and validation in a larger set of patients is warranted.
CANIT0002987	32047958	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	30	N/A	Retrospective analysis	High tumor mutational load (TML) was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007).	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	HLAB (P01889); 	No loss of HLA class-I	Gene expression signature on/in immune cell	 2020 May	Tumor mutational load, CD8(+) T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients.	 Cancer Immunol Immunother	OBJECTIVES: A minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitors. A rational combination of biomarkers is needed. The objective was to determine the predictive value of tumor mutational load (TML), CD8+ T cell infiltration, HLA class-I and PD-L1 expression in the tumor.MATERIALS AND METHODS: Metastatic NSCLC patients were prospectively included in an immune-monitoring trial (NTR7015) between April 2016-August 2017, retrospectively analyzed in FFPE tissue for TML (NGS: 409 cancer-related-genes) and by IHC staining to score PD-L1, CD8+ T cell infiltration, HLA class-I. PFS (RECISTv1.1) and OS were analyzed by Kaplan-Meier methodology.RESULTS: 30 patients with adenocarcinoma (67%) or squamous cell carcinoma (33%) were included. High TML was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007).CONCLUSION: This proof-of-concept study suggests that a combination of PD-L1 expression, TML, CD8+ T cell infiltration and HLA class-I functions as a better predictive biomarker for response to anti-PD-1 immunotherapy. Consequently, refinement of this set of biomarkers and validation in a larger set of patients is warranted.
CANIT0002988	32047958	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	30	N/A	Retrospective analysis	High tumor mutational load (TML) was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007).	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2020 May	Tumor mutational load, CD8(+) T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients.	 Cancer Immunol Immunother	OBJECTIVES: A minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitors. A rational combination of biomarkers is needed. The objective was to determine the predictive value of tumor mutational load (TML), CD8+ T cell infiltration, HLA class-I and PD-L1 expression in the tumor.MATERIALS AND METHODS: Metastatic NSCLC patients were prospectively included in an immune-monitoring trial (NTR7015) between April 2016-August 2017, retrospectively analyzed in FFPE tissue for TML (NGS: 409 cancer-related-genes) and by IHC staining to score PD-L1, CD8+ T cell infiltration, HLA class-I. PFS (RECISTv1.1) and OS were analyzed by Kaplan-Meier methodology.RESULTS: 30 patients with adenocarcinoma (67%) or squamous cell carcinoma (33%) were included. High TML was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007).CONCLUSION: This proof-of-concept study suggests that a combination of PD-L1 expression, TML, CD8+ T cell infiltration and HLA class-I functions as a better predictive biomarker for response to anti-PD-1 immunotherapy. Consequently, refinement of this set of biomarkers and validation in a larger set of patients is warranted.
CANIT0002989	32047958	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	30	N/A	Retrospective analysis	High tumor mutational load (TML) was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007).	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2020 May	Tumor mutational load, CD8(+) T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients.	 Cancer Immunol Immunother	OBJECTIVES: A minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitors. A rational combination of biomarkers is needed. The objective was to determine the predictive value of tumor mutational load (TML), CD8+ T cell infiltration, HLA class-I and PD-L1 expression in the tumor.MATERIALS AND METHODS: Metastatic NSCLC patients were prospectively included in an immune-monitoring trial (NTR7015) between April 2016-August 2017, retrospectively analyzed in FFPE tissue for TML (NGS: 409 cancer-related-genes) and by IHC staining to score PD-L1, CD8+ T cell infiltration, HLA class-I. PFS (RECISTv1.1) and OS were analyzed by Kaplan-Meier methodology.RESULTS: 30 patients with adenocarcinoma (67%) or squamous cell carcinoma (33%) were included. High TML was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007).CONCLUSION: This proof-of-concept study suggests that a combination of PD-L1 expression, TML, CD8+ T cell infiltration and HLA class-I functions as a better predictive biomarker for response to anti-PD-1 immunotherapy. Consequently, refinement of this set of biomarkers and validation in a larger set of patients is warranted.
CANIT0002990	32049805	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	30	N/A	N/A	There was no significant association between skeletal muscle (SM) loss and immune-related adverse events. The SM loss group had undergone significantly more prior chemotherapy cycles (P = .04). SM loss was significantly associated with fewer nivolumab cycles (P = .01). No patients in the SM loss group achieved a partial response. Patients with SM loss had a significantly shorter progression-free survival period (P = .008) and median overall survival than those with normal SM mass (10 vs 25 months, respectively, P = .03). SM loss was an independent prognostic factor of poor survival.	N/A	N/A	N/A	Abnormal skeletal muscle mass (MP:0004819); 	Skeletal muscle mass	Personal feature	 2020 Feb	Skeletal muscle mass predicts the outcome of nivolumab treatment for non-small cell lung cancer.	 Medicine (Baltimore)	Nivolumab, a monoclonal antibody targeting programmed cell death-1, significantly prolongs survival for patients with advanced non-small-cell lung cancer (NSCLC). However, little is known about the value of predictive biomarkers. Hence, we investigated the impact of skeletal muscle (SM) mass loss on clinical outcomes in NSCLC patients undergoing nivolumab treatment. Thirty patients with histologically confirmed NSCLC treated with nivolumab were included in this study. Computed tomography was used to determine SM loss based on the SM index (SMI). The SMI is the cross-sectional area of the bilateral psoas muscles at the third lumbar vertebra, divided by height squared. The cut-off values were defined as 6.36 cm/m for men and 3.92 cm/m for women. Among the 30 patients, 13 (43%) had SM loss. There was no significant association between SM loss and immune-related adverse events. The SM loss group had undergone significantly more prior chemotherapy cycles (P = .04). SM loss was significantly associated with fewer nivolumab cycles (P = .01). No patients in the SM loss group achieved a partial response. Patients with SM loss had a significantly shorter progression-free survival period (P = .008) and median overall survival than those with normal SM mass (10 vs 25 months, respectively, P = .03). SM loss was an independent prognostic factor of poor survival. In conclusion, SM loss may be a predictive factor of poor outcomes in NSCLS patients undergoing nivolumab therapy.
CANIT0002991	32051381	Case report	A patient	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	1	N/A	Case	We herein report a patient with non-small-cell lung cancer treated previously with thoracic radiotherapy who developed severe radiation recall dermatitis (RRD) induced by atezolizumab	Radiation recall dermatitis	N/A	N/A	N/A	N/A	N/A	 2020 May 1	Non-small-cell Lung Cancer with Severe Skin Manifestations Related to Radiation Recall Dermatitis after Atezolizumab Treatment.	 Intern Med	Radiation recall dermatitis (RRD) is an inflammatory reaction that occurs at previously irradiated skin regions after drug administration. We herein report a patient with non-small-cell lung cancer treated previously with thoracic radiotherapy who developed severe RRD induced by atezolizumab [anti-programmed death 1 ligand 1 (PD-L1) antibody]. Immunohistochemistry of the skin biopsy showed dermatitis with infiltration of CD8+ lymphocytes, suggesting that atezolizumab might provoke an immune-related inflammatory reaction at previously irradiated skin regions. When administering anti-PD-L1 antibody to patients who have undergone radiotherapy previously, physicians should carefully monitor the irradiated skin for the potential occurrence of RRD.
CANIT0002992	32060053	Clinical research	Triple negative and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus capecitabine	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); capecitabine (DB01101); 	30	N/A	Single-arm, phase II study	Compared with historical controls, pembrolizumab with capecitabine did not improve progression-free survival in this biomarker unselected, pretreated cohort. However, some patients had prolonged disease control.	The most common adverse events were low grade and consistent with those seen in MBC patients receiving capecitabine, including hand-foot syndrome, gastrointestinal symptoms, fatigue and cytopenias. Toxicities at least possibly from pembrolizumab included grade 3 or 4 liver test abnormalities (7%), rash (7%) and diarrhea (3%), as well as grade 5 hepatic failure in a patient with liver metastases.	N/A	N/A	N/A	N/A	N/A	 2020 Feb	Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer.	 J Immunother Cancer	BACKGROUND: Response rates to single agent immune checkpoint blockade in unselected pretreated HER2-negative metastatic breast cancer (MBC) are low. However, they may be augmented when combined with chemotherapy.METHODS: We conducted a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) MBC who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. The primary end point was median progression-free survival (mPFS) compared with historic controls and secondary end points were overall response rate (ORR), safety and tolerability. The study had 80% power to detect a 2-month improvement in mPFS with the addition of pembrolizumab over historic controls treated with capecitabine alone.RESULTS: Thirty patients, 16 TN and 14 HR+ MBC, were enrolled from 2017 to 2018. Patients had a median age of 51 years and received a median of 1 (range 0-6) prior lines of therapy for MBC. Of 29 evaluable patients, the mPFS was 4.0 (95% CI 2.0 to 6.4) months and was not significantly longer than historic controls of 3 months. The median overall survival was 15.4 (95% CI 8.2 to 20.3) months. The ORR was 14% (n=4), stable disease (SD) was 41% (n=12) and clinical benefit rate (CBR=partial response+SD>6 months) was 28% (n=8). The ORR and CBR were not significantly different between disease subtypes (ORR 13% and 14%, CBR 25% and 29% for TN and HR+, respectively). The 1-year PFS rate was 20.7% and three patients have ongoing responses. The most common adverse events were low grade and consistent with those seen in MBC patients receiving capecitabine, including hand-foot syndrome, gastrointestinal symptoms, fatigue and cytopenias. Toxicities at least possibly from pembrolizumab included grade 3 or 4 liver test abnormalities (7%), rash (7%) and diarrhea (3%), as well as grade 5 hepatic failure in a patient with liver metastases.CONCLUSIONS: Compared with historical controls, pembrolizumab with capecitabine did not improve PFS in this biomarker unselected, pretreated cohort. However, some patients had prolonged disease control.TRIAL REGISTRATION NUMBER: NCT03044730.
CANIT0002993	32066648	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); BRAF (P15056); 	PD-1; BRAF	Nivolumab followed by vemurafenib plus cobimetinib followed by tocilizumab plus infliximab followed by dabrafenib and trametinib	N/A	Immune checkpoint therapy followed by Target therapy	Nivolumab (DB09035); dabrafenib (DB08912); vemurafenib (DB08881); cobimetinib (DB05239); tocilizumab (DB06273); infliximab (DB00065); trametinib (DB08911); 	1	N/A	Case	Tocilizumab and infliximab target treatment of very severe adverse events (AEs) may afford an immediate resolution of potentially life-threatening symptoms and reduce the duration and the costs of hospitalization. Maintenance of therapeutic infliximab blood concentrations permits an early switch to dabrafenib after vemurafenib-related AEs.	Postnivolumab vemurafenib-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome	N/A	N/A	BRAF (P15056); 	BRAF V600E mutation	Mutational status	 2020 Feb	Rapid recovery of postnivolumab vemurafenib-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome after tocilizumab and infliximab administration.	 J Immunother Cancer	BACKGROUND: Immune checkpoint inhibitors such as nivolumab and targeted BRAF inhibitors have dramatically altered the treatment outcomes of metastatic melanoma over the past few years. Skin toxicity is the most common adverse event (AE) related to the commonly used BRAF inhibitor vemurafenib, affecting more than 90% of patients. Vemurafenib-related severe AEs with early onset are reported in patients who were previously treated with anti-programmed cell death-1 (anti PD-1) antibodies. A prolonged administration of systemic steroids is the first-line treatment of severe or life-threatening AEs. We report the case of a woman suffering from vemurafenib-related severe, rapidly worsening Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, resolved in a few hours after single-dose administration of a combination of TNF-a antagonist infliximab with interleukin (IL)-6 receptor antagonist tocilizumab.CASE PRESENTATION: A 41-year-old woman treated with single-agent nivolumab presented with a melanoma progression. Biopsy samples were revised, revealing a BRAF V600E mutation. The patient was started on vemurafenib and cobimetinib treatment only 10 days after the last administration of nivolumab. On the third day of anti-BRAF therapy, profound lymphopenia was detected, and maculopapular eruption appeared afterward. Subsequently, the clinical conditions deteriorated further, and the woman was admitted on an emergency basis with high fever, respiratory and cardiocirculatory failure, diffuse rash, generalized edema, and lymphadenopathy. Diagnosis of DRESS syndrome with overexpressed capillary leakage was made. A single dose of tocilizumab was administered with an improvement of cardiocirculatory and renal function in a few hours. Because of worsening of liver function, skin lesions and mucositis, a single dose of infliximab was prescribed, and dramatic improvement was noted over the next 24 hours. Dabrafenib and trametinib were initiated, and coinciding with washout of infliximab from the patient's blood, the drug toxicity recurred.CONCLUSION: Anti-IL-6 and anti-TNF-a target treatment of very severe AEs may afford an immediate resolution of potentially life-threatening symptoms and reduce the duration and the costs of hospitalization. Maintenance of therapeutic infliximab blood concentrations permits an early switch to dabrafenib after vemurafenib-related AEs.
CANIT0002994	32086984	Clinical research	Malignant diseases	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Patients were divided into two groups: those who developed thyroid immune-related adverse event (irAE), and those without immune-related adverse events. Comparing the two groups, early increase (=<4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1beta, IL-2, and GM-CSF at baseline, and early decrease of IL-8, GM-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen.In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.	Thyroid immune-related adverse events	N/A	N/A	CCL2 (P13500); 	Early decrease of MCP1 levels	Gene expression signature in serum	 2020 May	Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.	 Cancer Sci	Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (<=4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1¦Â, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.
CANIT0002995	32086984	Clinical research	Malignant diseases	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Patients were divided into two groups: those who developed thyroid immune-related adverse event (irAE), and those without immune-related adverse events. Comparing the two groups, early increase (=<4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1beta, IL-2, and GM-CSF at baseline, and early decrease of IL-8, GM-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen.In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.	Thyroid immune-related adverse events	N/A	N/A	G-CSF (Q99062); 	Early decrease of G-CSF levels	Gene expression signature in serum	 2020 May	Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.	 Cancer Sci	Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (<=4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1¦Â, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.
CANIT0002996	32086984	Clinical research	Malignant diseases	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Patients were divided into two groups: those who developed thyroid immune-related adverse event (irAE), and those without immune-related adverse events. Comparing the two groups, early increase (=<4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1beta, IL-2, and GM-CSF at baseline, and early decrease of IL-8, GM-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen.In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.	Thyroid immune-related adverse events	N/A	N/A	GM-CSF (P04141); 	Baseline serum GM-CSF levels	Gene expression signature in serum	 2020 May	Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.	 Cancer Sci	Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (<=4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1¦Â, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.
CANIT0002997	32086984	Clinical research	Malignant diseases	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Patients were divided into two groups: those who developed thyroid immune-related adverse event (irAE), and those without immune-related adverse events. Comparing the two groups, early increase (=<4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1beta, IL-2, and GM-CSF at baseline, and early decrease of IL-8, GM-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen.In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.	Thyroid immune-related adverse events	N/A	N/A	IL1B (P01584); 	Baseline serum IL1B levels	Gene expression signature in serum	 2020 May	Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.	 Cancer Sci	Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (<=4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1¦Â, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.
CANIT0002998	32086984	Clinical research	Malignant diseases	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Patients were divided into two groups: those who developed thyroid immune-related adverse event (irAE), and those without immune-related adverse events. Comparing the two groups, early increase (=<4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1beta, IL-2, and GM-CSF at baseline, and early decrease of IL-8, GM-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen.In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.	Thyroid immune-related adverse events	N/A	N/A	IL2 (P60568); T-Lymphocyte (NCIT:C12476); 	Baseline serum IL2 levels	Gene expression signature in serum	 2020 May	Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.	 Cancer Sci	Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (<=4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1¦Â, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.
CANIT0002999	32086984	Clinical research	Malignant diseases	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Patients were divided into two groups: those who developed thyroid immune-related adverse event (irAE), and those without immune-related adverse events. Comparing the two groups, early increase (=<4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1beta, IL-2, and GM-CSF at baseline, and early decrease of IL-8, GM-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen.In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.	Thyroid immune-related adverse events	N/A	N/A	IL8 (P10145); 	Serum IL8 expression levels	Gene expression signature in serum	 2020 May	Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.	 Cancer Sci	Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (<=4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1¦Â, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.
CANIT0003000	32086984	Clinical research	Malignant diseases	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Patients were divided into two groups: those who developed thyroid immune-related adverse event (irAE), and those without immune-related adverse events. Comparing the two groups, early increase (=<4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1beta, IL-2, and GM-CSF at baseline, and early decrease of IL-8, GM-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen.In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.	Thyroid immune-related adverse events	N/A	N/A	THYG (P01266); 	Early increase (<=4 wk) in serum thyroglobulin (Tg) levels	Gene expression signature in serum	 2020 May	Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.	 Cancer Sci	Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (<=4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1¦Â, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.
CANIT0003001	32086984	Clinical research	Malignant diseases	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	26	N/A	Retrospective analysis	Patients were divided into two groups: those who developed thyroid immune-related adverse event (irAE), and those without immune-related adverse events. Comparing the two groups, early increase (=<4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1beta, IL-2, and GM-CSF at baseline, and early decrease of IL-8, GM-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen.In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.	Thyroid immune-related adverse events	N/A	N/A	Thyroid autoantibodie ()	Early increase (<=4 wk) in serum thyroid autoantibodies	Gene expression signature in serum	 2020 May	Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.	 Cancer Sci	Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (<=4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1¦Â, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.
CANIT0003002	32097933	Clinical research	Gastroesophageal cancers	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab plus Irinotecan plus 5-Fluorouracil	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); irinotecan (DB00762); 	15	N/A	N/A	Disease control (response or stability) on first scan was 73.3% (n = 11). Median PFS and OS for the entire group was 7 and 13.3 months, respectively.In this small cohort of patients, combination of nivolumab, irinotecan, and 5-Fluorouracil is quite feasible and resulted in prolonged stability in some patients. Further development of this regimen is warranted.	The most common reason for dose delay or adjustment was grade 2 fatigue. 	N/A	N/A	N/A	N/A	N/A	2020	Nivolumab in Combination with Irinotecan and 5-Fluorouracil (FOLFIRI) for Refractory Advanced Gastroesophageal Cancer.	 Oncology	INTRODUCTION: Advanced unresectable gastroesophageal cancers continue to confer a dismal patient prognosis. Limited options remain once the cancer is refractory to cytotoxics/biologics (like irinotecan, taxane, and ramucirumab). Recently, anti-programmed death-1 (anti-PD-1) inhibitors have been used with limited efficacy in select patients with adenocarcinoma. Similarly, irinotecan-based therapy has marginal efficacy. We combined irinotecan plus a fluoropyrimidine with an anti-PD-1 antibody, nivolumab, with hopes of having a higher advantage for patients.OBJECTIVES: Primary objective was to assess safety judged by toxicities, dose delays, or dose reductions. Secondary endpoints included the assessment of response, overall survival (OS), and progression-free survival (PFS).METHODS: We treated 15 patients with this combination during July 2017 to April 2019. Patients were included if they had follow-up at our institution.RESULTS: Median doses given were nivolumab 240 mg + irinotecan 120 mg/m2 + 5-FU 2,000 mg/m2 over 46-48 h (or capecitabine 1,250 mg/m2/day; 7 days on, 7 days off) given every 2 weeks. Median age of the patients was 55 years, and all patients had an ECOG performance status of 0-1. The patients had a median of 1 prior therapy. Slightly over half of the patients had PD-L1 expression. The median number of cycles was 7. Five patients (33%) had a dose delay or dose adjustment. The most common reason for dose delay or adjustment was grade 2 fatigue. Disease control (response or stability) on first scan was 73.3% (n = 11). Median PFS and OS for the entire group was 7 and 13.3 months, respectively.CONCLUSION: In this small cohort of patients, we conclude that this combination is quite feasible and resulted in prolonged stability in some patients. Further development of this regimen is warranted.
CANIT0003003	32101306	Clinical research	Cancers	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); TGFB1 (P01137); 	CTLA-4 ;  PD-1 ;  PD-L1 	Avelumab or ipilimumab or nivolumab or pembrolizumab or Bintrafusp alfa	N/A	Immune checkpoint therapy	Avelumab (DB11945); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	8	N/A	Multicentre, retrospective analysis	These findings suggest that advanced imaging may help to distinguish ICI-induced inflammatory arthritis from other causes of joint pain, aid in identifying patients at increased risk of joint damage, and provide utility in monitoring inflammatory arthritis treatment response in patients receiving ICI therapy.	Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis	N/A	N/A	N/A	N/A	N/A	 2020 Feb 5	Use of Magnetic Resonance Imaging to Identify Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis.	 JAMA Netw Open	IMPORTANCE: Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for an ever-increasing number of cancers. However, their use has also led to the emergence of immune-related adverse events, such as ICI-induced inflammatory arthritis. A reproducible, reliable, and accessible modality is needed to assess and distinguish early ICI-induced inflammatory arthritis and help in management. Magnetic resonance imaging (MRI) of joints may be helpful for early diagnosis, guiding therapeutic decision-making, and identifying patients at high risk for erosive disease.OBJECTIVE: To assess the role of MRI of joints in patients with ICI-induced inflammatory arthritis.DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series included patients enrolled at the National Institutes of Health Clinical Center in Bethesda, Maryland. Patients were evaluated by the rheumatology consultation service between December 27, 2016, and May 28, 2019. A retrospective health record review was performed to determine demographic characteristics, clinical characteristics of inflammatory arthritis and malignant tumors, and imaging findings. Inclusion criteria were patients who were enrolled on various institutional review board-approved protocols of ICIs, developed joint-related symptoms, and had MRI data for at least 1 joint. Data were analyzed from June 1, 2019, to September 1, 2019.EXPOSURES: Undergoing MRI of at least 1 joint.MAIN OUTCOMES AND MEASURES: All MRIs were reviewed for synovitis, tenosynovitis, bone marrow edema, and soft tissue conditions.RESULTS: A total of 8 patients (mean [SD] age, 58.8 [5.2] years; 6 women and 2 men) between the ages of 50 and 65 years who were undergoing ICI therapy for a variety of malignant tumors were included in this study. Only 1 patient was receiving combined ICI therapy. The results of 13 separate MRI examinations were reviewed. The most commonly performed MRIs were of the hands and wrists (9 MRIs), followed by knee examinations (3 MRIs). Tenosynovitis and synovitis were frequently seen in the hands and wrists. Bone marrow edema and erosions were also found in 3 patients, suggesting early damage. In larger joints (ie, knees and ankles), joint effusions and synovial thickening were characteristic. Most patients (5 patients) were treated with corticosteroids and had good responses. In patients with high-risk features on MRI imaging (eg, bone marrow edema, erosions), disease-modifying antirheumatic drug therapy was also discussed as a treatment option.CONCLUSIONS AND RELEVANCE: These findings suggest that advanced imaging may help to distinguish ICI-induced inflammatory arthritis from other causes of joint pain, aid in identifying patients at increased risk of joint damage, and provide utility in monitoring inflammatory arthritis treatment response in patients receiving ICI therapy.
CANIT0003004	32107211	Basic research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab plus hybrid TT-OVA-PeptiCRAd containing both tetanus toxoid- and tumor-specific peptides	N/A	Immune checkpoint therapy plus oncolytic virus	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	These findings establish a novel technology that enhances oncolytic cancer immunotherapy by capitalizing on pre-acquired immunity to pathogens to convert a weak antitumor immune response into a much stronger one.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jun 15	Exploiting Preexisting Immunity to Enhance Oncolytic Cancer Immunotherapy.	 Cancer Res	Because of the high coverage of international vaccination programs, most people worldwide have been vaccinated against common pathogens, leading to acquired pathogen-specific immunity with a robust memory T-cell repertoire. Although CD8+ antitumor cytotoxic T lymphocytes (CTL) are the preferred effectors of cancer immunotherapy, CD4+ T-cell help is also required for an optimal antitumor immune response to occur. Hence, we investigated whether the pathogen-related CD4+ T-cell memory populations could be reengaged to support the CTLs, converting a weak primary antitumor immune response into a stronger secondary one. To this end, we used our PeptiCRAd technology that consists of an oncolytic adenovirus coated with MHC-I-restricted tumor-specific peptides and developed it further by introducing pathogen-specific MHC-II-restricted peptides. Mice preimmunized with tetanus vaccine were challenged with B16.OVA tumors and treated with the newly developed hybrid TT-OVA-PeptiCRAd containing both tetanus toxoid- and tumor-specific peptides. Treatment with the hybrid PeptiCRAd significantly enhanced antitumor efficacy and induced TT-specific, CD40 ligand-expressing CD4+ T helper cells and maturation of antigen-presenting cells. Importantly, this approach could be extended to naturally occurring tumor peptides (both tumor-associated antigens and neoantigens), as well as to other pathogens beyond tetanus, highlighting the usefulness of this technique to take full advantage of CD4+ memory T-cell repertoires when designing immunotherapeutic treatment regimens. Finally, the antitumor effect was even more prominent when combined with the immune checkpoint inhibitor anti-PD-1, strengthening the rationale behind combination therapy with oncolytic viruses. SIGNIFICANCE: These findings establish a novel technology that enhances oncolytic cancer immunotherapy by capitalizing on pre-acquired immunity to pathogens to convert a weak antitumor immune response into a much stronger one.
CANIT0003005	32140762	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Platinum-based chemotherapy followed by nivolumab	N/A	Chemotherapy followed by Immune checkpoint therapy	Nivolumab (DB09035); Platinum (DB12257); 	531	N/A	Retrospective analysis	The pooled exploratory analysis demonstrates improved clinical benefit to nivolumab in NSCLC patients, which was after failing platinum-based chemotherapy, experiencing irAEs. We also observed negative impact of immune-related adverse events (irAEs)-related treatment discontinuation on survival in this group of patients.	N/A	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	Immune-related adverse events	Adverse events	 2020 Jul	Outcomes associated with immune-related adverse events in metastatic non-small cell lung cancer treated with nivolumab: a pooled exploratory analysis from a global cohort.	 Cancer Immunol Immunother	BACKGROUND: Immune-related adverse events (irAEs) comprise a distinct spectrum of auto-inflammatory manifestations triggered due to immune checkpoint inhibitors (ICI). Current data on the association of irAEs with outcomes in NSCLC treated with nivolumab are limited.METHODS AND OBJECTIVES: We pooled data from 531 metastatic NSCLC patients from five centers treated with nivolumab after failing platinum-based chemotherapy. The primary objective was to investigate the relationship between irAEs with clinical benefit to nivolumab as well as to elucidate patterns of irAE-related ICI discontinuations and their impact on survival.RESULTS: 33.0% (173/531) of patients treated with nivolumab were noted to have an irAE. Patients with irAEs had a significantly longer median PFS [6.1 vs. 3.1 months, HR 0.68 95% CI (0.55-0.85); p = 0.001] and OS [14.9 vs. 7.4 months, HR 0.66 95% CI (0.52-0.82); p < 0.001)] compared to those without irAEs. In multivariate analysis, the presence of irAEs showed a significantly better PFS [HR 0.69, 95% CI (0.55-0.87); p = 0.002] and a trend for better OS [HR 0.62, 95% CI (0.55-1.03); p = 0.057]. Patients with permanent ICI discontinuation secondary to index irAE had a significantly shorter median PFS [2.3 vs. 6.6 months, HR 1.74 95% CI (1.06-2.80); p = 0.02] and median OS [3.6 vs. 17.6 months; HR 2.61 95% CI (1.61-4.21); p < 0.001] compared to those that did not have permanent ICI discontinuation.CONCLUSIONS: Our pooled exploratory analysis demonstrates improved clinical benefit to nivolumab in NSCLC patients experiencing irAEs. We also observed negative impact of irAE-related treatment discontinuation on survival in this group of patients.
CANIT0003006	32145474	Clinical research	Gastric/gastroesophageal junction (G/GEJ) cancer	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus S-1 plus oxaliplatin	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); oxaliplatin (DB00526); 	54	N/A	Non-randomised, multicentre, open-label phase IIb study	S-1 plus oxaliplatin with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of advanced gastric/gastroesophageal junction cancer.	Grade >=3 treatment-related adverse events (TRAEs) were reported by 57.4% of patients. The most common grade >=3 TRAEs were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%).	N/A	N/A	N/A	N/A	N/A	 2020 Apr	Safety and efficacy of pembrolizumab in combination with S-1 plus oxaliplatin as a first-line treatment in patients with advanced gastric/gastroesophageal junction cancer: Cohort 1 data from the KEYNOTE-659 phase IIb study.	 Eur J Cancer	AIM: The KEYNOTE-659 study evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy as the first-line treatment in Japanese patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer. In this paper, we report results from cohort 1 (S-1 plus oxaliplatin [SOX] with pembrolizumab).METHODS: This was a non-randomised, multicentre, open-label phase IIb study in patients with advanced programmed death-ligand 1 (PD-L1)-positive, human epidermal growth factor receptor 2-negative G/GEJ tumours. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Exploratory analyses were performed based on the PD-L1 combined positive score (CPS) status.RESULTS: Fifty-four patients were evaluated. The median follow-up was 10.1 months. ORR and DCR by BICR were 72.2% (95% confidence interval [CI] 58.4-83.5) and 96.3% (95% CI 87.3-99.5), respectively. Median DOR, TTR, PFS and OS were as follows: not reached, 1.5 months, 9.4 months and not reached. The ORR was 73.9% in patients with CPS >=1 to <10 and 71.0% in those with CPS >=10. Grade >=3 treatment-related adverse events (TRAEs) were reported by 57.4% of patients. The most common grade >=3 TRAEs were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%).CONCLUSIONS: SOX with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of advanced G/GEJ cancer.TRIAL REGISTRATION: NCT03382600/JapicCTI-183829.
CANIT0003007	32146284	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	Meta-analysis	Use of antibiotics may be associated with worse outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs). A total of 20 retrospective studies were included. The median OS (7.9 months versus 17.65 months) and PFS (2.4 months versus 4.4 months) of the antibiotics use group were shorter compared to control group. Meta-analysis also showed that the risks of death (HR = 1.90, 95 % CI: 1.55-2.34; P < 0.01) and disease progression (HR=1.53, 95 % CI: 1.30-1.79; P < 0.01) in antibiotics positive group were significantly higher than that of the negative group. The prognostic role of antibiotics use was still significant regardless of cancer types and timing of antibiotics (P < 0.01 for all).	N/A	N/A	N/A	Antibiotics (NCIT:C258); 	Antibiotics use	Exposure factors/status	 2020 May	The association between antibiotics use and outcome of cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.	 Crit Rev Oncol Hematol	OBJECTIVE: This meta-analysis was to evaluate the impact of antibiotics use on survival of cancer patients with immune checkpoint inhibitors (ICIs).METHODS: Electronic databases including Pubmed, Emabse, and the Cochrane library were searched. The primary endpoints were overall survival (OS) and progression-free survival (PFS).RESULTS: A total of 20 retrospective studies were included. The median OS (7.9 months versus 17.65 months) and PFS (2.4 months versus 4.4 months) of the antibiotics use group were shorter compared to control group. Meta-analysis also showed that the risks of death (HR = 1.90, 95 % CI: 1.55-2.34; P < 0.01) and disease progression (HR=1.53, 95 % CI: 1.30-1.79; P < 0.01) in antibiotics positive group were significantly higher than that of the negative group. The prognostic role of antibiotics use was still significant regardless of cancer types and timing of antibiotics (P < 0.01 for all).CONCLUSION: Use of antibiotics may be associated with worse outcomes in cancer patients treated with ICIs.
CANIT0003008	32156916	Case report	A 74-year-old man underwent distal gastrectomy for gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Chemotherapy followed by Nivolumab	N/A	Chemoradiotherapy followed by Immune checkpoint therapy	Nivolumab (DB09035); chemotherapy (NCIT:C15632); 	1	N/A	Case	A case of lymph node metastasis from gastric cancer successfully treated with nivolumab chemotherapy	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec	[A Case of Long Survival with Hilar Lymph Node Metastasis from Gastric Cancer Successfully Treated with Nivolumab Immunotherapy].	 Gan To Kagaku Ryoho	A 74-year-old man underwent distal gastrectomy for gastric cancer(CY1, fStage ¢ô). About 18 months after surgery, abdominal CT scans revealed multiple lymph node metastases along the portal vein. Systemic chemotherapy was administered comprising a capecitabine/oxaliplatin(CAPOX)regimen. After 4 courses of chemotherapy, an adverse reaction of Grade 2 diarrhea and peripheral neuropathy occurred, although regression of the lymph node metastasis was confirmed. Ramucirumab was administered as the second-line regimen, but CT imaging revealed lymph node progression after several courses. Although irinotecan(CPT-11)was selected as the third-line chemotherapy, the lymph node progression remained uncontrolled. Nivolumab was selected as the fourth-line chemotherapy. After 23 courses, nivolumab immunotherapy induced a partial response to the lymph node metastasis. Nivolumab immunotherapy continues to be administered until now, 5 years after the operation. We experienced a case of lymph node metastasis from gastric cancer successfully treated with nivolumab chemotherapy.
CANIT0003009	32156967	Case report	Gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A 68-year-old man was diagnosed with gastric cancer and Virchow lymph node, para-aortic lymph node, and multiple liver metastases at another hospital. He was referred to our hospital from Yamashita Naika Syokakika. We administrated 4 courses of S-1 plus CDDP. The main tumor and all metastatic lesions were significantly reduced. Subsequently, total gastrectomy, partial liver resection, and left neck and para-aortic lymph node resection(conversion surgery)were performed. The cancer cell was remnant at the main tumor and para-gastric lymph node. No cancer cells were detected in another lesion(R0 resection). Postoperatively, only S-1 was administered. However, 28 months after undergoing gastrectomy, liver metastasis occurred. Therefore, S-1 plus oxaliplatin, paclitaxel plus ramucirumab, and CPT-11 plus CDDP were administered. Liver metastases again increased and decreased, respectively. However, 46 months after gastrectomy, liver metastasis recurred and nivolumab was administered. Subsequently, liver metastases disappeared. At 55 months after gastrectomy, rectal resection was performed against rectal cancer and partial liver resection against liver metastases. Cancer cells were not detected in the resected specimens.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Dec	[Long-Term Survival of Gastric Cancer with Multiple Liver and Lymph Node Metastases-A Case Report].	 Gan To Kagaku Ryoho	Currently, chemotherapy against unresectable advanced gastric cancer is progressing with the development new drugs and due to results of several clinical trials. Here, we reported a case of long-term survival of gastric cancer with multiple liver and lymph node metastases. A 68-year-old man was diagnosed with gastric cancer and Virchow lymph node, para-aortic lymph node, and multiple liver metastases at another hospital. He was referred to our hospital from Yamashita Naika Syokakika. We administrated 4 courses of S-1 plus CDDP. The main tumor and all metastatic lesions were significantly reduced. Subsequently, total gastrectomy, partial liver resection, and left neck and para-aortic lymph node resection(conversion surgery)were performed. The cancer cell was remnant at the main tumor and para-gastric lymph node. No cancer cells were detected in another lesion(R0 resection). Postoperatively, only S-1 was administered. However, 28 months after undergoing gastrectomy, liver metastasis occurred. Therefore, S-1 plus oxaliplatin, paclitaxel plus ramucirumab, and CPT-11 plus CDDP were administered. Liver metastases again increased and decreased, respectively. However, 46 months after gastrectomy, liver metastasis recurred and nivolumab was administered. Subsequently, liver metastases disappeared. At 55 months after gastrectomy, rectal resection was performed against rectal cancer and partial liver resection against liver metastases. Cancer cells were not detected in the resected specimens.
CANIT0003010	32180046	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	282	N/A	N/A	In conclusion, the incidence of adrenal insufficiency (AI) among NSCLC patients treated with anti-PD-1 antibodies was similar to previous studies. Corticosteroid replacement improved PS, symptoms, and laboratory data of patients with AI and suspicious of AI. Corticosteroid replacement may contribute to continuation of anti-PD-1 antibodies and survival outcome was preferable in patients with AI and suspicious of AI receiving corticosteroid treatment.	Adrenal insufficiency	N/A	N/A	Corticosteroids (NCIT:C211); 	Corticosteroid use	Exposure factors/status	 2020 Mar 16	Clinical characteristics of adrenal insufficiency as an immune-related adverse event in non-small-cell lung cancer.	 Med Oncol	Adrenal insufficiency (AI) is an immune-related adverse event of immune checkpoint inhibitors and on occasion could be serious. There have been few reports of clinical information regarding AI associated with anti-programmed cell death protein-1 (anti-PD-1) antibody in non-small-cell lung cancer (NSCLC) patients. Patients with advanced NSCLC treated with anti-PD-1 antibodies between December 2015 and October 2017 were identified from the medical records of our institution. We investigated the frequency, symptoms, test results, and treatment outcomes of AI, and prognosis of patients who developed AI. In total, 282 NSCLC patients were treated with anti-PD-1 antibodies, and 4 patients (1.4%) were diagnosed as AI and 6 patients (2.1%) as suspicious of AI according to the laboratory data or clinical findings. The median follow-up period was 13.6 months. All patients with AI and suspicious of AI were treated with corticosteroid replacement, and performance status (PS) was improved in 50% of patients. Two of 10 patients were thought to have central AI. Six patients of 10 patients continued to receive anti-PD-1 antibodies with corticosteroid hormone replacement after diagnosis. The median progression-free survival and overall survival were 10.2 and 15.4 months, respectively. In conclusion, the incidence of AI among NSCLC patients treated with anti-PD-1 antibodies was similar to previous studies. Corticosteroid replacement improved PS, symptoms, and laboratory data of patients with AI and suspicious of AI. Corticosteroid replacement may contribute to continuation of anti-PD-1 antibodies and survival outcome was preferable in patients with AI and suspicious of AI receiving corticosteroid treatment.
CANIT0003011	32183719	Clinical research	10 patients	Oral squamous cell carcinoma	EFO:0000199	Oral cavity	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	N/A	These results show nivolumab causes opposing effects on CD4+ and CD8+ cell populations, with CD4+ cell levels declining but increasing the proportion of Treg cells, and unconventional CD8+ T-cell levels increasing with increased expression of immune mediators by CD8+ T-cell subpopulations	Increase in levels of unconventional CD8dimCD3+ T-cells. It also caused an increase in expression of granzyme B by these unconventional T-cells as well as by the conventional CD8hiCD3+ cells. The CD8hiCD3+ subpopulation also had a near-significant increase in IFN-¦Ã expression.	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD4 (+) and CD8 (+) T-cells	N/A	 2020 Mar 17	Immunological effects of nivolumab immunotherapy in patients with oral cavity squamous cell carcinoma.	 BMC Cancer	BACKGROUND: Although checkpoint blockades have become widely used, the immunological impact in cancer patients, especially those with oral cavity squamous cell carcinoma (OCSCC), has not been well studied.METHODS: The present study assessed the immunological impact of anti-PD-1 (nivolumab) treatment in 10 patients with OCSCC. This involved phenotypic analyses of peripheral blood T-cell subpopulations and their expression of immune mediators prior to and following nivolumab treatment. The focus was on immunological effects of treatment without regard to possible clinical responses.RESULTS: Nivolumab caused a decline in the frequency of blood CD4+ cells but did not affect their expression of IFN-¦Ã. However, nivolumab increased the proportion of CD4+ cells expressing the Treg-supporting factor Foxp3. Nivolumab treatment caused an increase in the proportion of CD8+ cells. While their expression of granzyme B increased, it did not attain significance. Analyses of CD8+ cell subpopulations showed nivolumab caused an increase in levels of unconventional CD8dimCD3+ T-cells. It also caused an increase in expression of granzyme B by these unconventional T-cells as well as by the conventional CD8hiCD3+ cells. The CD8hiCD3+ subpopulation also had a near-significant increase in IFN-¦Ã expression. Treatment with nivolumab had no effect on the levels of the NK containing CD8dimCD3- subpopulation of cells or their expression of IFN-¦Ã or granzyme B.CONCLUSIONS: These results show nivolumab causes opposing effects on CD4+ and CD8+ cell populations, with CD4+ cell levels declining but increasing the proportion of Treg cells, and unconventional CD8+ T-cell levels increasing with increased expression of immune mediators by CD8+ T-cell subpopulations.
CANIT0003012	32193378	Clinical research	Ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); PARP1 (P09874); 	PD-1; PARP1	Pembrolizumab plus niraparib	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); niraparib (DB11793); 	62	N/A	Phase I/II trial	We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Mutational signature 3 reflecting defective homologous recombination DNA repair (); 	DNA mismatch repair-deficient	Mutational status	 2020 Mar 19	Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer.	 Nat Commun	Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.
CANIT0003013	32193378	Clinical research	Ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); PARP1 (P09874); 	PD-1; PARP1	Pembrolizumab plus niraparib	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); niraparib (DB11793); 	62	N/A	Phase I/II trial	We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	A surrogate of interferon-primed exhausted CD8 (+) T-cells in the tumor microenvironment.	Tumor-infiltrating immune cell	 2020 Mar 19	Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer.	 Nat Commun	Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.
CANIT0003014	32199466	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	112	N/A	Multicentre, single-arm, open-label, phase 2 trial	Between Jan 4, 2017, and Feb 13, 2018, of 112 patients assessed for eligibility, we recruited 62 patients. 60 patients were evaluable for the co-primary outcomes. Median age was 72 years (IQR 65-75); 33 (55%) of participants were male and 27 (45%) were female. The observed incidence for durable clinical benefit (DCB) was 38% (95% CI 21-57) in first-line patients (n=24) and 36% (22-52) in subsequent-line patients (n=36); DCB was 22% (11-41) in patients with a tumour proportion score (TPS) less than 1% (n=27), 47% (25-70) in patients with a TPS of 1-49% (n=15), and 53% (30-75) in patients with a TPS of 50% or greater (n=15). An increase in DCB incidences with TPS was also shown in model-based estimates. Toxicity was observed in 28% (95% CI 19-41) of patients, 11 (18%) of 60 due to dose delay and 6 (10%) of 60 due to drug discontinuation. No grade 5 treatment-related adverse events were observed and no early deaths were attributed to hyperprogression.  Patients with NSCLC of performance status 2 (PS2)  are a group of patients of unmet therapeutic need. The trial shows that pembrolizumab can be safely administered to these patients, with no increase in the risk of immune-related or other toxicities. Efficacy outcomes are at least as good as those in patients with performance status 0-1 and the data provides clinicians with the confidence to incorporate pembrolizumab into the treatment pathway of patients with NSCLC of PS2.	Toxicity was observed in 28% (95% CI 19-41) of patients, 11 (18%) of 60 due to dose delay and 6 (10%) of 60 due to drug discontinuation. No grade 5 treatment-related adverse events were observed and no early deaths were attributed to hyperprogression. The most common grade 3-4 adverse events were dyspnoea (n=9), hyponatraemia (n=5), and anorexia (n=4). There were ten serious adverse events considered to be related to treatment, comprising diarrhoea (n=3) and acute kidney injury, adrenal insufficiency, hyperbilirubinaemia, oral mucositis, rash, urinary tract infection, and vomiting (n=1 each).	N/A	N/A	Tumour proportion score (); 	Tumour proportion score	Disease status	 2020 Sep	Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial.	 Lancet Respir Med	BACKGROUND: Therapeutic blockade of the axis of programmed cell death 1 (PD-1) and its ligand (PD-L1) has transformed the management of non-small-cell lung cancer (NSCLC). Clinical trials with pembrolizumab have enrolled patients with performance status (PS) 0-1. However, around 18% of patients with NSCLC are PS2, and the activity and safety of pembrolizumab in these patients is unclear. We aimed to evaluate the safety and efficacy of pembrolizumab in these patients.METHODS: We did a multicentre, single-arm, open-label, phase 2 trial (PePS2) in ten hospitals in the UK, in which patients with NSCLC and a rigorous ascription of PS2 were given pembrolizumab 200 mg every 3 weeks. No masking was used in this trial. We stratified the treatment evaluation by tumour proportion score (TPS) and line of therapy. Co-primary outcomes were: (1) durable clinical benefit (DCB), defined as the occurrence of complete response, partial response, or stable disease that continues until at least the second CT scan scheduled at 18 weeks; and (2) toxicity, defined as the occurrence at any time of treatment-related dose delay or treatment discontinuation due to an adverse event. Analysis included all patients who received any pembrolizumab. As well as reporting simple observed incidence for the co-primary outcomes, DCB and toxicity, we also estimated incidence using a model-based method for correlated binary outcomes. This study is registered with ClinicalTrials.gov, NCT02733159; EudraCT, 2015-002241-55; and ISRCTN, 10047797.FINDINGS: Between Jan 4, 2017, and Feb 13, 2018, of 112 patients assessed for eligibility, we recruited 62 patients. 60 patients were evaluable for the co-primary outcomes. Median age was 72 years (IQR 65-75); 33 (55%) of participants were male and 27 (45%) were female. The observed incidence for DCB was 38% (95% CI 21-57) in first-line patients (n=24) and 36% (22-52) in subsequent-line patients (n=36); DCB was 22% (11-41) in patients with a TPS less than 1% (n=27), 47% (25-70) in patients with a TPS of 1-49% (n=15), and 53% (30-75) in patients with a TPS of 50% or greater (n=15). An increase in DCB incidences with TPS was also shown in model-based estimates. Toxicity was observed in 28% (95% CI 19-41) of patients, 11 (18%) of 60 due to dose delay and 6 (10%) of 60 due to drug discontinuation. No grade 5 treatment-related adverse events were observed and no early deaths were attributed to hyperprogression. The most common grade 3-4 adverse events were dyspnoea (n=9), hyponatraemia (n=5), and anorexia (n=4). There were ten serious adverse events considered to be related to treatment, comprising diarrhoea (n=3) and acute kidney injury, adrenal insufficiency, hyperbilirubinaemia, oral mucositis, rash, urinary tract infection, and vomiting (n=1 each).INTERPRETATION: Patients with NSCLC of PS2 are a group of patients of unmet therapeutic need. The PePS2 trial shows that pembrolizumab can be safely administered to these patients, with no increase in the risk of immune-related or other toxicities. Efficacy outcomes are at least as good as those in patients with PS0-1 and the data provides clinicians with the confidence to incorporate pembrolizumab into the treatment pathway of patients with NSCLC of PS2.FUNDING: Merck, Sharp & Dohme.
CANIT0003015	32200422	Basic research	Ovarian cancer	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Nivolumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); 	Cell lines	N/A	Basic research	Altogether, the results suggest a 'cross resistance' model, where the acquired chemotherapy resistance in cancer cells may confer resistance to immune checkpoint blockade therapy through down-regulation of antigen presentation machinery. As such, agents that can restore HLA expression may be a suitable combination partner for immunotherapy in chemotherapy-relapsed human ovarian cancer patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	HLA (P04439); 	HLA expression	Gene expression signature on/in immune cell	 2020 Aug	Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade.	 Cancer Immunol Immunother	Immune checkpoint blocking antibodies are currently being tested in ovarian cancer (OC) patients and have shown some responses in early clinical trials. However, it remains unclear how human OC cancer cells regulate lymphocyte activation in response to therapy. In this study, we have established and optimised an in vitro tumour-immune co-culture system (TICS), which is specifically designed to quantify the activation of multiple primary human lymphocyte subsets and human cancer cell killing in response to PD-1/L1 blockade. Human OC cell lines and treatment na ve patient ascites show differential effects on lymphocyte activation and respond differently to PD-1 blocking antibody nivolumab in TICS. Using paired OC cell lines established prior to and after chemotherapy relapse, our data reveal that the resistant cells express low levels of HLA and respond poorly to nivolumab, relative to the treatment na ve cells. In accordance, knockdown of IFN¦Ã receptor expression compromises response to nivolumab in the treatment na ve OC cell line, while enhanced HLA expression induced by a DNA methyltransferase inhibitor promotes lymphocyte activation in TICS. Altogether, our results suggest a 'cross resistance' model, where the acquired chemotherapy resistance in cancer cells may confer resistance to immune checkpoint blockade therapy through down-regulation of antigen presentation machinery. As such, agents that can restore HLA expression may be a suitable combination partner for immunotherapy in chemotherapy-relapsed human ovarian cancer patients.
CANIT0003016	32234921	Clinical research	Metastatic gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or nivolumab followed by chemotherapy	N/A	Immune checkpoint therapy followed by Chemotherapy	Atezolizumab (DB11595); nivolumab (DB09035); 	84	N/A	Retrospective analysis	Cytotoxic chemotherapy after progression on anti-PD-(L)1 antibody demonstrated a favourable efficacy in intensively treated patients with metastatic gastric cancer.	Immune-related AEs did not worsen and were manageable, while new immune-related AEs were not observed.	N/A	N/A	N/A	N/A	N/A	 2020 Apr	Efficacy of Cytotoxic Agents After Progression on Anti-PD-(L)1 Antibody for Pre-treated Metastatic Gastric Cancer.	 Anticancer Res	BACKGROUND/AIM: The efficacy of treatment using the anti-programmed cell death-1 (anti-PD-1) antibody for metastatic gastric cancer (mGC) has been established previously. Exploratory analyses in various types of tumours suggest that prior exposure to immune checkpoint inhibitors can enhance the efficacy of subsequent cytotoxic chemotherapy (CTx). Our aim is to evaluate the efficacy and safety of CTx for mGC after progression on anti-PD-(ligand) 1 [anti-PD-(L)1] antibody.PATIENTS AND METHODS: We retrospectively evaluated patients with mGC who underwent CTx. The patients received CTx after progression on anti-PD-(L)1 antibody (cohort A) or as a third-line treatment without prior exposure to anti-PD-(L)1 antibody (cohort B). We evaluated: i) clinical characteristics, ii) efficacies, iii) prognoses, and iv) adverse events (AEs).RESULTS: In cohorts A and B, 16 and 68 patients fulfilled the criteria, respectively. In the univariate analysis, the overall response rate was significantly higher in cohort A compared to cohort B (31% vs. 10%, respectively; Odds Ratio:3.96, 95% Confidence Interval:1.06-14.8, p=0.040). The multivariate analysis showed a similar trend. Immune-related AEs did not worsen and were manageable, while new immune-related AEs were not observed.CONCLUSION: CTx after progression on anti-PD-(L)1 antibody demonstrated a favourable efficacy in intensively treated patients with mGC.
CANIT0003017	32239889	Case report	Prostate cancer	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Radiotherapy followed by pembrolizumab plus carboplatin-pemetrexed	N/A	Radiotherapy followed by Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); carboplatin (DB00958); pemetrexed (DB00642); 	1	N/A	Case	A case of transient acantholytic dermatosis occurring in a patient with a history of prostate cancer status post radiation, now being treated with combination therapy with pembrolizumab and carboplatin-pemetrexed for advanced lung adenocarcinoma.The case emphasizes the importance of being cognizant of TAD and its associations, particularly in cancer patients.	Transient acantholytic dermatosis	N/A	N/A	N/A	N/A	N/A	 2020 Feb 15	Transient acantholytic dermatosis in a patient with prostate cancer.	 Dermatol Online J	Transient acantholytic dermatosis (TAD) is a relatively common entity that has been also noted to occur in patients with cancer. Herein, we describe a case of transient acantholytic dermatosis occurring in a patient with a history of prostate cancer status post radiation, now being treated with combination therapy with pembrolizumab and carboplatin-pemetrexed for advanced lung adenocarcinoma. Our case emphasizes the importance of being cognizant of TAD and its associations, particularly in cancer patients.
CANIT0003018	32246174	Basic research	Cell lines	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	Cell lines	N/A	Basic research	The findings hereby demonstrate a differential steroid effect on T cell function, which should be taken into consideration for patients undergoing immunotherapy. Also, the clinical analysis of a patient who exhibited immune-related adverse events following combination (anti-PD-1/CTLA-4) therapy indicated complete metabolic response in the presence of glucocorticoids. Therefore, concomitant use of prednisone does not appear to interfere with the function of immune checkpoint blockade.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	N/A	N/A	N/A	 2020 Aug	The glucocorticoids prednisone and dexamethasone differentially modulate T cell function in response to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade.	 Cancer Immunol Immunother	On-treatment steroids for countering immune checkpoint inhibitor-induced inflammatory responses (irAEs) are a hallmark of cancer immunotherapy. However, the suppressive nature of steroids has raised questions regarding their ability to compromise the function of the 'proliferative burst' of effector T cells induced by immune checkpoint antibodies. We investigated the effector functions and the co-inhibitory receptor profile of stimulated peripheral blood mononuclear cells (PBMCs) pre-treated with prednisone and dexamethasone alone or in the presence of anti-PD-1/CTLA-4 antibodies. Also, clinical analysis of a patient who exhibited irAEs following combination (anti-PD-1/CTLA-4) in the presence of glucocorticoids was done. We found that prednisone in contrast to dexamethasone did not compromise T cell cytokine production (IL-2, IFN-¦Ã and TNF-a) and proliferation in the absence or presence of anti-PD-1/CTLA-4 antibodies, when a physiological concentration was used. Neither single prednisone treatment nor co-treatment with checkpoint inhibitors impacted the expression of co-inhibitory receptors PD-1, CTLA-4, TIM-3 and LAG-3. In contrast, dexamethasone treatment promoted downregulation of LAG-3 expression by T cells. In addition, co-treatment of PD-1 + Jurkat cells with prednisone and/or dexamethasone with anti-PD-1 before stimulation significantly reduced SHP-2 phosphorylation, indicative of increased T cell function. Our findings hereby demonstrate a differential steroid effect on T cell function, which should be taken into consideration for patients undergoing immunotherapy. Also, the clinical analysis of a patient who exhibited irAEs following combination (anti-PD-1/CTLA-4) therapy indicated complete metabolic response in the presence of glucocorticoids. Therefore, concomitant use of prednisone does not appear to interfere with the function of immune checkpoint blockade.
CANIT0003019	32268262	Case report	Myelodysplastic syndrome or melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	3	N/A	Case	Three patients with ICI-induced myocarditis (2 with positive biopsies and 1 based on cardiac magnetic resonance imaging with negative biopsy) underwent a complete cardiovascular workup, including cardiac catheterization with endomyocardial biopsy. Treatment was with intravenous immunoglobulins (IVIG) and statins in all cases, with additional colchicine (2 cases) or hydroxychloroquine (1 case). Immunohistochemical analysis demonstrated varied subsets of T cells involved in the inflammatory response. Therapy with IVIG and statins led to symptom resolution and cardiac function normalization at 1-month follow-up in all patients. Cancer therapy was resumed in all patients. One patient expired 10 months after the myocarditis episode due to advanced malignancy; two patients were alive, free of heart failure symptoms and cancer progression, at 1-year follow-up, and 1 patient was rechallenged with ICI.	Immune checkpoint inhibitor (ICI)-induced myocarditis	N/A	N/A	N/A	N/A	N/A	 2020 Jul-Aug	Immunomodulatory treatment of immune checkpoint inhibitor-induced myocarditis: Pathway toward precision-based therapy.	 Cardiovasc Pathol	Immune checkpoint inhibitor (ICI)-induced myocarditis carries a poor prognosis and is not fully understood. Similar to lymphocytic myocarditis and acute cellular rejection in heart transplant, ICI-induced myocarditis requires immune suppressive strategies. We aimed to describe ICI-induced myocarditis by presenting findings of comprehensive cardiovascular evaluations and outcomes of patients following a therapeutic approach similar to autoimmune disorders or allograft transplant rejection, and to discuss the molecular basis of the benefits of immune modulation and statins in ICI-myocarditis. Three patients with ICI-induced myocarditis (2 with positive biopsies and 1 based on cardiac magnetic resonance imaging with negative biopsy) underwent a complete cardiovascular workup, including cardiac catheterization with endomyocardial biopsy. Treatment was with intravenous immunoglobulins (IVIG) and statins in all cases, with additional colchicine (2 cases) or hydroxychloroquine (1 case). Immunohistochemical analysis demonstrated varied subsets of T cells involved in the inflammatory response. Therapy with IVIG and statins led to symptom resolution and cardiac function normalization at 1-month follow-up in all patients. Cancer therapy was resumed in all patients. One patient expired 10 months after the myocarditis episode due to advanced malignancy; two patients were alive, free of heart failure symptoms and cancer progression, at 1-year follow-up, and 1 patient was rechallenged with ICI. We suggest that treatment with IVIG and statins may allow for a prompt resumption of anti-cancer therapy (including ICI) and improve outcomes.
CANIT0003020	32276540	Case report	Two patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); 	2	N/A	Case	We present two patients who underwent salvage thoracoscopic resection for residual diseases (left lower lobectomy and paratracheal lymph node resection, respectively) after chemotherapy and immunotherapy for stage IV adenocarcinoma. The indications, intraoperative findings, and histopathological findings are discussed in this report.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 May	Salvage thoracoscopic resection after nivolumab for stage IV.	 Asian Cardiovasc Thorac Ann	There are limited data on the surgical management of localized and residual diseases in patients with stage IV non-small-cell lung cancer that was treated with nivolumab. Herein, we present two patients who underwent salvage thoracoscopic resection for residual diseases (left lower lobectomy and paratracheal lymph node resection, respectively) after chemotherapy and immunotherapy for stage IV adenocarcinoma. The indications, intraoperative findings, and histopathological findings are discussed in this report.
CANIT0003021	32277531	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Nivolumab (DB09035); 	24	N/A	Phase Ib	Nivolumab and platinum-based chemotherapy combinations showed long-term tolerability. A moderate proportion of patients in arm C showed 5-year progression-free and overall survival.No unexpected severe adverse events or treatment-related deaths occurred. 	No unexpected severe adverse events or treatment-related deaths occurred.	N/A	N/A	N/A	N/A	N/A	 2020 Jun	Five-year safety and efficacy data from a phase Ib study of nivolumab and chemotherapy in advanced non-small-cell lung cancer.	 Cancer Sci	Combination antiprogrammed death 1/programmed death-ligand 1 Ab and platinum-based chemotherapy is standard first-line treatment for advanced non-small-cell lung cancer without targetable oncogene alterations. We describe the long-term safety and efficacy data from a previously reported phase Ib study of nivolumab and chemotherapy. Japanese patients with non-small-cell lung cancer were assigned to a treatment arm based on histology and treatment history. Nivolumab (10 mg/kg, i.v.) and chemotherapy (4 arms) were given every 3 weeks: arm A, 4 cycles of cisplatin and gemcitabine (first-line); arm B, 4 cycles of cisplatin and pemetrexed followed by pemetrexed maintenance therapy (first-line); arm C, 4-6 cycles of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab (first-line); and arm D, docetaxel (second- or third-line). Study treatments were continued every 3 weeks as maintenance therapy until disease progression. Minimum follow-up period was 57.9 months. Median progression-free survival (median [range, plus sign indicates censored data]) was 6.3 (0.7+-47.8), 11.8 (1.4-65.1+), 40.7 (5.3-60.8+), and 3.2 (1.9-10.9) months, and 5-year progression-free survival was observed in 0/6, 1/6, 1/6, and 0/6 patients in arms A, B, C, and D, respectively. Median overall survival was 13.2 (11.0-55.4), 28.5 (14.6-66.2+), not reached (24.2-67.4+), and 12.5 (9.8-16.9) months; the number of patients surviving 5 years were 0/6, 1/6, 4/6, and 0/6 in arms A, B, C, and D, respectively. No unexpected severe adverse events or treatment-related deaths occurred. Nivolumab and platinum-based chemotherapy combinations showed long-term tolerability. A moderate proportion of patients in arm C showed 5-year progression-free and overall survival.
CANIT0003022	32286191	Clinical research	Relapsed or refractory Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	45	N/A	Retrospective analysis	Early CT and PET/CT at a median of 2 months after initiation of nivolumab predicted overall survival in relapsed or refractory Hodgkin lymphoma. Early PET detected additional patients with complete metabolic response. 	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jun	Performance of CT Compared with (18)F-FDG PET in Predicting the Efficacy of Nivolumab in Relapsed or Refractory Hodgkin Lymphoma.	 Radiology	Background CT and fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT performances following immune therapy are not well known in patients with relapsed or refractory Hodgkin lymphoma (RRHL). Purpose To compare CT and PET/CT for prognostic value of early response evaluation following nivolumab therapy. Materials and Methods This retrospective study included patients from 34 institutions who underwent early imaging response evaluation from July 2013 to April 2017. Three experienced readers classified imaging response by using Cheson et al and 2016 Lymphoma Response to Immunomodulatory Therapy Criteria as follows: complete (metabolic) response, partial (metabolic) response, stable disease or no metabolic response, or progressive (metabolic) disease. Primary CT and PET assessments were performed at a median of 2.0 months (interquartile range, 1.7-3.7 months) after nivolumab initiation. Kaplan-Meier analysis was used to determine the relationship of primary CT and PET assessment response categories to overall survival (OS). Agreements between primary and secondary imaging assessments were assessed by using ¦Ê analysis. Results A total of 45 patients (median age, 37 years; range, 18-77 years; 25 men) underwent a primary assessment using CT and PET/CT; 36 patients also underwent a subsequent assessment. Eleven patients (24%) died after a median follow-up of 21.2 months. CT and PET response categories were associated with OS (P = .03 for primary CT assessment; P = .02 for primary PET assessment). There was no pseudoprogression at primary CT and PET assessments. At the primary assessment, response categories by using CT were reclassified by using PET in 44% (20 of 45) of patients. Among these, 55% (11 of 20) were reclassified to complete metabolic response (complete metabolic response rate: 29% [13 of 45 patients] vs complete response rate: 4% [two of 45 patients]), with a 2-year OS probability of 100%. At the secondary assessment, complete response rate using CT increased to 17% (six of 36 patients), hence a better agreement with PET (¦Ê = 0.78; P < .001). Conclusion Early CT and PET/CT at a median of 2 months after initiation of nivolumab predicted overall survival in relapsed or refractory Hodgkin lymphoma. Early PET detected additional patients with complete metabolic response.   RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Scott and Wang in this issue.
CANIT0003023	32296919	Basic research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Durvalumab or nivolumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); nivolumab (DB09035); 	Cell lines	N/A	Basic research	PD-1(+) natural killer cells in human non-small cell lung cancer can be activated by PD-1/PD-L1 blockade.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-1 (Q15116); Natural killer-cells (NCIT:C98762); 	PD-1(+) natural killer cells	Gene expression signature on/in immune cell	 2020 Aug	PD-1(+) natural killer cells in human non-small cell lung cancer can be activated by PD-1/PD-L1 blockade.	 Cancer Immunol Immunother	Natural killer (NK) cells are critically involved in anti-tumor immunity by targeting tumor cells. In this study, we show that intratumoral NK cells from NSCLC patients expressed elevated levels of the immune checkpoint receptor PD-1 on their cell surface. In contrast to the expression of activating receptors, PD-1+ NK cells co-expressed more inhibitory receptors compared to PD-1- NK cells. Intratumoral NK cells were less functional compared to peripheral NK cells, and this dysfunction correlated with PD-1 expression. Tumor cells expressing PD-L1 inhibited the functionality of PD-1+ NK cells in ex vivo models and induced PD-1 clustering at the immunological synapse between NK cells and tumor cells. Notably, treatment with PD-1 blockade was able to reverse PD-L1-mediated inhibition of PD-1+ NK cells. Our findings highlight the therapeutic potential of PD-1+ NK cells in immune checkpoint blockade and could guide the development of NK cell-stimulating agents in combination with PD-1 blockade.
CANIT0003024	32305010	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	2993	N/A	N/A	The 400 mg dose every 6 weeks (Q6W) had similar predicted exposure (Cavg,ss, geometric mean ¡«1% higher) as the 200 mg dose every 3 weeks (Q3W). Fewer than 1% of subjects had transiently lower Cmin,ss than that observed for 200 mg and 2 mg/kg Q3W. Despite these reductions, similar target saturation is expected. The predicted peak concentrations (Cmax,ss) for 400 mg Q6W were substantially (¡«65%) lower than the 10 mg/kg Q2W dose.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 May	A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation.	 Eur J Cancer	BACKGROUND: Pembrolizumab is approved for multiple cancer types at 200 mg and 2 mg/kg dose every 3 weeks (Q3W). We used a model-based approach to compare the exposure of pembrolizumab 400 mg dose every 6 weeks (Q6W) with the Q3W regimens.METHODS: The Q6W dose was selected by matching exposure with the 200 mg and 2 mg/kg Q3W doses. Concentration-time profiles were simulated using the established population pharmacokinetic model of pembrolizumab based on 2993 subjects from five clinical trials across tumour types. Efficacy was bridged by evaluating projections of average concentration over the dosing interval (Cavg) and trough concentration (Cmin) at steady state (ss). Safety was bridged by ensuring that concentrations were below those at 10 mg/kg dose every 2 weeks (Q2W), the maximum clinical dose.RESULTS: The 400 mg Q6W dose had similar predicted exposure (Cavg,ss, geometric mean ¡«1% higher) as the 200 mg Q3W dose. Fewer than 1% of subjects had transiently lower Cmin,ss than that observed for 200 mg and 2 mg/kg Q3W. Despite these reductions, similar target saturation is expected. The predicted peak concentrations (Cmax,ss) for 400 mg Q6W were substantially (¡«65%) lower than the 10 mg/kg Q2W dose.CONCLUSIONS: Exposures expected for pembrolizumab 400 mg Q6W were similar to the 200 mg and 2 mg/kg Q3W and below the 10 mg/kg Q2W regimens. Established exposure-response relationships for pembrolizumab over a 5-fold dose range (2 mg/kg Q3W to 10 mg Q2W) support that clinical efficacy and safety of 400 mg Q6W would be similar to the 200 mg and 2 mg/kg Q3W doses across tumour types.CLINICAL TRIAL REGISTRATION NUMBERS: NCT01295827, NCT01704287, NCT01866319, NCT01905657, NCT02142738.
CANIT0003025	32306129	Clinical research	Median age of 66 years with lung cancer (n = 45, 42.5%), melanoma (n = 30, 28.3%), renal and bladder cancers (GU cancers) (n = 26, 24.5%), head and neck (H&N) cancer (n = 4, 3.8%), and colorectal cancer (n = 1, 0.9%)	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	106	N/A	Retrospective analysis	The median (m) OS for the whole population was 14 months (CI 9.7-18.3), 9 months (CI 6.3-11.7) for patients with no IO-free period (n = 64, 62.1%), and 27.0 months (CI 20.6-33.4, p = 0.000001) for patients (n = 39) with IO-free period. The mIO-free survival was 10.0 months (CI 7.1-12.9) for the whole cohort, 8.0 months (CI 1.7-14.3) for lung cancer, 23.0 months (CI 2.6-43.4) for melanoma, and 14.0 months (CI 0.0-20.4) for renal and bladder cancers. From the IO-free cohort, 19 patients needed re-treatment during follow-up, of which 8 were re-challenged with anti-PD-(L)1 therapy. The clinical benefit rate of anti-PD-(L)1 re-challenge was 37.5%. The study shows that long IO-free periods can be achieved with limited duration of anti-PD-(L)1 therapy with excellent survival outcomes, and that anti-PD-(L)1 re-challenge is feasible in clinical practice.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Aug	Treatment discontinuation and re-initiation of anti-PD-(L)1 agents in metastatic cancers.	 J Cancer Res Clin Oncol	INTRODUCTION: Immune checkpoint inhibitors (ICIs) are approved in multiple indications for cancer care. Most of the clinical trials have not questioned shorter than until disease progression approaches. In this study, we present results from a cohort of multiple advanced cancers treated with restricted anti-PD-(L)1 therapy.METHODS: All patients with advanced cancers treated with anti-PD-(L)1 therapy outside clinical trials at Oulu University Hospital 2014-19 were retrospectively identified from pharmacy records. Clinical variables, treatment history and survival were collected.RESULTS: 106 patients with median age of 66 years with lung cancer (n = 45, 42.5%), melanoma (n = 30, 28.3%), renal and bladder cancers (GU cancers) (n = 26, 24.5%), head and neck (H&N) cancer (n = 4, 3.8%), and colorectal cancer (n = 1, 0.9%) were included in the study. The median (m) OS for the whole population was 14 months (CI 9.7-18.3), 9 months (CI 6.3-11.7) for patients with no IO-free period (n = 64, 62.1%), and 27.0 months (CI 20.6-33.4, p = 0.000001) for patients (n = 39) with IO-free period. The mIO-free survival was 10.0 months (CI 7.1-12.9) for the whole cohort, 8.0 months (CI 1.7-14.3) for lung cancer, 23.0 months (CI 2.6-43.4) for melanoma, and 14.0 months (CI 0.0-20.4) for GU cancer. From the IO-free cohort, 19 patients needed re-treatment during follow-up, of which 8 were re-challenged with anti-PD-(L)1 therapy. The clinical benefit rate of anti-PD-(L)1 re-challenge was 37.5%.CONCLUSIONS: Our study shows that long IO-free periods can be achieved with limited duration of anti-PD-(L)1 therapy with excellent survival outcomes, and that anti-PD-(L)1 re-challenge is feasible in clinical practice.
CANIT0003026	32307380	Case report	A 52-year old man	Kidney cancer	MONDO:0002367	Kidney	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A case of metastatic renal cell carcinoma still maintained the therapeutic effect of neviramab even after interstitial pneumonia	Interstitial pneumonia 	N/A	N/A	N/A	N/A	N/A	2019	[A CASE OF METASTATIC KIDNEY CANCER FOR WHICH THE EFFICACY OF NIVOLUMAB THERAPY WAS MAINTAINED EVEN AFTER THE DEVELOPMENT OF INTERSTITIAL PNEUMONIA].	 Nihon Hinyokika Gakkai Zasshi	The patient was a 52-year old man who underwent laparoscopic radical nephrectomy for kidney cancer. Left adrenal and lung metastases occurred 5 and 11 years after the surgery, respectively. Various molecular-targeted therapies were ineffective, so nivolumab treatment was started 12 years after the surgery. Treatment was discontinued when the patient developed interstitial pneumonia after three courses of nivolumab treatment. After steroid treatment for interstitial pneumonia, both the symptoms and findings of the imaging tests improved quickly. On the other hand, while the effect of Partial Response (PR) was evident in the lungs and adrenal glands, on the basis of the image assessments performed after three courses of treatment, the effect was maintained without regrowth even at the last follow-up, 10 months after discontinuing the treatment.
CANIT0003027	32307579	Clinical research	Small cell lung cancer	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	45	N/A	Retrospective analysis	This is the first report of real-world data on immune-checkpoint inhibitors in relapsed relapsed small-cell lung carcinoma also including patients with poor ECOG performance status. Promising durable responses were observed. No biological prognostic marker could be identified.Overall response rate was 29% and median progression-free survival and overall survival were 2.3 and 6.5 months, respectively. Median duration of response was 9 months (95% CI 2.8-NA). Five patients maintained their response for > 6 months, all of them receiving combination treatment. 	There were no new safety signals.	N/A	N/A	N/A	N/A	N/A	 2020 Aug	Outcomes with immune checkpoint inhibitors for relapsed small-cell lung cancer in a Swiss cohort.	 Cancer Immunol Immunother	OBJECTIVES: Early clinical trials showed promising outcomes with immune-checkpoint inhibitors (ICI) in a subset of patients with relapsed small-cell lung carcinoma (SCLC). The aim of this retrospective analysis was to assess the efficacy and safety of ICI for relapsed SCLC in a real-world patient population.METHODS: Nine cancer centres in Switzerland contributed data to this cohort. Responses were assessed by the local investigators using standard RECIST v1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were analysed by the Kaplan-Meier method. Associations between potential predictive markers and survival endpoints were probed by Cox proportional hazards.RESULTS: Forty-five patients were included in the analysis. Median age was 63 years, 73% were males and 18% had an ECOG performance status (PS) >= 2. ICIs were given as second-line treatment in 60%. Twenty-four patients (53%) received ipilimumab with nivolumab. Twenty-eight patients (62%) had undergone irradiation (RT) prior to or during ICI. Overall response rate (ORR) was 29% and median PFS and OS were 2.3 and 6.5 months, respectively. Median duration of response was 9 months (95% CI 2.8-NA). Five patients maintained their response for > 6 months, all of them receiving combination treatment. There were no new safety signals.CONCLUSION: This is the first report of real-world data on ICI in relapsed SCLC also including patients with poor PS. Promising durable responses were observed. No biological prognostic marker could be identified.
CANIT0003028	32312493	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Avelumab or Atezolizumab or Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	3326	N/A	Retrospective analysis	The study shows that cardiovascular (CV) factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. History of acute coronary syndrome help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.	N/A	N/A	N/A	Acute coronary syndrome (NCIT:C53652); 	History of acute coronary syndrome	Personal feature	 2020 Jun 15	Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.	 Am J Cardiol	Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.
CANIT0003029	32312493	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Avelumab or Atezolizumab or Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	3326	N/A	Retrospective analysis	The study shows that cardiovascular (CV) factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. Age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2020 Jun 15	Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.	 Am J Cardiol	Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.
CANIT0003030	32312493	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Avelumab or Atezolizumab or Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	3326	N/A	Retrospective analysis	The study shows that cardiovascular (CV) factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality.In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. 	N/A	N/A	N/A	Hypercholesterolemia (NCIT:C37967); 	Hypercholesterolemia	Metabolite	 2020 Jun 15	Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.	 Am J Cardiol	Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.
CANIT0003031	32312493	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Avelumab or Atezolizumab or Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	3326	N/A	Retrospective analysis	The study shows that cardiovascular (CV) factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. 	N/A	N/A	N/A	Hypertension (NCIT:C3117); 	Hypertension	Personal feature	 2020 Jun 15	Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.	 Am J Cardiol	Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.
CANIT0003032	32312493	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Avelumab or Atezolizumab or Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	3326	N/A	Retrospective analysis	The study shows that cardiovascular (CV) factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. 	N/A	N/A	N/A	Obesity (NCIT:C3283); 	Obesity	Personal feature	 2020 Jun 15	Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.	 Am J Cardiol	Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.
CANIT0003033	32312493	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Avelumab or Atezolizumab or Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	3326	N/A	Retrospective analysis	The study shows that cardiovascular (CV) factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. History of heart failure help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	History of heart failure	Disease status	 2020 Jun 15	Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.	 Am J Cardiol	Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.
CANIT0003034	32312493	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Avelumab or Atezolizumab or Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	3326	N/A	Retrospective analysis	The study shows that cardiovascular (CV) factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. Smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. 	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2020 Jun 15	Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.	 Am J Cardiol	Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.
CANIT0003035	32312493	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Avelumab or Atezolizumab or Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); atezolizumab (DB11595); ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	3326	N/A	Retrospective analysis	The study shows that cardiovascular (CV) factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality.	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Pretreatment beta blocker use	Exposure factors/status	 2020 Jun 15	Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.	 Am J Cardiol	Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.
CANIT0003036	32333081	Clinical research	Fifteen melanoma patients with multiple hepatic metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus cryoablation	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); cryoablation (NCIT:C15215); 	15	N/A	An ambispective, proof-of-concept cohort study	A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of cryoablation with transarterial infusion of pembrolizumab therapy. The cryoablation with transarterial infusion of pembrolizumab therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis	The most frequent treatment-related grade 1¨C2 AEs were fatigue (53.4%), arthralgia (33.3%), nausea (33.3%), pruritus (20.0%), and elevation of aspartate transaminase (AST) or alanine transaminase (ALT) (20.0%). No grade 3¨C4 AEs were observed	N/A	N/A	CD3 (P07766); CD16 (P08637); CD56 (P13591); Natural killer-cells (NCIT:C98762); 	CD3-CD16 (+) CD56 (+) natural killer cells	Gene expression signature on/in immune cell	 2020 Sep	Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study.	 Cancer Immunol Immunother	BACKGROUND: The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients.METHODS: This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples.RESULTS: Of the 15 patients enrolled, no grade 3-4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3-49.0%) and 33.3% (95% CI 2.5-64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5-5.5) and 5.73 (95% CI 1.1-10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage.CONCLUSIONS: The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.
CANIT0003037	32333081	Clinical research	Fifteen melanoma patients with multiple hepatic metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus cryoablation	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); cryoablation (NCIT:C15215); 	15	N/A	An ambispective, proof-of-concept cohort study	A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of cryoablation with transarterial infusion of pembrolizumab therapy. The cryoablation with transarterial infusion of pembrolizumab therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis	The most frequent treatment-related grade 1¨C2 AEs were fatigue (53.4%), arthralgia (33.3%), nausea (33.3%), pruritus (20.0%), and elevation of aspartate transaminase (AST) or alanine transaminase (ALT) (20.0%). No grade 3¨C4 AEs were observed	N/A	N/A	CD4 (P01730); CD25 (P01589); Treg cells (CL:0000815); T-Lymphocyte (NCIT:C12478); 	CD4 (+) CD25 (+) Treg cells	Gene expression signature on/in immune cell	 2020 Sep	Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study.	 Cancer Immunol Immunother	BACKGROUND: The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients.METHODS: This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples.RESULTS: Of the 15 patients enrolled, no grade 3-4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3-49.0%) and 33.3% (95% CI 2.5-64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5-5.5) and 5.73 (95% CI 1.1-10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage.CONCLUSIONS: The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.
CANIT0003038	32333081	Clinical research	Fifteen melanoma patients with multiple hepatic metastases	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus cryoablation	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); cryoablation (NCIT:C15215); 	15	N/A	An ambispective, proof-of-concept cohort study	A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of cryoablation with transarterial infusion of pembrolizumab therapy. The cryoablation with transarterial infusion of pembrolizumab therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis	The most frequent treatment-related grade 1¨C2 AEs were fatigue (53.4%), arthralgia (33.3%), nausea (33.3%), pruritus (20.0%), and elevation of aspartate transaminase (AST) or alanine transaminase (ALT) (20.0%). No grade 3¨C4 AEs were observed	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2020 Sep	Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study.	 Cancer Immunol Immunother	BACKGROUND: The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients.METHODS: This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples.RESULTS: Of the 15 patients enrolled, no grade 3-4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3-49.0%) and 33.3% (95% CI 2.5-64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5-5.5) and 5.73 (95% CI 1.1-10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage.CONCLUSIONS: The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.
CANIT0003039	32339189	Clinical research	201 patients	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	201	N/A	Post hoc analysis of the single-arm, phase 1/2 Study	These findings support the utility of a combined tumor cell (TC)/immune cell (IC) algorithm for predicting response to durvalumab in patients with urothelial carcinoma (UC), with PD-L1 expression on TCs>= 25%/ PD-L1 expression on tumor-infiltrating IC>= 25% cutoff optimal when used with the VENTANA (SP263) IHC Assay.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on immune cells	Gene expression signature on/in immune cell	 2020 Apr 27	Optimal PD-L1-high cutoff for association with overall survival in patients with urothelial cancer treated with durvalumab monotherapy.	 PLoS One	BACKGROUND: Studies have indicated that programmed death ligand 1 (PD-L1) expression may have utility as a predictive biomarker in patients with advanced/metastatic urothelial carcinoma (UC). Different immunohistochemical (IHC) assays are in development to assess PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs).METHODS: In this post hoc analysis of the single-arm, phase 1/2 Study 1108 (NCT01693562), PD-L1 expression was evaluated from tumor samples obtained prior to second-line treatment with durvalumab in patients with advanced/metastatic UC using the VENTANA (SP263) IHC Assay. The primary objective was to determine whether the TC >= 25%/IC >= 25% algorithm (i.e., cutoff of >= 25% TC or >= 25% IC with PD-L1 staining at any intensity above background) was optimal for predicting response to durvalumab. PD-L1 expression data were available from 188 patients.RESULTS: After a median follow-up of 15.8 and 14.6 months, higher PD-L1 expression was associated with longer overall survival (OS) and progression-free survival (PFS), respectively, with significant separation in survival curves for PD-L1-high and-low expressing patients for the TC >= 25%/IC >= 25% cutoff (median OS: 19.8 vs 4.8 months; hazard ratio: 0.46; 90% confidence interval: 0.33, 0.639). OS was also prolonged for PD-L1-high compared with-low patients when samples were categorized using TC/IC combined positive score >= 10 and IC>= 5% cutoffs. In multivariate analysis, IC but not TC PD-L1 expression was significantly associated with OS, PFS, and objective response rate (P < 0.001 for each), although interaction analysis showed similar directionality of benefit for ICs and TCs.CONCLUSIONS: These findings support the utility of a combined TC/IC algorithm for predicting response to durvalumab in patients with UC, with the TC>= 25%/IC>= 25% cutoff optimal when used with the VENTANA (SP263) IHC Assay.
CANIT0003040	32339189	Clinical research	201 patients	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	201	N/A	Post hoc analysis of the single-arm, phase 1/2 Study	These findings support the utility of a combined tumor cell (TC)/immune cell (IC) algorithm for predicting response to durvalumab in patients with urothelial carcinoma (UC), with PD-L1 expression on TCs>= 25%/ PD-L1 expression on tumor-infiltrating IC>= 25% cutoff optimal when used with the VENTANA (SP263) IHC Assay.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Apr 27	Optimal PD-L1-high cutoff for association with overall survival in patients with urothelial cancer treated with durvalumab monotherapy.	 PLoS One	BACKGROUND: Studies have indicated that programmed death ligand 1 (PD-L1) expression may have utility as a predictive biomarker in patients with advanced/metastatic urothelial carcinoma (UC). Different immunohistochemical (IHC) assays are in development to assess PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs).METHODS: In this post hoc analysis of the single-arm, phase 1/2 Study 1108 (NCT01693562), PD-L1 expression was evaluated from tumor samples obtained prior to second-line treatment with durvalumab in patients with advanced/metastatic UC using the VENTANA (SP263) IHC Assay. The primary objective was to determine whether the TC >= 25%/IC >= 25% algorithm (i.e., cutoff of >= 25% TC or >= 25% IC with PD-L1 staining at any intensity above background) was optimal for predicting response to durvalumab. PD-L1 expression data were available from 188 patients.RESULTS: After a median follow-up of 15.8 and 14.6 months, higher PD-L1 expression was associated with longer overall survival (OS) and progression-free survival (PFS), respectively, with significant separation in survival curves for PD-L1-high and-low expressing patients for the TC >= 25%/IC >= 25% cutoff (median OS: 19.8 vs 4.8 months; hazard ratio: 0.46; 90% confidence interval: 0.33, 0.639). OS was also prolonged for PD-L1-high compared with-low patients when samples were categorized using TC/IC combined positive score >= 10 and IC>= 5% cutoffs. In multivariate analysis, IC but not TC PD-L1 expression was significantly associated with OS, PFS, and objective response rate (P < 0.001 for each), although interaction analysis showed similar directionality of benefit for ICs and TCs.CONCLUSIONS: These findings support the utility of a combined TC/IC algorithm for predicting response to durvalumab in patients with UC, with the TC>= 25%/IC>= 25% cutoff optimal when used with the VENTANA (SP263) IHC Assay.
CANIT0003041	32344435	Clinical research	Cancer	Cancer	EFO:0000311	Other	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	130	N/A	Prospective analysis	In the cohort, immune checkpoint inhibitor (ICI)-induced musculoskeletal manifestations developed in 7.7% of patients. Imaging evidence of myofasciitis was found in most patients, indicating that the muscle/fascia is more frequently involved than the synovium. During the study period, a total of 130 patients were treated with ICIs. Of these, 10 (7.7%) developed ICI-induced Ir-AEsimmune-related adverse events (ir-AEs)an time from ICI treatment since development of symptoms was 2.5 months. Three different patterns of musculoskeletal manifestations were found: (i) prominent joint involvement (n = 3); (ii) prominent 'periarticular' involvement (n = 4). These patients had diffuse swelling of the hands, feet or knees. MRI depicted mild synovitis with more prominent myositis and/or fasciitis in the surrounding tissues in all cases; (iii) myofasciitis (n = 3). Clinically, these patients presented with pain in the knee(s)/thigh(s), whereas MRI depicted myofasciitis of the surrounding muscles. Patients with musculoskeletal ir-AEs had significantly higher oncologic response rates compared with patients not exhibiting musculoskeletal ir-AEs (50% vs 12.5%, respectively, P = 0.0016). Cytokine levels associated with a Th1/Th2/Th17 response were similar between patients with and without musculoskeletal ir-AEs. Overall, symptoms were mild/moderate and responded well to treatment, with no need for ICI discontinuation.	Immune checkpoint inhibitor (ICI)-induced musculoskeletal immune-related adverse events	N/A	N/A	N/A	N/A	N/A	 2020 May 1	An MRI study of immune checkpoint inhibitor-induced musculoskeletal manifestations myofasciitis is the prominent imaging finding.	 Rheumatology (Oxford)	OBJECTIVE: To assess: (i) the prevalence, and clinical and imaging characteristics of immune checkpoint inhibitor (ICI)-induced musculoskeletal immune-related adverse events (ir-AEs) in a prospective manner and (ii) whether serum levels of cytokines associated with the Th1/Th2/Th17 response are differentially expressed in patients with and without musculoskeletal Ir-AEs.METHODS: All patients treated with ICI who developed musculoskeletal manifestations were referred to the Rheumatology Department, and an MRI of the involved area(s) was performed.RESULTS: During the study period, a total of 130 patients were treated with ICIs. Of these, 10 (7.7%) developed ICI-induced Ir-AEs. The median time from ICI treatment since development of symptoms was 2.5 months. Three different patterns of musculoskeletal manifestations were found: (i) prominent joint involvement (n = 3); (ii) prominent 'periarticular' involvement (n = 4). These patients had diffuse swelling of the hands, feet or knees. MRI depicted mild synovitis with more prominent myositis and/or fasciitis in the surrounding tissues in all cases; (iii) myofasciitis (n = 3). Clinically, these patients presented with pain in the knee(s)/thigh(s), whereas MRI depicted myofasciitis of the surrounding muscles. Patients with musculoskeletal ir-AEs had significantly higher oncologic response rates compared with patients not exhibiting musculoskeletal ir-AEs (50% vs 12.5%, respectively, P = 0.0016). Cytokine levels associated with a Th1/Th2/Th17 response were similar between patients with and without musculoskeletal ir-AEs. Overall, symptoms were mild/moderate and responded well to treatment, with no need for ICI discontinuation.CONCLUSION: In our cohort, ICI-induced musculoskeletal manifestations developed in 7.7% of patients. Imaging evidence of myofasciitis was found in most patients, indicating that the muscle/fascia is more frequently involved than the synovium.
CANIT0003042	32358520	Basic research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines/ animal models	N/A	Basic research	High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that systemic short chain fatty acids (SCFA) limits anti-CTLA-4 activity.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	Butyrate (NCIT:C2337); 	High blood butyrate levels	Metabolite	 2020 May 1	Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer.	 Nat Commun	Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
CANIT0003043	32358520	Basic research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	Cell lines/ animal models	N/A	Basic research	High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that systemic short chain fatty acids (SCFA) limits anti-CTLA-4 activity.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	Propionate (NCIT:C28934); 	High blood propionate levels	Metabolite	 2020 May 1	Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer.	 Nat Commun	Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
CANIT0003044	32366425	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	29	N/A	N/A	Median progression-free survival in the Higher group was significantly longer than that in the Lower group. IFNG levels in the non-progression disease group were significantly higher than those in the progression disease group. IFNG levels at 14 days before treatment in patients with immune-related adverse events were significantly lower compared to those at 22+/-7 days.	N/A	N/A	N/A	IFNG (P01579); 	IFNG-response gene expression signature	Gene expression signature on/in immune cell	 2020 May	Significance of Quantitative Interferon-gamma Levels in Non-small-cell Lung Cancer Patients' Response to Immune Checkpoint Inhibitors.	 Anticancer Res	BACKGROUND/AIM: We aimed to study the association between the quantitative interferonG (IFN-¦Ã) levels and clinical outcomes in non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs).PATIENTS AND METHODS: Sample collection for IFN-¦Ã release assay (IGRA) was performed within 14 days before treatment (T1), on day 22+/-7 (T3), and on day 43+/-7 (T4). The stored specimens over 10 IU/ml in IGRA were re-examined using the dilution method (with saline as the dilution medium). The patients were classified into Lower and Higher groups by 7.06 IU/ml as a cut-off of IFN-¦Ã levels at T1.RESULTS: Median progression-free survival in the Higher group was significantly longer than that in the Lower group. IFN-¦Ã levels in the non-progression disease group were significantly higher than those in the progression disease group. IFN-¦Ã levels at T1 in patients with immune-related adverse events were significantly lower compared to those at T3.CONCLUSION: IFN-¦Ã could be a biomarker for NSCLC patients receiving ICIs.
CANIT0003045	32380346	Basic research	Neuro-2a Neuroblastoma	Neuroblastoma	EFO:0000621	Nervous system	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	Cell lines/ animal models	N/A	Basic research	Dim expression of PD-L1 was observed on the cell surface of cultured Neuro-2a cells. Growth of subcutaneous tumors was significantly suppressed, and PD-L1-expressing tumor cells were depleted by the antibody treatment. We confirmed that Neuro-2a cells opsonized by the anti-PD-L1 antibody were phagocytosed in the in vitro setting. In the treated tumor microenvironments, CD8A+ lymphocyte and CD11c+ MHC II+ cells were significantly accumulated in comparison with the control group. These CD11c+ MHC II+ cells expressed CD80, CD86, CD14, and CD40, but not CD205, PD-L1, or CTLA4. PD-1 expression was detected dimly. Immune suppressive effects of CD11b+Gr-1+ myeloid-derived suppressor cells by the administration of anti-PD-1 and PD-L1 antibodies were not observed in spleen, regional lymph nodes, or tumor microenvironment.The findings raise the possibility that co-administration of anti-PD-1 and anti-PD-L1 antibodies have a synergistic effect on inhibition of tumor growth and could be an effective therapy against neuroblastoma with dim expression of PD-L1.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	ECO:0007120 - animal model system study evidence used in manual assertion	N/A	N/A	N/A	 2020 Sep	Immune Checkpoint Inhibition Followed by Tumor Infiltration of Dendritic Cells in Murine Neuro-2a Neuroblastoma.	 J Surg Res	BACKGROUND: Most tumors responding to immunotherapy with monoclonal antibodies targeting programmed cell death protein1 (PD1) and programmed death ligand-1 (PD-L1) show surface expression of PD-L1. Neuroblastoma has been reported to show low PD-L1 surface expression.METHODS: The effect of immune checkpoint inhibitor on mouse neuroblastoma was investigated, and host immune cells were analyzed in the tumor microenvironment. Expression of co-stimulatory molecules by Neuro-2a mouse neuroblastoma cells was analyzed using flow cytometer. Neuro-2a cells were inoculated subcutaneously into A/J mice, followed by intraperitoneal injection of antibodies targeting PD-1 and PD-L1. Mice were sacrificed for the measurement of tumor weights on day 14 following tumor inoculation, and tumor-infiltrating cells were analyzed using a flow cytometer.RESULTS: Dim expression of PD-L1 was observed on the cell surface of cultured Neuro-2a cells. Growth of subcutaneous tumors was significantly suppressed, and PD-L1-expressing tumor cells were depleted by the antibody treatment. We confirmed that Neuro-2a cells opsonized by the anti-PD-L1 antibody were phagocytosed in the in vitro setting. In the treated tumor microenvironments, CD8a+ lymphocyte and CD11c+ MHC II+ cells were significantly accumulated in comparison with the control group. These CD11c+ MHC II+ cells expressed CD80, CD86, CD14, and CD40, but not CD205, PD-L1, or CTLA4. PD-1 expression was detected dimly. Immune suppressive effects of CD11b+Gr-1+ myeloid-derived suppressor cells by the administration of anti-PD-1 and PD-L1 antibodies were not observed in spleen, regional lymph nodes, or tumor microenvironment.CONCLUSIONS: Our findings raise the possibility that co-administration of anti-PD-1 and anti-PD-L1 antibodies have a synergistic effect on inhibition of tumor growth and could be an effective therapy against neuroblastoma with dim expression of PD-L1.
CANIT0003046	32386568	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab plus nab-paclitaxel plus carboplatin followed by surgical resection	N/A	Immune checkpoint therapy plus Chemotherapy followed by Surgery	Atezolizumab (DB11595); nab-paclitaxel (DB01229); 	30	N/A	Open-label, multicentre, single-arm, phase 2 trial	Atezolizumab plus carboplatin and nab-paclitaxel could be a potential neoadjuvant regimen for resectable non-small-cell lung cancer, with a high proportion of patients achieving a major pathological response, and manageable treatment-related toxic effects, which did not compromise surgical resection. 23 (77%) of patients had stage IIIA disease. 29 (97%) patients were taken into the operating theatre, and 26 (87%) underwent successful R0 resection. At the data cutoff (Aug 7, 2019), the median follow-up period was 12.9 months (IQR 6.2-22.9). 17 (57%; 95% CI 37-75) of 30 patients had a major pathological response.	The most common treatment-related grade 3-4 adverse events were neutropenia (15 [50%] of 30 patients), increased alanine aminotransferase concentrations (two [7%] patients), increased aspartate aminotransferase concentration (two [7%] patients), and thrombocytopenia (two [7%] patients). Serious treatment-related adverse events included one (3%) patient with grade 3 febrile neutropenia, one (3%) patient with grade 4 hyperglycaemia, and one (3%) patient with grade 2 bronchopulmonary haemorrhage. There were no treatment-related deaths.	N/A	N/A	N/A	N/A	N/A	 2020 Jun	Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.	 Lancet Oncol	BACKGROUND: Approximately 25% of all patients with non-small-cell lung cancer present with resectable stage IB-IIIA disease, and although perioperative chemotherapy is the standard of care, this treatment strategy provides only modest survival benefits. On the basis of the activity of immune checkpoint inhibitors in metastatic non-small-cell lung cancer, we designed a trial to test the activity of the PD-L1 inhibitor, atezolizumab, with carboplatin and nab-paclitaxel given as neoadjuvant treatment before surgical resection.METHODS: This open-label, multicentre, single-arm, phase 2 trial was done at three hospitals in the USA. Eligible patients were aged 18 years or older and had resectable American Joint Committee on Cancer-defined stage IB-IIIA non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1, and a history of smoking exposure. Patients received neoadjuvant treatment with intravenous atezolizumab (1200 mg) on day 1, nab-paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1, of each 21-day cycle. Patients without disease progression after two cycles proceeded to receive two further cycles, which were then followed by surgical resection. The primary endpoint was major pathological response, defined as the presence of 10% or less residual viable tumour at the time of surgery. All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT02716038, and is ongoing but no longer recruiting participants.FINDINGS: Between May 26, 2016, and March 1, 2019, we assessed 39 patients for eligibility, of whom 30 patients were enrolled. 23 (77%) of these patients had stage IIIA disease. 29 (97%) patients were taken into the operating theatre, and 26 (87%) underwent successful R0 resection. At the data cutoff (Aug 7, 2019), the median follow-up period was 12.9 months (IQR 6.2-22.9). 17 (57%; 95% CI 37-75) of 30 patients had a major pathological response. The most common treatment-related grade 3-4 adverse events were neutropenia (15 [50%] of 30 patients), increased alanine aminotransferase concentrations (two [7%] patients), increased aspartate aminotransferase concentration (two [7%] patients), and thrombocytopenia (two [7%] patients). Serious treatment-related adverse events included one (3%) patient with grade 3 febrile neutropenia, one (3%) patient with grade 4 hyperglycaemia, and one (3%) patient with grade 2 bronchopulmonary haemorrhage. There were no treatment-related deaths.INTERPRETATION: Atezolizumab plus carboplatin and nab-paclitaxel could be a potential neoadjuvant regimen for resectable non-small-cell lung cancer, with a high proportion of patients achieving a major pathological response, and manageable treatment-related toxic effects, which did not compromise surgical resection.FUNDING: Genentech and Celgene.
CANIT0003047	32435885	Clinical research	Cervical adenocarcinoma	Cervical adenocarcinoma	EFO:0001416	Cervix	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	82	N/A	Retrospective analysis	It shows a significant inverse correlation between the expression of PD-1 and CD8 (p = 0.001, chi-square test). We also found a significant inverse correlation between the expression of PD-L1 and CD8 (p = 0.027). The overall survival and progression-free survival rates were significantly worse in patients with positive PD-1 expression (p = 0.031; p = 0.087, respectively).These results suggest that a high PD-1 expression is associated with a poor prognosis in patients with CA. Further research is necessary to identify the molecular mechanisms that mediate this association.	N/A	N/A	N/A	PD-1 (Q15116); 	PD-1 expression levels	Gene expression signature on/in tumor cell	 2020 Jul	High PD-1 expression level is associated with an unfavorable prognosis in patients with cervical adenocarcinoma.	 Arch Gynecol Obstet	PURPOSE: The effectiveness of immunotherapy for cervical adenocarcinoma (CA) has not been demonstrated yet. Programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and CD8 may be used as biomarkers of response to immune therapy in CA patients. In the present study, we aimed to investigate whether the expression levels of PD-1, PD-L1, and CD8 can predict the prognosis of patients with CA and their response to immune checkpoint inhibition therapy.METHODS: In the present study, the clinical stage for all 82 patients with cervical adenocarcinoma was classified according to the guidelines of the International Federation of Gynecology and Obstetrics (FIGO); there were 5, 48, 5, 14, 8, and 2 patients with stage IA, IB, IIA, IIB, IIIB, and IVB disease, respectively. The levels of PD-1, PD-L1, and CD8 were analyzed by the immunohistochemical analysis of the formalin-fixed paraffin-embedded tumor samples. The correlation between the expression levels and patient prognosis was analyzed using the Kaplan-Meier method and univariate and multivariate Cox proportional hazard regression models.RESULTS: We observed a significant inverse correlation between the expression of PD-1 and CD8 (p = 0.001, chi-square test). We also found a significant inverse correlation between the expression of PD-L1 and CD8 (p = 0.027). The overall survival and progression-free survival rates were significantly worse in patients with positive PD-1 expression (p = 0.031; p = 0.087, respectively).CONCLUSION: Our results suggest that a high PD-1 expression is associated with a poor prognosis in patients with CA. Further research is necessary to identify the molecular mechanisms that mediate this association.
CANIT0003048	32437664	Clinical research	HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); HER2 (P04626); 	PD-1; HER2	Pembrolizumab plus trastuzumab plus cisplatin	N/A	Immune checkpoint therapy plus Target therapy plus Chemotherapy	Pembrolizumab (DB09037); cisplatin (DB00515); trastuzumab (DB00072); 	37	N/A	Investigator-initiated, open-label, non-randomised, single-arm, single centre, phase 2 trial	Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomised phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric cancer is underway. At the time of data cutoff on Aug 6, 2019, median follow-up among survivors was 13.0 months (IQR 11.7-23.5). The primary endpoint was achieved; 26 (70%; 95% CI 54-83) of 37 patients were progression-free at 6 months.	The most common treatment-related adverse event of any grade was neuropathy, which was reported in 36 (97%) of 37 patients. The most common grade 3 or 4 adverse events were lymphocytopenia (seven [19%] patients with grade 3 and two [5%] with grade 4), grade 3 decreased electrolytes (six [16%] patients), and grade 3 anaemia (four [11%] patients). Serious adverse events occurred in two patients patients (both grade 3 nephritis leading to treatment discontinuation). Four patients discontinued pembrolizumab because of immune-related adverse events. There were no treatment-related deaths.	N/A	N/A	N/A	N/A	N/A	 2020 Jun	First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial.	 Lancet Oncol	BACKGROUND: Addition of trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and activity of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric (gastric, oesophageal, or gastroesophageal junction) cancer.METHODS: This study was an investigator-initiated, open-label, non-randomised, single-arm, single centre, phase 2 trial in patients aged 18 years or older with HER2-positive metastatic oesophagogastric cancer. Eligible patients had measurable or evaluable non-measurable disease, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and left ventricular ejection fraction of at least 53%. Patients were eligible to receive an initial induction cycle of 200 mg flat dose of intravenous pembrolizumab and 8 mg/kg loading dose of intravenous trastuzumab. For subsequent cycles, patients received 130 mg/m2 of intravenous oxaliplatin or 80 mg/m2 of cisplatin on day 1, 850 mg/m2 of oral capecitabine twice a day for 2 weeks followed by 1 week off (or intravenous 5-fluorouracil, 800 mg/m2 per day on days 1-5), and a 200 mg flat dose of intravenous pembrolizumab, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival, defined as the proportion of patients alive and free of progression at 6 months, assessed in patients who received at least one dose of trastuzumab and pembrolizumab. The regimen would be considered worthy of further investigation if 26 or more of 37 patients were progression-free at 6 months. This trial is registered with ClinicalTrials.gov, NCT02954536, and is ongoing, but closed to enrolment.FINDINGS: Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, median follow-up among survivors was 13.0 months (IQR 11.7-23.5). The primary endpoint was achieved; 26 (70%; 95% CI 54-83) of 37 patients were progression-free at 6 months. The most common treatment-related adverse event of any grade was neuropathy, which was reported in 36 (97%) of 37 patients. The most common grade 3 or 4 adverse events were lymphocytopenia (seven [19%] patients with grade 3 and two [5%] with grade 4), grade 3 decreased electrolytes (six [16%] patients), and grade 3 anaemia (four [11%] patients). Serious adverse events occurred in two patients patients (both grade 3 nephritis leading to treatment discontinuation). Four patients discontinued pembrolizumab because of immune-related adverse events. There were no treatment-related deaths.INTERPRETATION: Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive metastatic oesophagogastric cancer. A randomised phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic oesophagogastric cancer is underway.FUNDING: Merck & Co.
CANIT0003049	32451495	Clinical research	Pancreatic ductal adenocarcinoma	Pancreatic ductal adenocarcinoma	EFO:0002517	Pancreas	PD-1 (Q15116); CXCR4 (P61073); 	PD-1; CXCR4	Pembrolizumab plus motixafortide	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); motixafortide (DB14939); 	59	N/A	Phase IIa, open-label, two-cohort study	In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The disease control rate (DCR) was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively.These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	CD8(+) effector T cell tumor infiltration	Tumor-infiltrating immune cell	 2020 Jun	BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial.	 Nat Med	Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
CANIT0003050	32451495	Clinical research	Pancreatic ductal adenocarcinoma	Pancreatic ductal adenocarcinoma	EFO:0002517	Pancreas	PD-1 (Q15116); CXCR4 (P61073); 	PD-1; CXCR4	Pembrolizumab plus motixafortide	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); motixafortide (DB14939); 	59	N/A	Phase IIa, open-label, two-cohort study	In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The disease control rate (DCR) was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively.These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.	N/A	N/A	N/A	Monocytic myeloid-derived suppressor cells (NCIT:C129908); T-Lymphocyte (NCIT:C12476); 	Monocytic myeloid-derived suppressor cells counts	Cell percentage/counts in blood	 2020 Jun	BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial.	 Nat Med	Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
CANIT0003051	32451495	Clinical research	Pancreatic ductal adenocarcinoma	Pancreatic ductal adenocarcinoma	EFO:0002517	Pancreas	PD-1 (Q15116); CXCR4 (P61073); 	PD-1; CXCR4	Pembrolizumab plus motixafortide	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); motixafortide (DB14939); 	59	N/A	Phase IIa, open-label, two-cohort study	In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The disease control rate (DCR) was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively.These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.	N/A	N/A	N/A	Treg cells (CL:0000815); 	Circulating Treg frequencies	Cell percentage/counts in blood	 2020 Jun	BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial.	 Nat Med	Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials.
CANIT0003052	32453797	Clinical research	Metastatic castration resistant prostate cancer with inactivating mutations in mismatch repair genes or microsatellite instability 	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	Retrospective analysis	27 men with mismatch repair deficiency (MMRd) and/or microsatellite instability (MSI)-high metastatic prostate cancer (PC) were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score >=8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who achieved a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression at a median follow up of 12 months (range 3-20 months). MMRd PC is associated with high Gleason score and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high. Our study is limited by small sample size, and more research is needed to identify additional factors that may predict response to immunotherapy.	N/A	N/A	N/A	Microsatellite instability (NCIT:C36318); DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient/microsatellite instability-high	Mutational status	 2020 May 26	Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies.	 PLoS One	BACKGROUND: While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant prostate cancer (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct and clinically relevant subgroup's natural history and response to treatment.METHODS: We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic prostate cancer (PC). Clinical and pathologic characteristics at the time of diagnosis as well as response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (>=50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported.RESULTS: 27 men with MMRd and/or MSI-high metastatic PC were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score >=8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who achieved a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression at a median follow up of 12 months (range 3-20 months).CONCLUSIONS: MMRd PC is associated with high Gleason score and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high. Our study is limited by small sample size, and more research is needed to identify additional factors that may predict response to immunotherapy.
CANIT0003053	32462298	Clinical research	Non-small-cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); PD-L1 (Q9NZQ7); 	PD-1; PD-L1	Atezolizumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	157	N/A	Retrospective analysis	Polypharmacy is an independent prognostic factor in older patients with advanced NSCLC treated with immune checkpoint inhibitor (ICI). Also, polypharmacy could be utilized as a simple indicator of patients' comorbidities and symptoms or as a predictive marker of unexpected hospitalizations during ICI treatment.	N/A	N/A	N/A	Polypharmacy ()	Polypharmacy	Exposure factors/status	 2020 Oct	Polypharmacy as a prognostic factor in older patients with advanced non-small-cell lung cancer treated with anti-PD-1/PD-L1 antibody-based immunotherapy.	 J Cancer Res Clin Oncol	PURPOSE: Polypharmacy is a common problem among older adults. However, its prevalence and impact on the clinical outcomes of anticancer treatment, such as survival and adverse events, in older patients with advanced cancer have not been well investigated.METHODS: We retrospectively reviewed data from Japanese patients treated with an immune checkpoint inhibitor (ICI) for advanced or recurrent non-small-cell lung cancer (NSCLC) between 2016 and 2019.RESULTS: Among 157 older (aged >= 65 years) patients, the prevalence of polypharmacy, defined as >= 5 medications, was 59.9% (94/157). The prevalence of potentially inappropriate medication use, according to the screening tool of older people's prescription (STOPP) criteria version 2, was 38.2% (60/157). The median progression-free survival (PFS) in patients with and without polypharmacy was 3.7 and 5.5 months, respectively (P = 0.0017). The median overall survival (OS) in patients with and without polypharmacy was 9.5 and 28.1 months, respectively (P < 0.001). Multivariate analysis revealed marked associations between polypharmacy and OS, but no significant associations between polypharmacy and PFS. Polypharmacy was not associated with immune-related adverse events but was associated with higher rate of unexpected hospitalizations during ICI treatment (59.6% vs. 31.7%, P < 0.001).CONCLUSION: Polypharmacy is an independent prognostic factor in older patients with advanced NSCLC treated with ICI. Also, polypharmacy could be utilized as a simple indicator of patients' comorbidities and symptoms or as a predictive marker of unexpected hospitalizations during ICI treatment.
CANIT0003054	32474528	Case report	Primary anorectal malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus nab-paclitaxel	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); nab-paclitaxel (DB01229); 	2	N/A	Case	A combination of transcatheter arterial infusion (TAI) with pembrolizumab and temozolomide or with nab-paclitaxel appears to be a promising option for treating anorectal malignant melanoma	N/A	N/A	N/A	N/A	N/A	N/A	2020	Transcatheter arterial infusion of anti-programmed cell death 1 antibody pembrolizumab combined with temozolomide or nab-paclitaxel in patient with primary anorectal malignant melanoma: Four case reports.	 J Cancer Res Ther	Primary anorectal malignant melanoma (ARMM) is an extremely rare but aggressive tumor. We assessed the efficacy and safety of transcatheter arterial infusion (TAI) with anti-PD-1 antibody pembrolizumab at a dosage of 100 mg with 0.9% NaCl at a volume of 100 mL administered over a 30-min period every 3 weeks, combined with temozolomide or albumin-bound paclitaxel (nab-paclitaxel) in four patients with ARMM. Temozolomide was administered orally once per day at a dosage of 200 mg/m2/d for five consecutive days about every 4 weeks. Nab-paclitaxel was administered at a dosage of 200mg/m2/d once about every 3 weeks. Among four patients with a median follow-up of 8.9 months, two cases showed Murine Double Minute 2 (MDM2) amplification. Case 1 with Stage II ARMM showed pathological complete response after four cycles of TAI with pembrolizumab combined with nab-paclitaxel. Case 4 was at Stage II and showed stable disease consistently throughout the treatment. Case 2 was at stage II and Case 3 was at stage III, and they showed partial response after four or three cycles, respectively, of TAI with pembrolizumab combined with temozolomide. No Grades 3-4 adverse reactions were observed. Therefore, a combination of TAI with pembrolizumab and temozolomide or with nab-paclitaxel appears to be a promising option for treating ARMM. However, multicenter clinical trials are required to confirm the efficacy and safety of this procedure.
CANIT0003055	32474528	Case report	Primary anorectal malignant melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); TLR3 (O15455)	PD-1; TLR3	Pembrolizumab plus temozolomide	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); temozolomide (DB00853); 	2	N/A	Case	A combination of transcatheter arterial infusion (TAI) with pembrolizumab and temozolomide or with nab-paclitaxel appears to be a promising option for treating anorectal malignant melanoma	N/A	N/A	N/A	N/A	N/A	N/A	2020	Transcatheter arterial infusion of anti-programmed cell death 1 antibody pembrolizumab combined with temozolomide or nab-paclitaxel in patient with primary anorectal malignant melanoma: Four case reports.	 J Cancer Res Ther	Primary anorectal malignant melanoma (ARMM) is an extremely rare but aggressive tumor. We assessed the efficacy and safety of transcatheter arterial infusion (TAI) with anti-PD-1 antibody pembrolizumab at a dosage of 100 mg with 0.9% NaCl at a volume of 100 mL administered over a 30-min period every 3 weeks, combined with temozolomide or albumin-bound paclitaxel (nab-paclitaxel) in four patients with ARMM. Temozolomide was administered orally once per day at a dosage of 200 mg/m2/d for five consecutive days about every 4 weeks. Nab-paclitaxel was administered at a dosage of 200mg/m2/d once about every 3 weeks. Among four patients with a median follow-up of 8.9 months, two cases showed Murine Double Minute 2 (MDM2) amplification. Case 1 with Stage II ARMM showed pathological complete response after four cycles of TAI with pembrolizumab combined with nab-paclitaxel. Case 4 was at Stage II and showed stable disease consistently throughout the treatment. Case 2 was at stage II and Case 3 was at stage III, and they showed partial response after four or three cycles, respectively, of TAI with pembrolizumab combined with temozolomide. No Grades 3-4 adverse reactions were observed. Therefore, a combination of TAI with pembrolizumab and temozolomide or with nab-paclitaxel appears to be a promising option for treating ARMM. However, multicenter clinical trials are required to confirm the efficacy and safety of this procedure.
CANIT0003056	32474768	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1026	N/A	Retrospective analysis	The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. Bone metastases (p = 0.0003) was confirmed to be independent predictors of a worse ORR. Bone metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS.Bone metastases (p < 0.0001) was also confirmed to be independent predictors of a shortened OS.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Bone metastasis	Disease status	 2020 Nov	Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ¡Ý 50.	 Cancer Immunol Immunother	BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of >= 50%.METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-na ve NSCLC and a PD-L1 expression of >= 50%.RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS >= 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of >= 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.
CANIT0003057	32474768	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1026	N/A	Retrospective analysis	The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. Liver metastases (p < 0.0001) was also confirmed to be independent predictors of a worse PFS. Liver metastases (p < 0.0001) was also confirmed to be independent predictors of a shortened OS.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2020 Nov	Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ¡Ý 50.	 Cancer Immunol Immunother	BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of >= 50%.METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-na ve NSCLC and a PD-L1 expression of >= 50%.RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS >= 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of >= 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.
CANIT0003058	32474768	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1026	N/A	Retrospective analysis	The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. A PD-L1 expression of >= 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels	Gene expression signature on/in tumor cell	 2020 Nov	Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ¡Ý 50.	 Cancer Immunol Immunother	BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of >= 50%.METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-na ve NSCLC and a PD-L1 expression of >= 50%.RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS >= 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of >= 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.
CANIT0003059	32474768	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1026	N/A	Retrospective analysis	The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS >= 2 (p < 0.0001) was confirmed to be independent predictors of a worse ORR. ECOG-PS (p < 0.0001) was also confirmed to be independent predictors of a worse PFS. ECOG-PS (p < 0.0001) was also confirmed to be independent predictors of a shortened OS.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2020 Nov	Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ¡Ý 50.	 Cancer Immunol Immunother	BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of >= 50%.METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-na ve NSCLC and a PD-L1 expression of >= 50%.RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS >= 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of >= 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.
CANIT0003060	32474768	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1026	N/A	Retrospective analysis	The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively.Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis.  Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers.	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2020 Nov	Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ¡Ý 50.	 Cancer Immunol Immunother	BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of >= 50%.METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-na ve NSCLC and a PD-L1 expression of >= 50%.RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS >= 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of >= 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.
CANIT0003061	32474768	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1026	N/A	Retrospective analysis	The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively.Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033).	N/A	N/A	N/A	Treatment history (NCIT:C160179); 	Palliative radiation therapy	Exposure factors/status	 2020 Nov	Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ¡Ý 50.	 Cancer Immunol Immunother	BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of >= 50%.METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-na ve NSCLC and a PD-L1 expression of >= 50%.RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS >= 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of >= 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.
CANIT0003062	32481252	Case report	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Sintilimab	N/A	Immune checkpoint therapy	Sintilimab (DB15765); 	1	N/A	Case	Sintilimab is a promising drug for patients with locally advanced NSCLC. However, its efficacy still requires further clinical investigations.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 May 22	Promising response to a PD-1 inhibitor (sintilimab) in non-small cell lung cancer: A case report.	 Medicine (Baltimore)	RATIONALE: Lung cancer is the cancer with the highest incidence and mortality in China and worldwide. Among them, 85% are non-small cell lung cancer (NSCLC). No previous reports have been published to describe the clinical effect of the immune checkpoint inhibitor (ICI) sintilimab in NSCLC yet.PATIENT CONCERNS: We report a case of a 64-year-old woman with a 20-day history of chest pain with computed tomography scan showing a right lower lung mass.DIAGNOSES: Squamous NSCLC was diagnosed by bronchoscopy.INTERVENTIONS: The patient was treated with sintilimab plus nedaplatin and paclitaxel as neoadjuvant therapy for 3 cycles, followed by right thoracotomy, right middle lobectomy, right lower lobectomy, hilar lymphadenectomy, mediastinal lymphadenectomy, and pericardiostomy.OUTCOMES: The patient was discharged from the hospital 12 days after operation. Pathological report showed no cancer residue in the lung tissue, the bronchial stump, the anastomotic lung marginal tissue, 2nd, 4th, 7th, 9th, 10th, 11th lymph nodes or in the peribronchial lymph nodes after repeated sampling. The pathological stage was deemed T0N0M0. She remained disease free until the latest follow up in July 2019.LESSONS: Sintilimab is a promising drug for patients with locally advanced NSCLC. However, its efficacy still requires further clinical investigations.
CANIT0003063	32481351	Case report	A 78-year-old man was diagnosed with advanced gastric cancer with portal thrombosis	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	IgA nephropathy should be recognized as an uncommon renal adverse event during nivolumab therapy. After drug discontinuation, nivolumab-induced IgA nephropathy is likely to respond to moderate doses of steroid therapy with early tapering.	IgA nephropathy	N/A	N/A	N/A	N/A	N/A	 2020 May 22	Nivolumab-induced IgA nephropathy in a patient with advanced gastric cancer: A case report.	 Medicine (Baltimore)	INTRODUCTION: Immune checkpoint inhibitors including nivolumab, an antibody against programmed death-1, have been increasingly introduced in various cancer treatment regimens, and are reported to be associated with immune-related adverse events. Nivolumab-induced renal injury is generally caused by acute interstitial nephritis and is managed by drug discontinuation and steroid therapy. Although this agent can infrequently induce glomerulonephritis, the pathogenesis and therapeutic strategy remain undetermined.PATIENT CONCERNS: A 78-year-old man was diagnosed with advanced gastric cancer with portal thrombosis. First- and second-line chemotherapies were ineffective; thus, nivolumab monotherapy was initiated. Although it effectively prevented tumor growth, proteinuria and microhematuria appeared 2 months later. Despite drug discontinuation, serum creatinine progressively increased from 0.72 to 1.45 mg/dL. Renal biopsy revealed mesangial IgA and C3 deposition in immunofluorescence analysis and mesangial proliferation with crescent formation in light microscopy.DIAGNOSIS: The patient was diagnosed with IgA nephropathy. Based on the temporal relationship between the nivolumab therapy and abnormal urinalysis, IgA nephropathy was considered to have been induced by nivolumab.INTERVENTIONS: A moderate dose (0.6 mg/kg/day) of prednisolone was orally administrated, with tapering biweekly.OUTCOMES: Steroid therapy stabilized his serum creatinine levels and markedly reduced proteinuria. However, bacterial pneumonia substantially impaired his performance status; thus, nivolumab could not be restarted despite tumor regrowth.LESSONS: IgA nephropathy should be recognized as an uncommon renal adverse event during nivolumab therapy. After drug discontinuation, nivolumab-induced IgA nephropathy is likely to respond to moderate doses of steroid therapy with early tapering. However, more evidence is needed to determine whether nivolumab can be safely restarted during or after steroid therapy.
CANIT0003064	32512320	Clinical research	Non-metastatic bladder cancer	Bladder cancer	EFO:0000292	Bladder	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	N/A	Approximately 2% of CD45-negative tumor and stromal cells expressed PD-L1. Expression was not associated with the main clinicopathological characteristics of the disease or with survival. However, as tumors progressed the frequency of PD-L1+CD45hi cells and the mean expression of PD-1 on CD45hi cells increased remarkably on immune cells in tumor tissues and draining lymph nodes. In addition, frequency analysis showed that cell percentages as well as mean expression of PD-L2 on total CD45+ lymphocytes and their CD45hi subpopulation in tumor-draining lymph nodes was significantly associated with cancer-related death (P < 0.05). Multiple Cox regression also revealed that while CD45+ (hazard ratio: 0.596, 95 % CI 0.439-0.809, P = 0.001) was associated with improved survival, CD45neg (HR: 0.615, 95 % CI 0.454-0.831, P = 0.002), and PD-L2+CD45+ cells (hazard ratio: 1.472, 95 % CI 1.023-2.120, P = 0.038) in draining lymph nodes were associated with lower survival. The results suggest that in patients with BC, PD-1 and PD-L expression on immune cells, especially in draining lymph nodes, is valuable for predicting prognosis and survival, and possibly responsiveness to immunotherapy. However, expression of the inhibitor molecule or its ligands on tumor cells was not associated with prognosis. The results highlight the significance of PD-L2 as a second important suppressive molecule in tumors.	N/A	N/A	N/A	CD45 (P08575); T-Lymphocyte (NCIT:C12476); 	Lymphocytes CD45hi subpopulation in tumor-draining lymph nodes	Tumor-infiltrating immune cell	 2020 Aug	Clinical relevance and prognostic significance of PD-1/PD-Ls in non-metastatic bladder cancer: A role for PD-L2.	 Mol Immunol	BACKGROUND: Bladder cancer (BC) can be successfully treated by manipulating immune responses with intravesical Bacillus Calmette-Guerin instillation or targeting the PD-1/PD-L signaling pathway. In the present study we investigated the prognostic significance of the immune checkpoint inhibitor PD-1 and its ligands PD-L1 and PD-L2 on tumor cells and infiltrating lymphocytes, in the tumor microenvironment and draining lymph nodes in patients with non-metastatic BC.PATIENTS AND METHODS: Cells were mechanically isolated from tissues and draining lymph nodes from 58 patients, and surface-stained for CD45, PD-1, PD-L1 and PD-L2. The cells were then analyzed with a flow cytometric method.RESULTS: Approximately 2% of CD45-negative tumor and stromal cells expressed PD-L1. Expression was not associated with the main clinicopathological characteristics of the disease or with survival. However, as tumors progressed the frequency of PD-L1+CD45hi cells and the mean expression of PD-1 on CD45hi cells increased remarkably on immune cells in tumor tissues and draining lymph nodes. In addition, frequency analysis showed that cell percentages as well as mean expression of PD-L2 on total CD45+ lymphocytes and their CD45hi subpopulation in tumor-draining lymph nodes was significantly associated with cancer-related death (P < 0.05). Multiple Cox regression also revealed that while CD45+ (hazard ratio: 0.596, 95 % CI 0.439-0.809, P = 0.001) was associated with improved survival, CD45neg (HR: 0.615, 95 % CI 0.454-0.831, P = 0.002), and PD-L2+CD45+ cells (hazard ratio: 1.472, 95 % CI 1.023-2.120, P = 0.038) in draining lymph nodes were associated with lower survival.CONCLUSION: Our results suggest that in patients with BC, PD-1 and PD-L expression on immune cells, especially in draining lymph nodes, is valuable for predicting prognosis and survival, and possibly responsiveness to immunotherapy. However, expression of the inhibitor molecule or its ligands on tumor cells was not associated with prognosis. The results highlight the significance of PD-L2 as a second important suppressive molecule in tumors.
CANIT0003065	32512320	Clinical research	Non-metastatic bladder cancer	Bladder cancer	EFO:0000292	Bladder	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	N/A	Approximately 2% of CD45-negative tumor and stromal cells expressed PD-L1. Expression was not associated with the main clinicopathological characteristics of the disease or with survival. However, as tumors progressed the frequency of PD-L1+CD45hi cells and the mean expression of PD-1 on CD45hi cells increased remarkably on immune cells in tumor tissues and draining lymph nodes. In addition, frequency analysis showed that cell percentages as well as mean expression of PD-L2 on total CD45+ lymphocytes and their CD45hi subpopulation in tumor-draining lymph nodes was significantly associated with cancer-related death (P < 0.05). Multiple Cox regression also revealed that while CD45+ (hazard ratio: 0.596, 95 % CI 0.439-0.809, P = 0.001) was associated with improved survival, CD45neg (HR: 0.615, 95 % CI 0.454-0.831, P = 0.002), and PD-L2+CD45+ cells (hazard ratio: 1.472, 95 % CI 1.023-2.120, P = 0.038) in draining lymph nodes were associated with lower survival. The results suggest that in patients with BC, PD-1 and PD-L expression on immune cells, especially in draining lymph nodes, is valuable for predicting prognosis and survival, and possibly responsiveness to immunotherapy. However, expression of the inhibitor molecule or its ligands on tumor cells was not associated with prognosis. The results highlight the significance of PD-L2 as a second important suppressive molecule in tumors.	N/A	N/A	N/A	PD-1 (Q15116); CD45 (P08575); T-Lymphocyte (NCIT:C12476); 	The mean expression of PD-1 on CD45hi cells	Gene expression signature on/in immune cell	 2020 Aug	Clinical relevance and prognostic significance of PD-1/PD-Ls in non-metastatic bladder cancer: A role for PD-L2.	 Mol Immunol	BACKGROUND: Bladder cancer (BC) can be successfully treated by manipulating immune responses with intravesical Bacillus Calmette-Guerin instillation or targeting the PD-1/PD-L signaling pathway. In the present study we investigated the prognostic significance of the immune checkpoint inhibitor PD-1 and its ligands PD-L1 and PD-L2 on tumor cells and infiltrating lymphocytes, in the tumor microenvironment and draining lymph nodes in patients with non-metastatic BC.PATIENTS AND METHODS: Cells were mechanically isolated from tissues and draining lymph nodes from 58 patients, and surface-stained for CD45, PD-1, PD-L1 and PD-L2. The cells were then analyzed with a flow cytometric method.RESULTS: Approximately 2% of CD45-negative tumor and stromal cells expressed PD-L1. Expression was not associated with the main clinicopathological characteristics of the disease or with survival. However, as tumors progressed the frequency of PD-L1+CD45hi cells and the mean expression of PD-1 on CD45hi cells increased remarkably on immune cells in tumor tissues and draining lymph nodes. In addition, frequency analysis showed that cell percentages as well as mean expression of PD-L2 on total CD45+ lymphocytes and their CD45hi subpopulation in tumor-draining lymph nodes was significantly associated with cancer-related death (P < 0.05). Multiple Cox regression also revealed that while CD45+ (hazard ratio: 0.596, 95 % CI 0.439-0.809, P = 0.001) was associated with improved survival, CD45neg (HR: 0.615, 95 % CI 0.454-0.831, P = 0.002), and PD-L2+CD45+ cells (hazard ratio: 1.472, 95 % CI 1.023-2.120, P = 0.038) in draining lymph nodes were associated with lower survival.CONCLUSION: Our results suggest that in patients with BC, PD-1 and PD-L expression on immune cells, especially in draining lymph nodes, is valuable for predicting prognosis and survival, and possibly responsiveness to immunotherapy. However, expression of the inhibitor molecule or its ligands on tumor cells was not associated with prognosis. The results highlight the significance of PD-L2 as a second important suppressive molecule in tumors.
CANIT0003066	32512320	Clinical research	Non-metastatic bladder cancer	Bladder cancer	EFO:0000292	Bladder	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	N/A	Approximately 2% of CD45-negative tumor and stromal cells expressed PD-L1. Expression was not associated with the main clinicopathological characteristics of the disease or with survival. However, as tumors progressed the frequency of PD-L1+CD45hi cells and the mean expression of PD-1 on CD45hi cells increased remarkably on immune cells in tumor tissues and draining lymph nodes. In addition, frequency analysis showed that cell percentages as well as mean expression of PD-L2 on total CD45+ lymphocytes and their CD45hi subpopulation in tumor-draining lymph nodes was significantly associated with cancer-related death (P < 0.05). Multiple Cox regression also revealed that while CD45+ (hazard ratio: 0.596, 95 % CI 0.439-0.809, P = 0.001) was associated with improved survival, CD45neg (HR: 0.615, 95 % CI 0.454-0.831, P = 0.002), and PD-L2+CD45+ cells (hazard ratio: 1.472, 95 % CI 1.023-2.120, P = 0.038) in draining lymph nodes were associated with lower survival. The results suggest that in patients with BC, PD-1 and PD-L expression on immune cells, especially in draining lymph nodes, is valuable for predicting prognosis and survival, and possibly responsiveness to immunotherapy. However, expression of the inhibitor molecule or its ligands on tumor cells was not associated with prognosis. The results highlight the significance of PD-L2 as a second important suppressive molecule in tumors.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); CD45 (P08575); T-Lymphocyte (NCIT:C12476); 	The frequency of PD-L1(+)CD45hi cells	Gene expression signature on/in immune cell	 2020 Aug	Clinical relevance and prognostic significance of PD-1/PD-Ls in non-metastatic bladder cancer: A role for PD-L2.	 Mol Immunol	BACKGROUND: Bladder cancer (BC) can be successfully treated by manipulating immune responses with intravesical Bacillus Calmette-Guerin instillation or targeting the PD-1/PD-L signaling pathway. In the present study we investigated the prognostic significance of the immune checkpoint inhibitor PD-1 and its ligands PD-L1 and PD-L2 on tumor cells and infiltrating lymphocytes, in the tumor microenvironment and draining lymph nodes in patients with non-metastatic BC.PATIENTS AND METHODS: Cells were mechanically isolated from tissues and draining lymph nodes from 58 patients, and surface-stained for CD45, PD-1, PD-L1 and PD-L2. The cells were then analyzed with a flow cytometric method.RESULTS: Approximately 2% of CD45-negative tumor and stromal cells expressed PD-L1. Expression was not associated with the main clinicopathological characteristics of the disease or with survival. However, as tumors progressed the frequency of PD-L1+CD45hi cells and the mean expression of PD-1 on CD45hi cells increased remarkably on immune cells in tumor tissues and draining lymph nodes. In addition, frequency analysis showed that cell percentages as well as mean expression of PD-L2 on total CD45+ lymphocytes and their CD45hi subpopulation in tumor-draining lymph nodes was significantly associated with cancer-related death (P < 0.05). Multiple Cox regression also revealed that while CD45+ (hazard ratio: 0.596, 95 % CI 0.439-0.809, P = 0.001) was associated with improved survival, CD45neg (HR: 0.615, 95 % CI 0.454-0.831, P = 0.002), and PD-L2+CD45+ cells (hazard ratio: 1.472, 95 % CI 1.023-2.120, P = 0.038) in draining lymph nodes were associated with lower survival.CONCLUSION: Our results suggest that in patients with BC, PD-1 and PD-L expression on immune cells, especially in draining lymph nodes, is valuable for predicting prognosis and survival, and possibly responsiveness to immunotherapy. However, expression of the inhibitor molecule or its ligands on tumor cells was not associated with prognosis. The results highlight the significance of PD-L2 as a second important suppressive molecule in tumors.
CANIT0003067	32512320	Clinical research	Non-metastatic bladder cancer	Bladder cancer	EFO:0000292	Bladder	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	N/A	N/A	N/A	Approximately 2% of CD45-negative tumor and stromal cells expressed PD-L1. Expression was not associated with the main clinicopathological characteristics of the disease or with survival. However, as tumors progressed the frequency of PD-L1+CD45hi cells and the mean expression of PD-1 on CD45hi cells increased remarkably on immune cells in tumor tissues and draining lymph nodes. In addition, frequency analysis showed that cell percentages as well as mean expression of PD-L2 on total CD45+ lymphocytes and their CD45hi subpopulation in tumor-draining lymph nodes was significantly associated with cancer-related death (P < 0.05). Multiple Cox regression also revealed that while CD45+ (hazard ratio: 0.596, 95 % CI 0.439-0.809, P = 0.001) was associated with improved survival, CD45neg (HR: 0.615, 95 % CI 0.454-0.831, P = 0.002), and PD-L2+CD45+ cells (hazard ratio: 1.472, 95 % CI 1.023-2.120, P = 0.038) in draining lymph nodes were associated with lower survival. The results suggest that in patients with BC, PD-1 and PD-L expression on immune cells, especially in draining lymph nodes, is valuable for predicting prognosis and survival, and possibly responsiveness to immunotherapy. However, expression of the inhibitor molecule or its ligands on tumor cells was not associated with prognosis. The results highlight the significance of PD-L2 as a second important suppressive molecule in tumors.	N/A	N/A	N/A	PD-L2 (Q9BQ51); CD45 (P08575); T-Lymphocyte (NCIT:C12476); 	Cell percentages as well as mean expression of PD-L2 on total CD45(+) lymphocytes	Gene expression signature on/in immune cell	 2020 Aug	Clinical relevance and prognostic significance of PD-1/PD-Ls in non-metastatic bladder cancer: A role for PD-L2.	 Mol Immunol	BACKGROUND: Bladder cancer (BC) can be successfully treated by manipulating immune responses with intravesical Bacillus Calmette-Guerin instillation or targeting the PD-1/PD-L signaling pathway. In the present study we investigated the prognostic significance of the immune checkpoint inhibitor PD-1 and its ligands PD-L1 and PD-L2 on tumor cells and infiltrating lymphocytes, in the tumor microenvironment and draining lymph nodes in patients with non-metastatic BC.PATIENTS AND METHODS: Cells were mechanically isolated from tissues and draining lymph nodes from 58 patients, and surface-stained for CD45, PD-1, PD-L1 and PD-L2. The cells were then analyzed with a flow cytometric method.RESULTS: Approximately 2% of CD45-negative tumor and stromal cells expressed PD-L1. Expression was not associated with the main clinicopathological characteristics of the disease or with survival. However, as tumors progressed the frequency of PD-L1+CD45hi cells and the mean expression of PD-1 on CD45hi cells increased remarkably on immune cells in tumor tissues and draining lymph nodes. In addition, frequency analysis showed that cell percentages as well as mean expression of PD-L2 on total CD45+ lymphocytes and their CD45hi subpopulation in tumor-draining lymph nodes was significantly associated with cancer-related death (P < 0.05). Multiple Cox regression also revealed that while CD45+ (hazard ratio: 0.596, 95 % CI 0.439-0.809, P = 0.001) was associated with improved survival, CD45neg (HR: 0.615, 95 % CI 0.454-0.831, P = 0.002), and PD-L2+CD45+ cells (hazard ratio: 1.472, 95 % CI 1.023-2.120, P = 0.038) in draining lymph nodes were associated with lower survival.CONCLUSION: Our results suggest that in patients with BC, PD-1 and PD-L expression on immune cells, especially in draining lymph nodes, is valuable for predicting prognosis and survival, and possibly responsiveness to immunotherapy. However, expression of the inhibitor molecule or its ligands on tumor cells was not associated with prognosis. The results highlight the significance of PD-L2 as a second important suppressive molecule in tumors.
CANIT0003068	32535094	Clinical research	Patients	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	1288	N/A	Observational, retrospective, pharmacovigilance study	Clinicians should be aware of the spectrum of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE). Myositis can be particularly life-threatening, particularly when associated with myocarditis.	Immune checkpoint inhibitor-induced myositis	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2020 Aug	Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities.	 Autoimmun Rev	BACKGROUND: In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.PATIENTS METHODS: We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC025 (lower end of the IC 95% credibility interval) >0 is deemed significant.RESULTS: We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6-18.4], IC025 = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9-11.9]; IC025 = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2-9.2]; IC025 = 2.24), myositis (n = 465; ROR = 4.9 [4.5-5.4]; IC025 = 2.12), arthritis (n = 606; ROR = 1.4 [1.3-1.5]; IC025 = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2-3.2]; IC025 = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6-2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2-57.8]) and was the most delayed for scleroderma (395 days [323.8-457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p < .0001).CONCLUSIONS: Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.
CANIT0003069	32541169	Clinical research	20 patients(18 males, 2 females)	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	Neutrophil-to-lymphocyte ratios may be an effective prognostic factor in patients with advanced gastric cancer receiving nivolumab treatment	N/A	N/A	N/A	Neutrophil-to-lymphocyte ratios (NCIT:C141271); 	Neutrophil-to-lymphocyte ratios	Cell percentage/counts in blood	 2020 Jun	[Neutrophil-Lymphocyte Ratio as a Prognostic Indicator in Patients Treated with Nivolumab for Gastric Cancer].	 Gan To Kagaku Ryoho	BACKGROUND: Immune checkpoint inhibitors(nivolumab)have been recommended as third-line chemotherapy for advanced gastric cancer(AGC)according to the Guidelines of Gastric Cancer(5th edition). Therefore, they have been used in daily clinical practice. On the other hand, the neutrophil-lymphocyte ratio(NLR)has been reported to be associated with the prognosis of cancer patients.METHODS: Twenty patients treated with nivolumab for AGC between January 2018 and November 2019 were retrospectively examined.RESULTS: Median age of the 20 patients(18 males, 2 females)was 70 years(55- 84 years). Nivolumab was administered as second-, third-, fourth-, and fifth-line therapy in 1, 11, 7, and 1 case, respectively. The best tumor response evaluation was observed in PR 1, SD 7 and PD 10 cases. Median overall survival(OS)was 10 months, and median progression-free survival(PFS)was 3 months. No serious adverse events occurred. Compared to the NLR>2.0 group, OS significantly prolonged(2.2 months vs 21.9 months)and PFS tended to prolong(1.4 months vs 6.2 months)in the NLR<=2.0 group.CONCLUSION: NLR may be an effective prognostic factor in patients with AGC receiving nivolumab treatment.
CANIT0003070	32541476	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab plus anti-angiogenesis therapy	N/A	Immune checkpoint therapy plus Anti-angiogenesis therapy	Pembrolizumab (DB09037); niraparib (DB11793); 	69	N/A	Retrospective analysis	The real-world ORR, PFS, and OS were comparable to previous clinical trials, despite the patients' different baseline characteristics. Importantly, compared with patients having identified EGFR mutations, patients without EGFR mutations had a better PFS. Furthermore, these data support the use of anti-PD-1 combined with anti-angiogenesis therapy as a novel treatment approach for patients with NSCLC.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jun 12	Real-world treatment efficacy of anti-programmed death-1 combined with anti-angiogenesis therapy in non-small cell lung cancer patients.	 Medicine (Baltimore)	Anti-programmed death-1 (PD-1) therapy has been extensively used to treat cancer. Recently, the combination of immunotherapy and anti-angiogenic therapy has emerged as a novel treatment approach. Therefore, we designed a study to evaluate the real-world benefit of the combination of anti-PD-1 and anti-angiogenesis therapy in patients with non-small cell lung cancer (NSCLC).We obtained the medical records of patients at the Chinese People's Liberation Army General Hospital who received either nivolumab or pembrolizumab combined with anti-angiogenesis therapy from January 2015 to December 2018. The overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated for all patients.Sixty-nine patients with NSCLC were included in our study. The ORR was 31.9% (95% CI: 20.6-43.2%) and the median PFS was 8.37 months (95% CI: 6.5-10.0 months). The subgroup analysis statistically revealed a significant difference in ORR for patients receiving first-line treatment vs other lines, and the values were 58.8% (95% CI: 32.7-84.9%) compared with 23.1% (95% CI: 11.2-34.9%). We also observed a significant improvement in PFS, with a median value of 10.5 months (95% CI: 7.4-13.1 months) for patients without EGFR mutations and 5.4 months (95% CI: 4.0-6.3 months) for patients with EGFR mutations.The real-world ORR, PFS, and OS were comparable to previous clinical trials, despite the patients' different baseline characteristics. Importantly, compared with patients having identified EGFR mutations, patients without EGFR mutations had a better PFS. Furthermore, these data support the use of anti-PD-1 combined with anti-angiogenesis therapy as a novel treatment approach for patients with NSCLC.
CANIT0003071	32558769	Clinical research	Classical Hodgkin lymphoma	Classical Hodgkin lymphoma	EFO:0000183	Blood and lymph nodes	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	10	N/A	Retrospective analysis	Overall response rate was 70% for classical Hodgkin lymphoma (cHL) patients. One case of hyperprogression and one case with atypical response were radiologically detected in cHL patients. This single-institution observational study demonstrated that overall response rate was higher in patients with cHL undergoing ICI. Immune checkpoint inhibitor therapy has unique response patterns and toxicities in cHL patients that radiologists should keep in mind.	Hypothyroidism requiring treatment occurred in 2 (20%) of 10 cHL patients, one of which had imaging correlate.	N/A	N/A	N/A	N/A	N/A	 2020 Jul/Aug	Clinical, Imaging Findings, Responses, and Outcomes of Patients With Classical Hodgkin Lymphoma and Non-Hodgkin Lymphoma Undergoing Immune Checkpoint Inhibitor Therapy: A Single-Institution Experience.	 J Comput Assist Tomogr	OBJECTIVE: The aim of the study was to study clinical, imaging findings, response patterns, and immune-related adverse events in classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma (NHL) patients treated with immune checkpoint inhibitors (ICIs).METHODS: A retrospective search was performed to identify patients with relapsed/refractory cHL and NHL treated with ICIs from 2015 to 2019. Clinical and laboratory data were collected. Imaging studies were reviewed for treatment response and immune-related adverse events.RESULTS: Ten patients with relapsed/refractory cHL (median age, 41 years) and 14 patients with relapsed/refractory NHL (median age, 61 years) were identified. Overall response rate was 70% for cHL patients. None of the NHL patients demonstrated complete or partial response. One case of hyperprogression and one case with atypical response were radiologically detected in cHL patients. Hypothyroidism requiring treatment occurred in 2 (20%) of 10 cHL patients, one of which had imaging correlate. Of 14 NHL patients, 1 (7%) had radiologic evidence of pneumonitis and 1 (7%) had colitis.CONCLUSIONS: This single-institution observational study demonstrated that overall response rate was higher in patients with cHL undergoing ICI. Immune checkpoint inhibitor therapy has unique response patterns and toxicities in both cHL and NHL patients that radiologists should keep in mind.
CANIT0003072	32558769	Clinical research	Non-Hodgkin lymphoma	Non-hodgkins lymphoma	EFO:0005952	Blood and lymph nodes	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Immune checkpoint therapy	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	14	N/A	Retrospective analysis	14 patients with relapsed/refractory non-Hodgkin lymphoma (NHL) (median age, 61 years) were identified. Overall response rate was 70% for cHL patients. None of the NHL patients demonstrated complete or partial response. Immune checkpoint inhibitor therapy has unique response patterns and toxicities in non-Hodgkin lymphoma patients that radiologists should keep in mind.	Of 14 NHL patients, 1 (7%) had radiologic evidence of pneumonitis and 1 (7%) had colitis.	N/A	N/A	N/A	N/A	N/A	 2020 Jul/Aug	Clinical, Imaging Findings, Responses, and Outcomes of Patients With Classical Hodgkin Lymphoma and Non-Hodgkin Lymphoma Undergoing Immune Checkpoint Inhibitor Therapy: A Single-Institution Experience.	 J Comput Assist Tomogr	OBJECTIVE: The aim of the study was to study clinical, imaging findings, response patterns, and immune-related adverse events in classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma (NHL) patients treated with immune checkpoint inhibitors (ICIs).METHODS: A retrospective search was performed to identify patients with relapsed/refractory cHL and NHL treated with ICIs from 2015 to 2019. Clinical and laboratory data were collected. Imaging studies were reviewed for treatment response and immune-related adverse events.RESULTS: Ten patients with relapsed/refractory cHL (median age, 41 years) and 14 patients with relapsed/refractory NHL (median age, 61 years) were identified. Overall response rate was 70% for cHL patients. None of the NHL patients demonstrated complete or partial response. One case of hyperprogression and one case with atypical response were radiologically detected in cHL patients. Hypothyroidism requiring treatment occurred in 2 (20%) of 10 cHL patients, one of which had imaging correlate. Of 14 NHL patients, 1 (7%) had radiologic evidence of pneumonitis and 1 (7%) had colitis.CONCLUSIONS: This single-institution observational study demonstrated that overall response rate was higher in patients with cHL undergoing ICI. Immune checkpoint inhibitor therapy has unique response patterns and toxicities in both cHL and NHL patients that radiologists should keep in mind.
CANIT0003073	32575944	Clinical research	Non-small cell lung cancer	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab plus chemotherapy	N/A	Immune checkpoint therapy plus Chemotherapy	Pembrolizumab (DB09037); chemotherapy (NCIT:C15632); 	13	N/A	N/A	At the last time of follow-up on December 2, 2019, the objective response rate (ORR) and disease control rate (DCR) of these patients were 61.5% (95% CI 30.9%-92.1%) and 100%, respectively. The downregulation rate of disease stage was 61.5% (8/13). The resectable rate was 38.5% (5/13), among them, the major pathologic response (MPR) was 60.0% (3/5) and the complete pathologic response (CPR) was 20.0% (1/5).Immunotherapy combined with chemotherapy as a neoadjuvant treatment is an effective, low-toxicity treatment manner, which has perioperative safety and high rate of MPR for patients with resectable NSCLC. It is a promising treatment option for patients with stage II to III NSCLC	The neoadjuvant chemotherapy displayed a low incidence of adverse reaction. The main grade 3 to 4 toxicities were neutropenia (38.5%) and leukopenia (23.1%). There was no significant immune-related toxicity. The safety and tolerability of perioperative period of patients underwent resection were promising.	N/A	N/A	N/A	N/A	N/A	 2020 Jun 23	[The outcome and safety of neoadjuvant PD-1 blockade plus chemotherapy in stage ¢ò~¢ó non-small cell lung cancer].	 Zhonghua Zhong Liu Za Zhi	Objective: To explore the safety and therapeutic effect of programmed death 1 (PD-1) antibody combined with chemotherapy as a neoadjuvant therapy for patients with stage II to III non-small cell lung cancer (NSCLC). Methods: Thirteen patients, who had been diagnosed as stage II-III NSCLC and received PD-1 inhibitor plus chemotherapy as a neoadjuvant treatment in National Cancer Center/Cancer Hospital were recruited. The patients received consecutive neoadjuvant chemotherapy for 21 days as a cycle and the therapeutic efficacy was evaluated after two cycles. Results: At the last time of follow-up on December 2, 2019, the objective response rate (ORR) and disease control rate (DCR) of these patients were 61.5% (95% CI 30.9%-92.1%) and 100%, respectively. The downregulation rate of disease stage was 61.5% (8/13). The resectable rate was 38.5% (5/13), among them, the major pathologic response (MPR) was 60.0% (3/5) and the complete pathologic response (CPR) was 20.0% (1/5). The neoadjuvant chemotherapy displayed a low incidence of adverse reaction. The main grade 3 to 4 toxicities were neutropenia (38.5%) and leukopenia (23.1%). There was no significant immune-related toxicity. The safety and tolerability of perioperative period of patients underwent resection were promising. Conclusions: Immunotherapy combined with chemotherapy as a neoadjuvant treatment is an effective, low-toxicity treatment manner, which has perioperative safety and high rate of MPR for patients with resectable NSCLC. It is a promising treatment option for patients with stage II to III NSCLC.
CANIT0003074	32589866	Clinical research	Advanced gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); VEGFR1 (P17948); 	PD-1; VEGFR1	Pembrolizumab plus Lenvatinib	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); 	29	N/A	Open-label, single-arm, phase 2 trial	At data cutoff (March 20, 2020), the median follow-up was 12.6 months (IQR 10.5-14.3). 20 (69%, 95% CI 49-85) of 29 patients had an objective response. Lenvatinib plus pembrolizumab showed promising anti-tumour activity with an acceptable safety profile in patients with advanced gastric cancer. On the basis of these results, a confirmatory trial will be planned in the future.	The most common grade 3 treatment-related adverse events were hypertension (in 11 [38%] patients), proteinuria (five [17%]), and platelet count decrease (two [7%]). No grade 4 treatment-related adverse events, serious treatment-related adverse events, or treatment-related deaths occurred.	N/A	N/A	N/A	N/A	N/A	 2020 Aug	Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial.	 Lancet Oncol	BACKGROUND: Pembrolizumab, an anti-PD-1 antibody, results in tumour response in around 15% of patients with advanced gastric cancer who have a PD-L1 combined positive score of at least 1. Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased tumour-associated macrophages and increased infiltration of CD8 T cells, resulting in enhanced anti-tumour activity of PD-1 inhibitors in an in-vivo model. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced gastric cancer in a phase 2 study.METHODS: This study was an open-label, single-arm, phase 2 trial undertaken at the National Cancer Center Hospital East (Chiba, Japan). Eligible patients were aged 20 years or older and had metastatic or recurrent adenocarcinoma of the stomach or gastro-oesophageal junction, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), irrespective of the number of previous lines of treatment. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks until disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate according to RECIST, analysed in all patients who were eligible and received protocol treatment at least once. The safety analysis included all those who received protocol treatment at least once, regardless of eligibility. This study is registered at ClinicalTrials.gov, NCT03609359, and enrolment is complete.FINDINGS: Between Oct 15, 2018, and March 25, 2019, 29 patients were enrolled in the first-line or second-line settings. At data cutoff (March 20, 2020), the median follow-up was 12.6 months (IQR 10.5-14.3). 20 (69%, 95% CI 49-85) of 29 patients had an objective response. The most common grade 3 treatment-related adverse events were hypertension (in 11 [38%] patients), proteinuria (five [17%]), and platelet count decrease (two [7%]). No grade 4 treatment-related adverse events, serious treatment-related adverse events, or treatment-related deaths occurred.INTERPRETATION: Lenvatinib plus pembrolizumab showed promising anti-tumour activity with an acceptable safety profile in patients with advanced gastric cancer. On the basis of these results, a confirmatory trial will be planned in the future.FUNDING: Merck Sharp & Dohme.
CANIT0003075	32620661	Case report	 a 69-year-old male	Intrahepatic cholangiocellular carcinoma 	MONDO:0018531	Liver	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Intra-tumoral infiltration of both PD-1+ and CD8+ T cells may be a predictive factor of the efficacy of pembrolizumab. Expression of PD-L1 did not correlate with a therapeutic effect, but the tumor microenvironment of our patient's recurrent lesions may have been modified by conventional chemotherapy and CD8+ T cells	N/A	N/A	N/A	PD-1 (Q15116); CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	PD-1(+) and CD8(+) T-cells	Gene expression signature on/in immune cell	 2020 Jul	Effective Response of Intrahepatic Cholangiocarcinoma to Pembrolizumab: A Case Report.	 Anticancer Res	BACKGROUND/AIM: The efficacy of pembrolizumab for intrahepatic cholangiocellular carcinoma (IHCCC) is not widely reported.CASE REPORT: We began pembrolizumab treatment in a 69-year-old male with recurrent IHCCC at 18 months after his surgery because of the proven microsatellite instability (MSI)-high status. The patient had partial response, with an 82.5% reduction at the end of 18 courses. Immunostaining of the primary tumor revealed intra-tumoral infiltration of both PD-1+ and CD8+ T cells, and a low expression of PD-L1.CONCLUSION: Intra-tumoral infiltration of both PD-1+ and CD8+ T cells may be a predictive factor of the efficacy of pembrolizumab. Expression of PD-L1 did not correlate with a therapeutic effect, but the tumor microenvironment of our patient's recurrent lesions may have been modified by conventional chemotherapy and CD8+ T cells.
CANIT0003076	32653053	Clinical research	HER2-positive gastro-oesophageal adenocarcinoma	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); HER2 (P04626); 	PD-1; HER2	Pembrolizumab plus margetuximab	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); margetuximab (DB14967); 	95	N/A	Single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study	The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. Objective responses were observed in 17 (18.48%; 95% CI 11.15-27.93) of 92 evaluable patients.	The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported.	N/A	N/A	N/A	N/A	N/A	 2020 Aug	Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial.	 Lancet Oncol	BACKGROUND: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma.METHODS: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing.FINDINGS: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19.9 months (IQR 10.7-23.1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18.48%; 95% CI 11.15-27.93) of 92 evaluable patients.INTERPRETATION: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab).FUNDING: MacroGenics.
CANIT0003077	32669548	Case report	Metastatic rhabdomyosarcoma	Rhabdomyosarcoma	EFO:0000437	Soft tissue	PD-1 (Q15116); HER2 (P04626); 	PD-1; HER2	Pembrolizumab plus HER2 CAR T cells	N/A	Immune checkpoint therapy plus Cell immunotherapy	Pembrolizumab (DB09037); 	1	N/A	Case	Here we analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab to improve their efficacy. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report.	N/A	N/A	N/A	N/A	N/A	N/A	 2020 Jul 15	Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma.	 Nat Commun	Refractory metastatic rhabdomyosarcoma is largely incurable. Here we analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab to improve their efficacy. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report.
CANIT0003078	32681091	Clinical research	Estrogen receptor (ER)-positive breast cancer	Estrogen receptor-positive breast cancer	EFO:1000649	Breast	PD-1 (Q15116); HDAC (Q9UKV0); 	PD-1; HDAC	Pembrolizumab plus vorinostat	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); vorinostat (DB02546); 	34	N/A	Randomized phase II study	34 patients received vorinostat, tamoxifen and pembrolizumab with no excessive toxicity after progression on a median of five prior metastatic regimens. Objective response was 4% and clinical benefit rate (CR + PR + SD > 6 m) was 19%. T-cell exhaustion (CD8+ PD-1+/CTLA-4+) and treatment-induced depletion of regulatory T-cells (CD4+ Foxp3+/CTLA-4+) was seen in tumor or blood in 5/5 patients with clinical benefit, but only in one non-responder. Tumor lymphocyte infiltration was 0.17%. Only two non-responders had PD-L1 expression >1%. This data defines a novel immune signature in PD-L1-negative ER-positive breast cancer patients who are more likely to benefit from immune-checkpoint and histone deacetylase inhibition 	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2020 Jul 17	Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer.	 Nat Commun	Responses to immunotherapy are uncommon in estrogen receptor (ER)-positive breast cancer and to date, lack predictive markers. This randomized phase II study defines safety and response rate of epigenetic priming in ER-positive breast cancer patients treated with checkpoint inhibitors as primary endpoints. Secondary and exploratory endpoints included PD-L1 modulation and T-cell immune-signatures. 34 patients received vorinostat, tamoxifen and pembrolizumab with no excessive toxicity after progression on a median of five prior metastatic regimens. Objective response was 4% and clinical benefit rate (CR + PR + SD > 6 m) was 19%. T-cell exhaustion (CD8+ PD-1+/CTLA-4+) and treatment-induced depletion of regulatory T-cells (CD4+ Foxp3+/CTLA-4+) was seen in tumor or blood in 5/5 patients with clinical benefit, but only in one non-responder. Tumor lymphocyte infiltration was 0.17%. Only two non-responders had PD-L1 expression >1%. This data defines a novel immune signature in PD-L1-negative ER-positive breast cancer patients who are more likely to benefit from immune-checkpoint and histone deacetylase inhibition (NCT02395627).
CANIT0003079	32728772	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	837	N/A	Retrospective analysis	In multivariable analysis, age >= 65 years, lung cancer diagnosis, and inhaled corticosteroids (ICS) use remained statistically associated with the development of checkpoint inhibitor pneumonitis (CIP) , with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009).CONCLUSIONS: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age  >= 65 years and lung cancers as independent risk factors for CIP.	Checkpoint inhibitor pneumonitis	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2020 Nov	Brief report: inhaled corticosteroid use and the risk of checkpoint inhibitor pneumonitis in patients with advanced cancer.	 Cancer Immunol Immunother	BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that may complicate treatment with immune checkpoint inhibitors (ICI) and can cause significant morbidity. We sought to identify predictors for the development of CIP, and whether the use of inhaled corticosteroids (ICS) at time of ICI may be protective.METHODS: Patients with advanced cancer treated with ICI from 2011 and 2018 were included in this study. CIP attribution to ICI was determined by treating physician at time of diagnosis. Predictors were assessed by univariate and multivariable Cox proportional hazard models.RESULTS: We identified 837 pts treated with ICI, of whom 30 (3.6%) developed grade 2 or higher CIP. 82 patients (9.8%) were receiving ICS at time of ICI and had increased risk of developing CIP with hazard ration (HR) of 4.22 (95% CI 1.93-9.21, p < 0.001) compared to those patients not receiving ICS. Patients with age >= 65 years had increased risk of developing CIP (HR 2.12, 95% CI 1.02-4.40, p = 0.044), as did 209 patients with lung cancer (198 NSCLC and 11 SCLC) compared to other types of cancers (HR 3.15, 95% CI 1.54-6.46, p = 0.002). In multivariable analysis, age >= 65 years, lung cancer diagnosis, and ICS use remained statistically associated with the development of CIP, with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009).CONCLUSIONS: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age >= 65 years and lung cancers as independent risk factors for CIP.
CANIT0003080	32728772	Clinical research	Cancer	Cancer	EFO:0000311	Other	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); pembrolizumab (DB09037); nivolumab (DB09035); 	837	N/A	Retrospective analysis	In multivariable analysis, age >= 65 years, lung cancer diagnosis, and inhaled corticosteroids (ICS) use remained statistically associated with the development of checkpoint inhibitor pneumonitis (CIP) , with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009).CONCLUSIONS: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age  >= 65 years and lung cancers as independent risk factors for CIP.	Checkpoint inhibitor pneumonitis	N/A	N/A	Lung cancer (NCIT:C4878 ); 	Lung cancer	Disease status	 2020 Nov	Brief report: inhaled corticosteroid use and the risk of checkpoint inhibitor pneumonitis in patients with advanced cancer.	 Cancer Immunol Immunother	BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that may complicate treatment with immune checkpoint inhibitors (ICI) and can cause significant morbidity. We sought to identify predictors for the development of CIP, and whether the use of inhaled corticosteroids (ICS) at time of ICI may be protective.METHODS: Patients with advanced cancer treated with ICI from 2011 and 2018 were included in this study. CIP attribution to ICI was determined by treating physician at time of diagnosis. Predictors were assessed by univariate and multivariable Cox proportional hazard models.RESULTS: We identified 837 pts treated with ICI, of whom 30 (3.6%) developed grade 2 or higher CIP. 82 patients (9.8%) were receiving ICS at time of ICI and had increased risk of developing CIP with hazard ration (HR) of 4.22 (95% CI 1.93-9.21, p < 0.001) compared to those patients not receiving ICS. Patients with age >= 65 years had increased risk of developing CIP (HR 2.12, 95% CI 1.02-4.40, p = 0.044), as did 209 patients with lung cancer (198 NSCLC and 11 SCLC) compared to other types of cancers (HR 3.15, 95% CI 1.54-6.46, p = 0.002). In multivariable analysis, age >= 65 years, lung cancer diagnosis, and ICS use remained statistically associated with the development of CIP, with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009).CONCLUSIONS: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age >= 65 years and lung cancers as independent risk factors for CIP.
CANIT0003081	32829363	Case report	Stage IV gastric cancer	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by methylprednisolone	N/A	Immune checkpoint therapy	Nivolumab (DB09035); methylprednisolone (DB00959); 	1	N/A	Case	A 67-year-old man diagnosed with clinical Stage ¢ô gastric cancer was administered nivolumab as fourth-line chemotherapy. After 9 courses, he was emergently admitted with complaints of low blood pressure and general malaise. On the fourth hospital day, he had high-grade fever and elevated serum C-reactive protein. Computed tomography showed a moderate amount of pericardial effusion. He was administered 1.7 mg/kg of methylprednisolone and improved rapidly. A hormonal blood examination showed his adrenal gland disorder.	Pericardial effusion	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2020 Aug	[A Case of Gastric Cancer with Pericardial Effusion as an Immune-Reactive Adverse Events].	 Gan To Kagaku Ryoho	A 67-year-old man diagnosed with clinical Stage ¢ô gastric cancer was administered nivolumab as fourth-line chemotherapy. After 9 courses, he was emergently admitted with complaints of low blood pressure and general malaise. On the fourth hospital day, he had high-grade fever and elevated serum C-reactive protein. Computed tomography showed a moderate amount of pericardial effusion. He was administered 1.7 mg/kg of methylprednisolone and improved rapidly. A hormonal blood examination showed his adrenal gland disorder. This is the first case in our country of pericardial effusion as an immune-reactive adverse event, which is not well known in Japan.
CANIT0003082	32842245	Clinical research	Drug-resistant recurrent gestational trophoblastic neoplasia	Gestational trophoblastic neoplasia	Orphanet:59305	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	8	N/A	Retrospective analysis	After 2-3 courses of PD-1 inhibitor treatment, serum beta-hCG level came to normalization in 4 patients with drug-resistant recurrent gestational trophoblastic neoplasia (GTN). They were followed up for 2-7 months without any recurrence after 0-9 courses of consolidation treatment. One patient received 12 courses of PD-1 inhibitor treatment. The serum beta-hCG level normalized after the 6th courses but increased 1 months later, and then received bevacizumab treatment due to the progression of the disease. The remaining 3 patients received other chemotherapy regiments due to disease progression during PD-1 inhibitor treatment. PD-1 could be used as a remedial treatment for drug-resistant recurrent GTN, with a high effective rate and relatively mild adverse events (AE). However, more cases need to be accumulated clinically and efficacy should be comprehensively evaluated in combination with pathology and immunohistochemical examination.	N/A	N/A	N/A	Human chorionic gonadotropin (NCIT:C2275 ); 	Serum beta-hCG levels	Metabolite	 2020 Jun 25	[Preliminary study of PD-1 inhibitor in the treatment of drug-resistant recurrent gestational trophoblastic neoplasia].	 Zhonghua Fu Chan Ke Za Zhi	Objective: To investigate the therapeutic effect of programmed cell death receptor 1 (PD-1) inhibitor in drug-resistant recurrent gestational trophoblastic neoplasia (GTN). Methods: Clinicopathological features, previous treatments, PD-1 inhibitor treatment and prognosis of 8 patients with drug-resistant recurrent GTN treated with PD-1 inhibitor pembrolizumab£¬ in Peking Union Medical College Hospital of Chinese Academy of Medical Sciences from August 2018 to June 2019 were collected and retrospectively analyzed. Results: (1) Clinicopathological features: the average age of onset of 8 GTN patients was 32.9 years old (31-39 years old); pathological types: choriocarcinoma in 7 cases, epithelioid trophoblastic tumor in 1 case. International Federation of Gynecology and Obstetrics (FIGO) stages: stage III in 5 cases, stage ¢ô in 3 cases; FIGO score: 4 patients with 7-12 points (high-risk group) and 4 patients with >=13 points (ultra high-risk group). All the 8 patients had lung metastasis, 2 patients with brain metastasis, 1 patient with kidney and 1 patient with intestinal metastasis. (2) Previous treatments: ¢Ù Chemotherapy: 8 patients with GTN received an average of 21.1 courses (5-30 courses) of chemotherapy; the main route was systemic intravenous chemotherapy. One patient received intrathecal methotrexate chemotherapy due to brain metastasis. ¢Ú Surgery: 7 of 8 patients with GTN received surgical treatment, including 5 cases of pelvic surgury, 6 cases of pulmonary lobectomy and 1 case of right hemicolectomy. ¢Û Radiotherapy: 2 of 8 patients with GTN received radiotherapy, among which 1 patient received radiotherapy for lung for 8 times due to lung metastasis, and the other one received radiotherapy for lung, right sacroiliac joint and skull for a total of 22 times. (3) PD-1 inhibitor treatment: 8 patients with GTN received PD-1 inhibitor treatment with a mean course of 9 (2-12 courses). Six patients appeared ¢ñ-II grade of immune related adverse events (AE), and no severe AE occurred. (4) Prognosis: after 2-3 courses of PD-1 inhibitor treatment, serum ¦Â-hCG level came to normalization in 4 patients. They were followed up for 2-7 months without any recurrence after 0-9 courses of consolidation treatment. One patient received 12 courses of PD-1 inhibitor treatment. The serum ¦Â-hCG level normalized after the 6th courses but increased 1 months later, and then received bevacizumab treatment due to the progression of the disease. The remaining 3 patients received other chemotherapy regiments due to disease progression during PD-1 inhibitor treatment. Conclusions: PD-1 could be used as a remedial treatment for drug-resistant recurrent GTN, with a high effective rate and relatively mild AE. However, more cases need to be accumulated clinically and efficacy should be comprehensively evaluated in combination with pathology and immunohistochemical examination.
CANIT0003083	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003084	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Cutaneous lymphoma	MONDO:0018898	Blood and lymph nodes	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003085	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003086	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Duodenal carcinoma	MONDO:0021335	Intestines	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003087	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003088	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003089	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Merkel cell skin cancer	EFO:1001471	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003090	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003091	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Renal cell carcinoma	EFO:0000681	Kidney	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003092	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Skin carcinoma	EFO:0009259	Skin	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003093	29573850	Clinical research	Metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer (CRC), Hodgkin or cutaneous lymphoma, renal cell carcinoma (RCC), duodenal carcinoma, Merkel cell carcinoma, basal cell carcinoma of the skin, and squamous cell carcinoma of the skin.	Small cell lung carcinoma	EFO:0000702	Lung	CTLA-4 (P16410); PD-1 (Q15116); PD-L1 (Q9NZQ7); 	CTLA-4 ;  PD-1 ;  PD-L1 	Atezolizumab plus ipilimumab plus nivolumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); ipilimumab (DB06186); nivolumab (DB09035); 	30	N/A	N/A	Distinct inflammatory arthritis phenotypes may emerge with exposure to different immune checkpoint inhibitors regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Inflammatory arthritis	N/A	N/A	N/A	N/A	N/A	 2018 Dec	 Clinical presentation of immune checkpoint inhibitor-induced inflammatory  arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	 INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer  immunotherapy, increasingly utilized to treat malignancies. Inflammatory  arthritis (IA) is a potential consequence of ICI use, but there is limited  information to guide evaluation and management of this immune-related adverse  event (irAE). This study aimed to characterize clinical phenotypes, IA treatment   and response in the largest cohort of patients with ICI-induced IA reported to  date. METHODS: Patients with rheumatologist-confirmed IA occurring during or  after ICI treatment with no prior history of autoimmune disease were included.  Data were analyzed by ICI treatment regimen; treatments included combination  CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the   development of other irAEs, management of IA, and outcomes of IA management were   evaluated. RESULTS: Of 30 patients identified, those treated with combination ICI  therapy were more likely to present with knee arthritis, to have higher levels of  C-reactive protein, to have already had another irAE, and to have a reactive  arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were  more likely to have initial small joint involvement and to have IA as their only   irAE. Ten patients required additional immunosuppression beyond corticosteroids,   with TNF-inhibitors and/or methotrexate. Tumor progression while on  non-corticosteroid immunosuppression was not seen in those with initial tumor  response to ICIs. CONCLUSION: These data suggest that distinct IA phenotypes may   emerge with exposure to different ICI regimens. The majority of patients referred  to rheumatology required systemic immunosuppression to manage their IA symptoms.   Tumor progression was not seen in patients requiring TNF-inhibitors.CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
CANIT0003094	30273398	Clinical research	Metastatic melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	76	N/A	An observational multi-centre study.	The BMI correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients.	N/A	N/A	N/A	Body mass index (NCIT:C16358); 	Body mass index	Personal feature	2018	 Body mass index may predict the response to ipilimumab in metastatic melanoma: An  observational multi-centre study.	 PLoS One	 INTRODUCTION: Immunotherapy is a well-established treatment option in patients  with metastatic melanoma. However, biomarkers that can be used to predict a  response in these patients have not yet been found, putting patients at risk of  severe side effects. METHODS: In this retrospective analysis, we investigated the  association between the body mass index and ipilimumab treatment response in  patients with metastatic melanoma. Patients with metastatic melanoma who received  a monotherapy of up to 4 doses of ipilimumab (3 mg/kg) every 3 weeks from 2011 to  2014 in three major hospitals in Austria were included. Patients were classified   into two groups: normal group (BMI<25) and overweight group (BMI>/=25). RESULTS:   40 patients had a normal BMI, and 36 had a BMI above normal. Patients with a BMI   that was above normal showed significantly higher response rates (p = 0.024,  chi2), and lower likelihood of brain metastases (p = 0.012, chi2). No differences  were found between both groups with respect to gender (p = 0.324, chi2), T-stage   (p = 0.197, chi2), or the occurrence of side effects (p = 0.646, chi2). Patients   with a BMI above normal showed a trend towards longer overall survival (p =  0.056, Log-Rank), but no difference was found regarding progression-free survival  (p = 0.924, Log-Rank). CONCLUSIONS: The BMI correlated with the response to  ipilimumab treatment in a cohort of metastatic melanoma patients.
CANIT0003095	29573850	Clinical research	30  patients	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	6	N/A	Retrospective analysis	Of 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype.	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2018 Dec	Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy, increasingly utilized to treat malignancies. Inflammatory arthritis (IA) is a potential consequence of ICI use, but there is limited information to guide evaluation and management of this immune-related adverse event (irAE). This study aimed to characterize clinical phenotypes, IA treatment and response in the largest cohort of patients with ICI-induced IA reported to date.METHODS: Patients with rheumatologist-confirmed IA occurring during or after ICI treatment with no prior history of autoimmune disease were included. Data were analyzed by ICI treatment regimen; treatments included combination CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the development of other irAEs, management of IA, and outcomes of IA management were evaluated.RESULTS: Of 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.CONCLUSION: These data suggest that distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.
CANIT0003096	29573850	Clinical research	30  patients	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Durvalumab or nivolumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); nivolumab (DB09035); 	1	N/A	Retrospective analysis	Of 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype.	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2018 Dec	Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy, increasingly utilized to treat malignancies. Inflammatory arthritis (IA) is a potential consequence of ICI use, but there is limited information to guide evaluation and management of this immune-related adverse event (irAE). This study aimed to characterize clinical phenotypes, IA treatment and response in the largest cohort of patients with ICI-induced IA reported to date.METHODS: Patients with rheumatologist-confirmed IA occurring during or after ICI treatment with no prior history of autoimmune disease were included. Data were analyzed by ICI treatment regimen; treatments included combination CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the development of other irAEs, management of IA, and outcomes of IA management were evaluated.RESULTS: Of 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.CONCLUSION: These data suggest that distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.
CANIT0003097	29573850	Clinical research	30 patients	Non-small cell lung carcinoma	EFO:0003060	Lung	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	3	N/A	Retrospective analysis	Of 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype.	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2018 Dec	Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy, increasingly utilized to treat malignancies. Inflammatory arthritis (IA) is a potential consequence of ICI use, but there is limited information to guide evaluation and management of this immune-related adverse event (irAE). This study aimed to characterize clinical phenotypes, IA treatment and response in the largest cohort of patients with ICI-induced IA reported to date.METHODS: Patients with rheumatologist-confirmed IA occurring during or after ICI treatment with no prior history of autoimmune disease were included. Data were analyzed by ICI treatment regimen; treatments included combination CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the development of other irAEs, management of IA, and outcomes of IA management were evaluated.RESULTS: Of 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.CONCLUSION: These data suggest that distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.
CANIT0003098	29573850	Clinical research	30 patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Durvalumab or nivolumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); nivolumab (DB09035); 	9	N/A	Retrospective analysis	Of 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.	Those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype.	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2018 Dec	Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen.	 Semin Arthritis Rheum	INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a class of cancer immunotherapy, increasingly utilized to treat malignancies. Inflammatory arthritis (IA) is a potential consequence of ICI use, but there is limited information to guide evaluation and management of this immune-related adverse event (irAE). This study aimed to characterize clinical phenotypes, IA treatment and response in the largest cohort of patients with ICI-induced IA reported to date.METHODS: Patients with rheumatologist-confirmed IA occurring during or after ICI treatment with no prior history of autoimmune disease were included. Data were analyzed by ICI treatment regimen; treatments included combination CTLA-4/PD-1 inhibition, anti-PD-1 or anti-PD-L1 monotherapy. Relationship to the development of other irAEs, management of IA, and outcomes of IA management were evaluated.RESULTS: Of 30 patients identified, those treated with combination ICI therapy were more likely to present with knee arthritis, to have higher levels of C-reactive protein, to have already had another irAE, and to have a reactive arthritis-like phenotype. In contrast, patients treated with ICI monotherapy were more likely to have initial small joint involvement and to have IA as their only irAE. Ten patients required additional immunosuppression beyond corticosteroids, with TNF-inhibitors and/or methotrexate. Tumor progression while on non-corticosteroid immunosuppression was not seen in those with initial tumor response to ICIs.CONCLUSION: These data suggest that distinct IA phenotypes may emerge with exposure to different ICI regimens. The majority of patients referred to rheumatology required systemic immunosuppression to manage their IA symptoms. Tumor progression was not seen in patients requiring TNF-inhibitors.
CANIT0003099	29853658	Clinical research	Twenty-six patients	Biliary tract cancer	MONDO:0003060	Bilie duct	PD-1 (Q15116); VEGFR2 (P35968); 	PD-1; VEGFR2	Pembrolizumab plus ramucirumab	N/A	Immune checkpoint therapy plus Target therapy	Pembrolizumab (DB09037); ramucirumab (DB05578); 	26	N/A	Nonrandomized, open-label, phase I	Objective response rate was 4%. Median progression-free survival and overall survival were 1.6 months and 6.4 months, respectively.	Hypertension was the most common grade 3 treatment-related adverse event (TRAE), occurring in five patients. One patient experienced a grade 4 TRAE (neutropenia), and no treatment-related deaths occurred.	N/A	N/A	N/A	N/A	N/A	 2018 Dec	Ramucirumab Plus Pembrolizumab in Patients with Previously Treated Advanced or Metastatic Biliary Tract Cancer: Nonrandomized, Open-Label, Phase I Trial (JVDF).	 Oncologist	LESSONS LEARNED: Ramucirumab plus pembrolizumab revealed no unexpected safety findings in patients with advanced or metastatic biliary tract cancer, which is consistent with reports of other tumor cohorts within this phase Ia/b trial.Ramucirumab plus pembrolizumab did not demonstrate an improvement in overall survival when compared with historical controls in biomarker unselected, heavily pretreated patients with advanced or metastatic biliary tract cancer.Patients with programmed death-ligand 1 (PD-L1)-positive tumors had improved overall survival compared with patients with PD-L1-negative disease.BACKGROUND: Few treatment options exist for patients with advanced biliary tract cancer (BTC) following progression on gemcitabine-cisplatin. Preclinical evidence suggests that simultaneous blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) and programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) enhances antitumor effects. We assessed the safety and efficacy of ramucirumab, an IgG1 VEGFR-2 antagonist, with pembrolizumab, an IgG4 PD-1 antagonist, in biomarker-unselected patients with previously treated advanced or metastatic BTC.METHODS: Patients had previously treated advanced or metastatic adenocarcinoma of the gallbladder, intrahepatic and extrahepatic bile ducts, or ampulla of Vater. Ramucirumab 8 mg/kg was administered intravenously on days 1 and 8 with intravenous pembrolizumab 200 mg on day 1 every 3 weeks. The primary endpoint was safety and tolerability of the combination. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).RESULTS: Twenty-six patients were treated at 12 centers in five countries. Hypertension was the most common grade 3 treatment-related adverse event (TRAE), occurring in five patients. One patient experienced a grade 4 TRAE (neutropenia), and no treatment-related deaths occurred. Objective response rate was 4%. Median progression-free survival and overall survival were 1.6 months and 6.4 months, respectively.CONCLUSION: Ramucirumab-pembrolizumab showed limited clinical activity with infrequent grade 3-4 TRAEs in patients with biomarker-unselected progressive BTC.
CANIT0003100	29863795	Case report	A man in his 70s with a 3-year history of malignant melanoma complained of tingling in both hands	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A case of scleroderma-like syndrome following nivolumab that successfully resolved with oral corticosteroids	Scleroderma-like syndrome	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Scleroderma-like syndrome associated with nivolumab treatment in malignant melanoma.	 J Dermatol	Unable to provide
CANIT0003101	29984627	Case report	A 59-year-old Hispanic male	Squamous cell carcinoma	EFO:0000707	Other	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We report an unusual case of spontaneous intramuscular hematoma associated with antiproteinase 3 antibody in a patient with metastatic squamous cell carcinoma receiving nivolumab and the medical literature is reviewed	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jul	Spontaneous hematoma of the thigh associated with antiproteinase-3 antibody in a patient with metastatic squamous cell carcinoma treated with nivolumab.	 J Oncol Pharm Pract	We report an unusual case of spontaneous intramuscular hematoma associated with antiproteinase 3 antibody in a patient with metastatic squamous cell carcinoma receiving nivolumab and the medical literature is reviewed.
CANIT0003102	30035312	Case report	A man in his 50s with mucosal melanoma of the palate	Mucosal melanoma	MONDO:0000544	Soft tissue	PD-1 (Q15116); 	PD-1; 	Radiotherapy followed by Nivolumab	N/A	Radiotherapy followed by Immune checkpoint therapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	1	N/A	Case	A case of mucosal melanoma that did not respond to either nivolumab or ipilimumab monotherapy before RT but subsequently showed a remarkable clinical response when rechallenged with nivolumab after RT	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Successful rechallenge with nivolumab therapy after radiotherapy in mucosal melanoma.	 J Dermatol	Unable to provide
CANIT0003103	30058723	Clinical research	88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	88	N/A	N/A	When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.	N/A	N/A	N/A	CD40 (P25942); 	CD40 expression level	Gene expression signature on/in immune cell	 2019 Feb	A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.	 Clin Pharmacol Ther	To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.
CANIT0003104	30058723	Clinical research	88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	88	N/A	N/A	When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8(+) T lymphocytes	Gene expression signature on/in immune cell	 2019 Feb	A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.	 Clin Pharmacol Ther	To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.
CANIT0003105	30058723	Clinical research	88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	88	N/A	N/A	When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Feb	A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.	 Clin Pharmacol Ther	To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.
CANIT0003106	30058723	Clinical research	88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	88	N/A	N/A	When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.	N/A	N/A	N/A	IL18 (Q14116); 	Relative change in IL18	Gene expression signature in serum	 2019 Feb	A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.	 Clin Pharmacol Ther	To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.
CANIT0003107	30058723	Clinical research	88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	88	N/A	N/A	When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2019 Feb	A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.	 Clin Pharmacol Ther	To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.
CANIT0003108	30058723	Clinical research	88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	88	N/A	N/A	When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Number of metastatic sites	Disease status	2019 Feb	A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.	Clin Pharmacol Ther. 	To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.
CANIT0003109	30058723	Clinical research	88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	88	N/A	N/A	When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.	N/A	N/A	N/A	Smoking status ()	Smoking status	Exposure factors/status	 2019 Feb	A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.	 Clin Pharmacol Ther	To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.
CANIT0003110	30058723	Clinical research	88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) 	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	88	N/A	N/A	When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.	N/A	N/A	N/A	VCAM1 (P19320); 	Vascular cell adhesion molecule 1 (VCAM©\1) expression levels	Gene expression signature on/in tumor cell	 2019 Feb	A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.	 Clin Pharmacol Ther	To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL -18,d21 ). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL -18,d21 seemed relevant to the duration of the response.
CANIT0003111	30086678	Case report	Stevens-Johnson syndrome/toxic epidermal necrolysis	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	In our patient, the etiology of SJS was likely due to pembrolizumab therapy, with a Naranjo nomogram score of 6 (indicating a probable cause). Her other medications have not been reported in the literature as causative agents. Interestingly, she developed SJS late in the course of therapy after having tolerated several months of treatment. It is therefore important to note that this type of reaction does not necessarily always present at the initiation of therapy, and that initial tolerance to therapy does not preclude a later development of a life-threatening adverse reaction such as SJS/TEN	Several patches of painful, non-pruritic erythematous papules were distributed along her hands, feet, and knees bilaterally	N/A	N/A	N/A	N/A	N/A	 2019 Sep	Stevens-Johnson syndrome manifesting late in the course of pembrolizumab therapy.	 J Oncol Pharm Pract	Pembrolizumab is a humanized antibody that targets programmed cell death receptor-1. This agent is approved for use in the treatment of several malignancies. While pruritus and papulo-erythematous rash are not uncommon with its use, severe reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis are very rare. We present herein a case of Stevens-Johnson syndrome occurring in a patient who had previously tolerated pembrolizumab without significant side effects for seven months. Prompt recognition of Stevens-Johnson syndrome/toxic epidermal necrolysis and discontinuation of the offending agent are paramount to ensure a favorable outcome.
CANIT0003112	30128737	Clinical research	20 patients 	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	Dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Tim-3 (Q8TDQ0); T-Lymphocyte (NCIT:C12476); 	Elevations in %Tim-3(+)CD4 T-cell 	Gene expression signature on/in immune cell	 2018 Nov	Increased Tim-3(+) T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients.	 Cancer Immunol Immunother	The recent development of immune checkpoint inhibitors for many types of cancers has prompted us to identify markers that predict patients with clinical benefits. Several trials on nivolumab for the treatment of esophageal squamous cell carcinoma (ESCC) have been performed worldwide, and the identification of markers specific to ESCC is urgently needed. We conducted a clinical trial on nivolumab for advanced ESCC (JapicCTI-No.142422) and investigated markers using peripheral blood collected from 20 patients enrolled in our institute, including 1 with a complete response (CR), 5 with a partial response (PR), 6 with a stable disease (SD), and 8 with a progressive disease (PD) as clinical responses. The expression of surface molecules and cytokine production by T cells were analyzed using flow cytometry, and clinicopathological factors and general blood parameters were examined. Albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA-CD27-, and IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients. When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden. Among them, elevations in %Tim-3+CD4 had a marked impact on survival rates. In conclusion, dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients.
CANIT0003113	30128737	Clinical research	20 patients 	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	Albumin after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Albumin (P02768); 	Albumin concentrations	Gene expression signature on/in immune cell	 2018 Nov	Increased Tim-3(+) T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients.	 Cancer Immunol Immunother	The recent development of immune checkpoint inhibitors for many types of cancers has prompted us to identify markers that predict patients with clinical benefits. Several trials on nivolumab for the treatment of esophageal squamous cell carcinoma (ESCC) have been performed worldwide, and the identification of markers specific to ESCC is urgently needed. We conducted a clinical trial on nivolumab for advanced ESCC (JapicCTI-No.142422) and investigated markers using peripheral blood collected from 20 patients enrolled in our institute, including 1 with a complete response (CR), 5 with a partial response (PR), 6 with a stable disease (SD), and 8 with a progressive disease (PD) as clinical responses. The expression of surface molecules and cytokine production by T cells were analyzed using flow cytometry, and clinicopathological factors and general blood parameters were examined. Albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA-CD27-, and IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients. When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden. Among them, elevations in %Tim-3+CD4 had a marked impact on survival rates. In conclusion, dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients.
CANIT0003114	30128737	Clinical research	20 patients 	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	Neutrophil counts after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2018 Nov	Increased Tim-3(+) T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients.	 Cancer Immunol Immunother	The recent development of immune checkpoint inhibitors for many types of cancers has prompted us to identify markers that predict patients with clinical benefits. Several trials on nivolumab for the treatment of esophageal squamous cell carcinoma (ESCC) have been performed worldwide, and the identification of markers specific to ESCC is urgently needed. We conducted a clinical trial on nivolumab for advanced ESCC (JapicCTI-No.142422) and investigated markers using peripheral blood collected from 20 patients enrolled in our institute, including 1 with a complete response (CR), 5 with a partial response (PR), 6 with a stable disease (SD), and 8 with a progressive disease (PD) as clinical responses. The expression of surface molecules and cytokine production by T cells were analyzed using flow cytometry, and clinicopathological factors and general blood parameters were examined. Albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA-CD27-, and IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients. When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden. Among them, elevations in %Tim-3+CD4 had a marked impact on survival rates. In conclusion, dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients.
CANIT0003115	30128737	Clinical research	20 patients 	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	%OX40  T-cells after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	OX40 (P43488); T-Lymphocyte (NCIT:C12476); 	OX40 T-cells	Gene expression signature on/in immune cell	 2018 Nov	Increased Tim-3(+) T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients.	 Cancer Immunol Immunother	The recent development of immune checkpoint inhibitors for many types of cancers has prompted us to identify markers that predict patients with clinical benefits. Several trials on nivolumab for the treatment of esophageal squamous cell carcinoma (ESCC) have been performed worldwide, and the identification of markers specific to ESCC is urgently needed. We conducted a clinical trial on nivolumab for advanced ESCC (JapicCTI-No.142422) and investigated markers using peripheral blood collected from 20 patients enrolled in our institute, including 1 with a complete response (CR), 5 with a partial response (PR), 6 with a stable disease (SD), and 8 with a progressive disease (PD) as clinical responses. The expression of surface molecules and cytokine production by T cells were analyzed using flow cytometry, and clinicopathological factors and general blood parameters were examined. Albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA-CD27-, and IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients. When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden. Among them, elevations in %Tim-3+CD4 had a marked impact on survival rates. In conclusion, dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients.
CANIT0003116	30128737	Clinical research	20 patients 	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	%CD103  T-cells after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD103 (P38570); T-Lymphocyte (NCIT:C12476); 	CD103 T-cells	Gene expression signature on/in immune cell	 2018 Nov	Increased Tim-3(+) T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients.	 Cancer Immunol Immunother	The recent development of immune checkpoint inhibitors for many types of cancers has prompted us to identify markers that predict patients with clinical benefits. Several trials on nivolumab for the treatment of esophageal squamous cell carcinoma (ESCC) have been performed worldwide, and the identification of markers specific to ESCC is urgently needed. We conducted a clinical trial on nivolumab for advanced ESCC (JapicCTI-No.142422) and investigated markers using peripheral blood collected from 20 patients enrolled in our institute, including 1 with a complete response (CR), 5 with a partial response (PR), 6 with a stable disease (SD), and 8 with a progressive disease (PD) as clinical responses. The expression of surface molecules and cytokine production by T cells were analyzed using flow cytometry, and clinicopathological factors and general blood parameters were examined. Albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA-CD27-, and IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients. When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden. Among them, elevations in %Tim-3+CD4 had a marked impact on survival rates. In conclusion, dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients.
CANIT0003117	30128737	Clinical research	20 patients 	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	%CD45RA-CD27 T-cells after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	CD45 (P08575); CD27 (P26842); T-Lymphocyte (NCIT:C12476); 	CD45RA-CD27 T-cells	Gene expression signature on/in immune cell	 2018 Nov	Increased Tim-3(+) T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients.	 Cancer Immunol Immunother	The recent development of immune checkpoint inhibitors for many types of cancers has prompted us to identify markers that predict patients with clinical benefits. Several trials on nivolumab for the treatment of esophageal squamous cell carcinoma (ESCC) have been performed worldwide, and the identification of markers specific to ESCC is urgently needed. We conducted a clinical trial on nivolumab for advanced ESCC (JapicCTI-No.142422) and investigated markers using peripheral blood collected from 20 patients enrolled in our institute, including 1 with a complete response (CR), 5 with a partial response (PR), 6 with a stable disease (SD), and 8 with a progressive disease (PD) as clinical responses. The expression of surface molecules and cytokine production by T cells were analyzed using flow cytometry, and clinicopathological factors and general blood parameters were examined. Albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA-CD27-, and IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients. When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden. Among them, elevations in %Tim-3+CD4 had a marked impact on survival rates. In conclusion, dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients.
CANIT0003118	30128737	Clinical research	20 patients 	Esophageal squamous cell carcinoma	EFO:0005922	Esophagus	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	20	N/A	N/A	IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients.	N/A	ECO:0007695 - cell-based assay evidence used in manual assertion	N/A	IL1B (P01584); 	Baseline serum IL1B levels	Gene expression signature in serum	 2018 Nov	Increased Tim-3(+) T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients.	 Cancer Immunol Immunother	The recent development of immune checkpoint inhibitors for many types of cancers has prompted us to identify markers that predict patients with clinical benefits. Several trials on nivolumab for the treatment of esophageal squamous cell carcinoma (ESCC) have been performed worldwide, and the identification of markers specific to ESCC is urgently needed. We conducted a clinical trial on nivolumab for advanced ESCC (JapicCTI-No.142422) and investigated markers using peripheral blood collected from 20 patients enrolled in our institute, including 1 with a complete response (CR), 5 with a partial response (PR), 6 with a stable disease (SD), and 8 with a progressive disease (PD) as clinical responses. The expression of surface molecules and cytokine production by T cells were analyzed using flow cytometry, and clinicopathological factors and general blood parameters were examined. Albumin, neutrophils, %Tim3, %OX40, %CD103, %CD45RA-CD27-, and IL-1b after the first cycle of nivolumab treatment, but not at baseline, distinguished CR/PR from SD/PD patients. When markers to distinguish longer survivors with nivolumab therapy were analyzed, changes in these levels between baseline and after the first cycle of nivolumab treatment, but not levels at each period, were indicative, similar to the tumor burden. Among them, elevations in %Tim-3+CD4 had a marked impact on survival rates. In conclusion, dynamic elevations in %Tim-3 in T cells in the early period of nivolumab therapy have potential as a marker for the clinical responses and prognosis of advanced ESCC patients.
CANIT0003119	30131507	Case report	A 22-year-old woman	B-cell lymphoma	EFO:1001938	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by allogeneic hematopoietic cell transplantation	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	All three patients, however, developed severe ES and steroid-dependent GVHD. This suggested that avoidance of peripheral blood stem cells and 7-week interval from the last administration of nivolumab were not sufficient to reduce severe immune toxicities  	Severe ES accompanied by respiratory failure	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Severe immune-related complications early after allogeneic hematopoietic cell transplantation for nivolumab-pretreated lymphoma.	 Bone Marrow Transplant	Unable to provide
CANIT0003120	30131507	Case report	A 40-year-old woman	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by allogeneic hematopoietic cell transplantation	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	All three patients, however, developed severe ES and steroid-dependent GVHD. This suggested that avoidance of peripheral blood stem cells and 6-week interval from the last administration of nivolumab were not sufficient to reduce severe immune toxicities in allo-HCT after PD-1 blockade	Severe ES accompanied by respiratory failure	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Severe immune-related complications early after allogeneic hematopoietic cell transplantation for nivolumab-pretreated lymphoma.	 Bone Marrow Transplant	Unable to provide
CANIT0003121	30131507	Case report	A 43-year-old man	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by allogeneic hematopoietic cell transplantation	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	All three patients, however, developed severe ES and steroid-dependent GVHD. This suggested that avoidance of peripheral blood stem cells and 8-week interval from the last administration of nivolumab were not sufficient to reduce severe immune toxicities  	Severe ES accompanied by respiratory failure	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Severe immune-related complications early after allogeneic hematopoietic cell transplantation for nivolumab-pretreated lymphoma.	 Bone Marrow Transplant	Unable to provide
CANIT0003122	30219915	Clinical research	Thirty-two patients were enrolled	Head and neck carcinoma	MONDO:0002038	Head and neck	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	32	N/A	Phase I	Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level.	Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported	N/A	N/A	HPV (NCIT:C14226); 	HPV-positive	Microbiota	 2018 Nov 1	Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial.	 Ann Oncol	BACKGROUND: Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial.PATIENTS AND METHODS: Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated.RESULTS: Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had >=2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level.CONCLUSIONS: In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC. ClinicalTrials.gov number: NCT01375842.
CANIT0003123	30219915	Clinical research	Thirty-two patients were enrolled	Head and neck carcinoma	MONDO:0002038	Head and neck	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab 	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	32	N/A	Phase I	Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level.	Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2018 Nov 1	Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial.	 Ann Oncol	BACKGROUND: Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial.PATIENTS AND METHODS: Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated.RESULTS: Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had >=2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level.CONCLUSIONS: In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC. ClinicalTrials.gov number: NCT01375842.
CANIT0003124	30229873	Case report	Melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	The case confirms the hypothesis of immune responses targeting shared antigens between malignant and benign melanocytic lesions	Vitiligo	N/A	N/A	N/A	N/A	N/A	 2019 Jun	Multiple halo nevi occurring during pembrolizumab treatment for metastatic melanoma.	 Int J Dermatol	Unable to provide
CANIT0003125	30267200	Clinical research	Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy.	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	15	N/A	N/A	Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) mature-myeloid-derived suppressor cells, while doses of anti-PD1 correlated with decreased %PD1+mature- and immature- myeloid-derived suppressor cells. Although pre-treatment %PD1+ cytotoxic T lymphocytes did not predict response, a greater %PD1+ cytotoxic T lymphocytes within 9 weeks after ICI initiation correlated with objective response.Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.	N/A	N/A	N/A	PD-1 (Q15116); myeloid-derived suppressor cell counts ()	Decreased percentage of PD1(+)mature- and immature- myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2018 Oct	Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.	 Target Oncol	BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Gu¨¦rin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
CANIT0003126	30267200	Clinical research	Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy.	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	15	N/A	N/A	Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) mature-myeloid-derived suppressor cells, while doses of anti-PD1 correlated with decreased %PD1+mature- and immature- myeloid-derived suppressor cells. Although pre-treatment %PD1+ cytotoxic T lymphocytes did not predict response, a greater %PD1+ cytotoxic T lymphocytes within 9 weeks after ICI initiation correlated with objective response.Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.	N/A	N/A	N/A	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	Percentage of PD1(+) cytotoxic T lymphocytes	Gene expression signature on/in immune cell	 2018 Oct	Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.	 Target Oncol	BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Gu¨¦rin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
CANIT0003127	30267200	Clinical research	Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy.	Urothelial carcinoma	EFO:0008528	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	15	N/A	N/A	Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) mature-myeloid-derived suppressor cells, while doses of anti-PD1 correlated with decreased %PD1+mature- and immature- myeloid-derived suppressor cells. Although pre-treatment %PD1+ cytotoxic T lymphocytes did not predict response, a greater %PD1+ cytotoxic T lymphocytes within 9 weeks after ICI initiation correlated with objective response.Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); myeloid-derived suppressor cell counts ()	Decreased percentage of PDL1(+) (%PDL1(+)) mature-myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2018 Oct	Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.	 Target Oncol	BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Gu¨¦rin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
CANIT0003128	30267200	Clinical research	Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy.	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	23	N/A	N/A	Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) mature-myeloid-derived suppressor cells, while doses of anti-PD1 correlated with decreased %PD1+mature- and immature- myeloid-derived suppressor cells. Although pre-treatment %PD1+ cytotoxic T lymphocytes did not predict response, a greater %PD1+ cytotoxic T lymphocytes within 9 weeks after ICI initiation correlated with objective response.Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.	N/A	N/A	N/A	PD-1 (Q15116); myeloid-derived suppressor cell counts ()	Decreased percentage of PD1(+)mature- and immature- myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2018 Oct	Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.	 Target Oncol	BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Gu¨¦rin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
CANIT0003129	30267200	Clinical research	Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy.	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	23	N/A	N/A	Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) mature-myeloid-derived suppressor cells, while doses of anti-PD1 correlated with decreased %PD1+mature- and immature- myeloid-derived suppressor cells. Although pre-treatment %PD1+ cytotoxic T lymphocytes did not predict response, a greater %PD1+ cytotoxic T lymphocytes within 9 weeks after ICI initiation correlated with objective response.Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.	N/A	N/A	N/A	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	Percentage of PD1(+) cytotoxic T lymphocytes	Gene expression signature on/in immune cell	 2018 Oct	Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.	 Target Oncol	BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Gu¨¦rin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
CANIT0003130	30267200	Clinical research	Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy.	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	N/A	Immune checkpoint therapy	Atezolizumab (DB11595); 	23	N/A	N/A	Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) mature-myeloid-derived suppressor cells, while doses of anti-PD1 correlated with decreased %PD1+mature- and immature- myeloid-derived suppressor cells. Although pre-treatment %PD1+ cytotoxic T lymphocytes did not predict response, a greater %PD1+ cytotoxic T lymphocytes within 9 weeks after ICI initiation correlated with objective response.Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); myeloid-derived suppressor cell counts ()	Decreased percentage of PDL1(+) (%PDL1(+)) mature-myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2018 Oct	Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.	 Target Oncol	BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Gu¨¦rin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
CANIT0003131	30267200	Clinical research	Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy.	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	3	N/A	N/A	Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) mature-myeloid-derived suppressor cells, while doses of anti-PD1 correlated with decreased %PD1+mature- and immature- myeloid-derived suppressor cells. Although pre-treatment %PD1+ cytotoxic T lymphocytes did not predict response, a greater %PD1+ cytotoxic T lymphocytes within 9 weeks after ICI initiation correlated with objective response.Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.	N/A	N/A	N/A	PD-1 (Q15116); myeloid-derived suppressor cell counts ()	Decreased percentage of PD1(+)mature- and immature- myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2018 Oct	Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.	 Target Oncol	BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Gu¨¦rin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
CANIT0003132	30267200	Clinical research	Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy.	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	3	N/A	N/A	Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) mature-myeloid-derived suppressor cells, while doses of anti-PD1 correlated with decreased %PD1+mature- and immature- myeloid-derived suppressor cells. Although pre-treatment %PD1+ cytotoxic T lymphocytes did not predict response, a greater %PD1+ cytotoxic T lymphocytes within 9 weeks after ICI initiation correlated with objective response.Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.	N/A	N/A	N/A	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	Percentage of PD1(+) cytotoxic T lymphocytes	Gene expression signature on/in immune cell	 2018 Oct	Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.	 Target Oncol	BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Gu¨¦rin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
CANIT0003133	30267200	Clinical research	Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy.	Urothelial carcinoma	EFO:0008528	Bladder	PD-L1 (Q9NZQ7); 	PD-L1; 	Avelumab	N/A	Immune checkpoint therapy	Avelumab (DB11945); 	3	N/A	N/A	Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) mature-myeloid-derived suppressor cells, while doses of anti-PD1 correlated with decreased %PD1+mature- and immature- myeloid-derived suppressor cells. Although pre-treatment %PD1+ cytotoxic T lymphocytes did not predict response, a greater %PD1+ cytotoxic T lymphocytes within 9 weeks after ICI initiation correlated with objective response.Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); myeloid-derived suppressor cell counts ()	Decreased percentage of PDL1(+) (%PDL1(+)) mature-myeloid-derived suppressor cells	Gene expression signature on/in immune cell	 2018 Oct	Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.	 Target Oncol	BACKGROUND: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.OBJECTIVE: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).PATIENTS AND METHODS: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33+HLADR-) and CTL (CD8+CD4-) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14+CD15-), polymorphonuclear (PMN)-MDSC (CD14-CD15+), and immature (I)-MDSC (CD14-CD15-). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.RESULTS: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Gu¨¦rin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1+ (%PDL1+) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1+ M- and I-MDSC. Although pre-treatment %PD1+ CTL did not predict response, a greater %PD1+ CTL within 9 weeks after ICI initiation correlated with objective response.CONCLUSIONS: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.
CANIT0003134	30273233	Clinical research	82 metastatic melanoma 	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus pembrolizumab	Anti-PD1 monotherapy	Immune checkpoint therapy	Ipilimumab (DB06186); Pembrolizumab (DB09037); 	25	82	N/A	Of the 25 patients, 88% developed new cutaneous lesions since the treatment. Immune-related lesions; lichenoid reaction (64%) and vitiligo (28%) were the most frequent. The incidence of lichenoid reaction increased rapidly in the early phase of treatment. Approximately one-third developed their first lichenoid reaction within 12 days of commencing treatment in combination group compared to 14 months in the anti-PD1 monotherapy. The rate of incidence of vitiligo was comparable in both groups. There was no statistical significance in the development of cutaneous toxicities and the treatment response between the two groups. The time taken to develop immune-related cutaneous toxicities was shorter for those on combination therapy versus anti-PD1 monotherapy. Unlike cutaneous ir-AEs that appear in patients on antiPD1 monotherapy, similar ir-AEs appear earlier and more rapidly in the combination therapy group. Hence, we recommend intense dermatological surveillance earlier in the treatment for patients who are on the combination therapy.	Cutaneous toxicities	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Cutaneous adverse events of anti-programmed death 1 antibodies combined with anti-cytotoxic T-lymphocyte-associated protein 4 therapy use in patients with metastatic melanoma.	 Melanoma Res	To date, cutaneous toxicities of combination therapies of anti-programmed death-1 (anti-PD1) and ipilimumab are poorly described. Understanding cutaneous presentations will aid clinicians with early diagnoses and treatments. We aim to describe and compare the cutaneous toxicities between the combination therapies and anti-PD1 monotherapy. This is a cohort study comparing previously published data on 82 patients with metastatic melanoma on anti-PD1 monotherapy, with a new group of 25 patients with metastatic melanoma receiving combined ipilimumab and pembrolizumab between January 2015 to February 2016. A single institution, internal referrals were received from medical oncology teams from May 2012 to February 2015 for the anti-PD1 monotherapy group and from January 2015 to February 2016 for combination group. All patients who were treated with either anti-PD1 therapy or combination therapies during the timeframe within the institution were included in the study. Kaplan-Meier curves were used to illustrate the time taken to develop cutaneous toxicities in the monotherapy and combination groups. Of the 25 patients, 88% developed new cutaneous lesions since the treatment. Immune-related lesions; lichenoid reaction (64%) and vitiligo (28%) were the most frequent. The incidence of lichenoid reaction increased rapidly in the early phase of treatment. Approximately one-third developed their first lichenoid reaction within 12 days of commencing treatment in combination group compared to 14 months in the anti-PD1 monotherapy. The rate of incidence of vitiligo was comparable in both groups. There was no statistical significance in the development of cutaneous toxicities and the treatment response between the two groups. The time taken to develop immune-related cutaneous toxicities was shorter for those on combination therapy versus anti-PD1 monotherapy.
CANIT0003135	30273398	Clinical research	Seventy-six patients were included in this retrospective analysis: 30 female patients (39.5%), 13 (43.4%) of whom were overweight, and 46 (60.5%) male patients, 23 (50.0%) of whom were overweight	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	76	N/A	Retrospective analysis	No differences were found between both groups with respect to T-stage (p = 0.197, |?2).	Inflammation	N/A	N/A	AJCC stage (NCIT:C39315 ); 	T-stage	Disease status	 2018 Oct 1	Body mass index may predict the response to ipilimumab in metastatic melanoma: An observational multi-centre study.	 PLoS One	INTRODUCTION: Immunotherapy is a well-established treatment option in patients with metastatic melanoma. However, biomarkers that can be used to predict a response in these patients have not yet been found, putting patients at risk of severe side effects.METHODS: In this retrospective analysis, we investigated the association between the body mass index and ipilimumab treatment response in patients with metastatic melanoma. Patients with metastatic melanoma who received a monotherapy of up to 4 doses of ipilimumab (3 mg/kg) every 3 weeks from 2011 to 2014 in three major hospitals in Austria were included. Patients were classified into two groups: normal group (BMI<25) and overweight group (BMI>=25).RESULTS: 40 patients had a normal BMI, and 36 had a BMI above normal. Patients with a BMI that was above normal showed significantly higher response rates (p = 0.024, x2), and lower likelihood of brain metastases (p = 0.012, x2). No differences were found between both groups with respect to gender (p = 0.324, x2), T-stage (p = 0.197, x2), or the occurrence of side effects (p = 0.646, x2). Patients with a BMI above normal showed a trend towards longer overall survival (p = 0.056, Log-Rank), but no difference was found regarding progression-free survival (p = 0.924, Log-Rank).CONCLUSIONS: The BMI correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients.
CANIT0003136	30273398	Clinical research	Seventy-six patients were included in this retrospective analysis: 30 female patients (39.5%), 13 (43.4%) of whom were overweight, and 46 (60.5%) male patients, 23 (50.0%) of whom were overweight	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	76	N/A	Retrospective analysis	The Body mass index correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients	Inflammation	N/A	N/A	Body mass index (NCIT:C16358); 	Body mass index	Personal feature	 2018 Oct 1	Body mass index may predict the response to ipilimumab in metastatic melanoma: An observational multi-centre study.	 PLoS One	INTRODUCTION: Immunotherapy is a well-established treatment option in patients with metastatic melanoma. However, biomarkers that can be used to predict a response in these patients have not yet been found, putting patients at risk of severe side effects.METHODS: In this retrospective analysis, we investigated the association between the body mass index and ipilimumab treatment response in patients with metastatic melanoma. Patients with metastatic melanoma who received a monotherapy of up to 4 doses of ipilimumab (3 mg/kg) every 3 weeks from 2011 to 2014 in three major hospitals in Austria were included. Patients were classified into two groups: normal group (BMI<25) and overweight group (BMI>=25).RESULTS: 40 patients had a normal BMI, and 36 had a BMI above normal. Patients with a BMI that was above normal showed significantly higher response rates (p = 0.024, x2), and lower likelihood of brain metastases (p = 0.012, x2). No differences were found between both groups with respect to gender (p = 0.324, x2), T-stage (p = 0.197, x2), or the occurrence of side effects (p = 0.646, x2). Patients with a BMI above normal showed a trend towards longer overall survival (p = 0.056, Log-Rank), but no difference was found regarding progression-free survival (p = 0.924, Log-Rank).CONCLUSIONS: The BMI correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients.
CANIT0003137	30273398	Clinical research	Seventy-six patients were included in this retrospective analysis: 30 female patients (39.5%), 13 (43.4%) of whom were overweight, and 46 (60.5%) male patients, 23 (50.0%) of whom were overweight	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	76	N/A	Retrospective analysis	No differences were found between both groups with respect to gender (p = 0.324, |?2).	Inflammation	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2018 Oct 1	Body mass index may predict the response to ipilimumab in metastatic melanoma: An observational multi-centre study.	 PLoS One	INTRODUCTION: Immunotherapy is a well-established treatment option in patients with metastatic melanoma. However, biomarkers that can be used to predict a response in these patients have not yet been found, putting patients at risk of severe side effects.METHODS: In this retrospective analysis, we investigated the association between the body mass index and ipilimumab treatment response in patients with metastatic melanoma. Patients with metastatic melanoma who received a monotherapy of up to 4 doses of ipilimumab (3 mg/kg) every 3 weeks from 2011 to 2014 in three major hospitals in Austria were included. Patients were classified into two groups: normal group (BMI<25) and overweight group (BMI>=25).RESULTS: 40 patients had a normal BMI, and 36 had a BMI above normal. Patients with a BMI that was above normal showed significantly higher response rates (p = 0.024, x2), and lower likelihood of brain metastases (p = 0.012, x2). No differences were found between both groups with respect to gender (p = 0.324, x2), T-stage (p = 0.197, x2), or the occurrence of side effects (p = 0.646, x2). Patients with a BMI above normal showed a trend towards longer overall survival (p = 0.056, Log-Rank), but no difference was found regarding progression-free survival (p = 0.924, Log-Rank).CONCLUSIONS: The BMI correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients.
CANIT0003138	30273398	Clinical research	Seventy-six patients were included in this retrospective analysis: 30 female patients (39.5%), 13 (43.4%) of whom were overweight, and 46 (60.5%) male patients, 23 (50.0%) of whom were overweight	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	76	N/A	Retrospective analysis	No differences were found between both groups with respect to the occurrence of side effects (p = 0.646, |?2).	Inflammation	N/A	N/A	Immune-related adverse events (NCIT:C131137); 	The occurrence of side effects	Adverse events	 2018 Oct 1	Body mass index may predict the response to ipilimumab in metastatic melanoma: An observational multi-centre study.	 PLoS One	INTRODUCTION: Immunotherapy is a well-established treatment option in patients with metastatic melanoma. However, biomarkers that can be used to predict a response in these patients have not yet been found, putting patients at risk of severe side effects.METHODS: In this retrospective analysis, we investigated the association between the body mass index and ipilimumab treatment response in patients with metastatic melanoma. Patients with metastatic melanoma who received a monotherapy of up to 4 doses of ipilimumab (3 mg/kg) every 3 weeks from 2011 to 2014 in three major hospitals in Austria were included. Patients were classified into two groups: normal group (BMI<25) and overweight group (BMI>=25).RESULTS: 40 patients had a normal BMI, and 36 had a BMI above normal. Patients with a BMI that was above normal showed significantly higher response rates (p = 0.024, x2), and lower likelihood of brain metastases (p = 0.012, x2). No differences were found between both groups with respect to gender (p = 0.324, x2), T-stage (p = 0.197, x2), or the occurrence of side effects (p = 0.646, x2). Patients with a BMI above normal showed a trend towards longer overall survival (p = 0.056, Log-Rank), but no difference was found regarding progression-free survival (p = 0.924, Log-Rank).CONCLUSIONS: The BMI correlated with the response to ipilimumab treatment in a cohort of metastatic melanoma patients.
CANIT0003139	30280641	Clinical research	201 Extensive-Stage Small-Cell Lung Cancer patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group	Small cell lung carcinoma	EFO:0000702	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab plus carboplatin plus etoposide	Placebo plus carboplatin plus etoposide	Immune checkpoint therapy plus Chemotherapy	Atezolizumab (DB11595); carboplatin (DB00958); etoposide (DB00773); 	201	202	Double-blind, placebo-controlled, phase III	At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02).	The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed.	N/A	N/A	N/A	N/A	N/A	 2018 Dec 6	First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer.	 N Engl J Med	BACKGROUND: Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy.METHODS: We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population.RESULTS: A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed.CONCLUSIONS: The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).
CANIT0003140	30299577	Case report	A 57-year-old male with with metastatic uveal melanoma	Uveal melanoma	EFO:1000616	Eye	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	Although response rates to immunotherapy in uveal melanoma are generally poor, some patients benefit significantly from this treatment approach	Vitiligo, leucotrichia	N/A	N/A	N/A	N/A	N/A	 2018 Nov	Complete response to pembrolizumab after initial progress in a patient with metastatic uveal melanoma.	 J Dtsch Dermatol Ges	Unable to provide
CANIT0003141	30307363	Case report	An 84-year old woman	Peripheral T-cell lymphoma	MONDO:0019471	Blood and lymph nodes	PD-1 (Q15116); VEGFR2 (P35968); 	PD-1; VEGFR2	Nivolumab plus trametinib	N/A	Immune checkpoint therapy plus Target therapy	Nivolumab (DB09035); trametinib (DB08911); 	1	N/A	Case	The patient was discussed in Molecular Tumor Board with consensus opinion favoring a combination of the MEK inhibitor trametinib (for the NRAS alteration) and the checkpoint inhibitor nivolumab for the elevated mutational burden and PD-L1 positivity. Her abdominal pain resolved and she achieved a complete remission ongoing at 5+ months.	Side effects at five months included only low-grade rash and peripheral edema.	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	2019	Successful implementation of genomically based treatment of chemotherapy refractory peripheral T-cell lymphoma (PTCL).	 Cancer Biol Ther	BACKGROUND: The treatment of peripheral T-cell lymphoma (PTCL) after failure of standard therapy represents a significant clinical challenge as the best approach has not been defined. The outcomes of patients with peripheral T-cell lymphoma (PTCL) after relapse, in the absence of hematopoietic stem-cell transplantation, are poor with median overall survival is less than six months. Thus, relapsed/refractory PTCL presents an area of unmet medical need.CASE PRESENTATION: Herein, we report an 84-year old woman with stage IV PTCL with extensive involvement of the bowel and abdominal pain. She was treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy which was complicated by prolonged pancytopenia, without response. Disease progression was manifested by small bowel obstruction, for which she received palliative radiation therapy, further complicated by cardiac arrhythmia and sepsis. In the meantime, clinical-grade next generation sequencing of a lymph node (406 gene panel) showed six genomic alterations: NRAS Q61R, PTEN Q17*, CREBBP R768*, EP300 R1529*, SETD2 loss exons 19-21, along with an intermediate tumor mutational burden. Tissue PD-L1 staining was low positive by immunohistochemistry. The patient was discussed in Molecular Tumor Board with consensus opinion favoring a combination of the MEK inhibitor trametinib (for the NRAS alteration) and the checkpoint inhibitor nivolumab for the elevated mutational burden and PD-L1 positivity. Her abdominal pain resolved and she achieved a complete remission ongoing at 5+ months. Side effects at five months included only low-grade rash and peripheral edema.CONCLUSIONS: Our observations suggest that matching patients with hematologic malignancies with customized combinations based on genomic sequencing warrants further study as a way to achieve and/or deepen responses, including in patients who are elderly and/or have refractory disease and significant disease-related complications.
CANIT0003142	30310008	Case report	A 59-year-old man	Lung adenosquamous cell carcinoma	EFO:0000233	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	A 59-year-old man who had postoperative recurrence of lung adenosquamous cell carcinoma was administered nivolumab as 3rd-line chemotherapy. Although nivolumab was considered effective, bleeding from a metastatic lesion at the jejunum was recognized by double-balloon enteroscopy, and partial resection was performed. Although the re-administration of nivolumab was planned, the patient died of acute respiratory failure 6 days postoperatively.	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Oct	[Lung Adenosquamous Cell Carcinoma in which the Administration of Nivolumab Became Untenable due to Bleeding from Small Intestine Metastasis].	 Kyobu Geka	A 59-year-old man who had postoperative recurrence of lung adenosquamous cell carcinoma was administered nivolumab as 3rd-line chemotherapy. Although nivolumab was considered effective, bleeding from a metastatic lesion at the jejunum was recognized by double-balloon enteroscopy, and partial resection was performed. Although the re-administration of nivolumab was planned, the patient died of acute respiratory failure 6 days postoperatively.
CANIT0003143	30316010	Clinical research	109 patients began receiving third- or later-line nivolumab monotherapy	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	109	N/A	Phase I/II, multicenter, open-label study 	At a median follow-up of 28.3 months (from first dose to database lock), the objective response rate was 11.9% (95% confidence interval: 6.5-19.5) with a median duration of response of 17.9 months (range 3.0-42.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively.	Grade 3 to 4 treatment-related adverse events occurred in 11.9% of patients. Three patients (2.8%) discontinued because of treatment-related adverse events.	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Third-Line Nivolumab Monotherapy in Recurrent SCLC: CheckMate 032.	 J Thorac Oncol	INTRODUCTION: For patients with recurrent SCLC, topotecan remains the only approved second-line treatment, and the outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with one or more platinum-based chemotherapies. We report results of third- or later-line nivolumab monotherapy treatment in SCLC.METHODS: In this analysis, patients with limited-stage or extensive-stage SCLC and disease progression after two or more chemotherapy regimens received nivolumab monotherapy, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety.RESULTS: Between December 4, 2013, and November 30, 2016, 109 patients began receiving third- or later-line nivolumab monotherapy. At a median follow-up of 28.3 months (from first dose to database lock), the objective response rate was 11.9% (95% confidence interval: 6.5-19.5) with a median duration of response of 17.9 months (range 3.0-42.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 11.9% of patients. Three patients (2.8%) discontinued because of treatment-related adverse events.CONCLUSIONS: Nivolumab monotherapy provided durable responses and was well tolerated as a third- or later-line treatment for recurrent SCLC. These results suggest that nivolumab monotherapy is an effective third- or later-line treatment for this patient population.
CANIT0003144	30323086	Case report	A 54-year-old white male	Salivary gland carcinoma	MONDO:0004669	Salivary gland	BRAF (P15056); MEK (Q02750); 	BRAF; MEK	Dabrafenib plus trametinib followed by Immune checkpoint therapy and androgen blockade	N/A	Target therapy followed by Immune checkpoint therapy plus Hormone therapy	Trametinib (DB08911); dabrafenib (DB08912); 	1	N/A	Case	This is the first report of frontline BRAF-directed therapy eliciting a response in metastatic Salivary duct carcinoma	N/A	N/A	N/A	N/A	N/A	N/A	 2018 Oct	First-Line Treatment of Widely Metastatic BRAF-Mutated Salivary Duct Carcinoma With Combined BRAF and MEK Inhibition.	 J Natl Compr Canc Netw	Copyright   2018 by the National Comprehensive Cancer Network.
CANIT0003145	30326507	Case report	Melanoma with antiphospholipid syndrome	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We report the first case to our knowledge of Antiphospholipid Syndrome (APS) following treatment with pembrolizumab alone. The presence of both a clinical criterion (secondary Raynaud phenomenon, or microthrombosis) and an immunologic criterion (high levels of antiphospholipid antibodies) led to the diagnosis of APS	Bilateral secondary Raynaud phenomenon with the typical sequence of white, blue, then red discoloration of the hands and fingers	N/A	N/A	N/A	N/A	N/A	 2018 Nov 1	Antiphospholipid Syndrome Following Pembrolizumab Treatment of Stage IIIB Unresectable Melanoma.	 JAMA Dermatol	Unable to provide
CANIT0003146	30382073	Clinical research	10 patients 	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	10	N/A	Retrospective analysis	Long-term SD could be maintained when the nivolumab treatment was initiated in a patient with good PS	 itching sensation	N/A	N/A	N/A	N/A	N/A	 2018 Oct	[Experience with Nivolumab in the Treatment of Metastatic Gastric Cancer].	 Gan To Kagaku Ryoho	Immunological checkpoint inhibitors have effects on various advancedcancers. Nivolumab was approvedfor advanced gastric cancer after third-line treatment in 2017. In our hospital, 10 patients were treatedwith nivolumab from October 2017 to March 2018. Thus, we retrospectively examinedthe clinical background, treatment outcomes, andad verse events of those patients. The median age was 70 years; male-to-female ratio was 6:4; recurrence sites were peritoneal dissemination, liver, lymph nodes, brain, ovaries, and bone(8, 2, 2, 1, 1, and1 , respectively); andtreatment lines were third, fourth, andfifth(in 6, 3, and1 patients, respectively). The minimum number of cycles was 1 course, while the maximum was 11 courses. The best tumor response evaluation was SD, andthe adverse event was an itching sensation in only one patient. It was suggestedthat long-term SD couldbe maintainedwhen the nivolumab treatment was initiatedin a patient with goodPS. In the future, biomarker analysis is expectedto identify effective cases.
CANIT0003147	30400750	Clinical research	97 patients with advanced malign melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	97	N/A	Retrospective analysis	Univariate analysis of BRAF status revealed no significant association with OS.	N/A	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2019 Oct	Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study.	 J Oncol Pharm Pract	PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count.METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test.RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24-month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival.CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed.
CANIT0003148	30400750	Clinical research	97 patients with advanced malign melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	97	N/A	Retrospective analysis	Absolute lymphocytes count was significantly related to survival.	N/A	N/A	N/A	Lymphocyte (NCIT:C12535); 	Absolute lymphocyte counts	Cell percentage/counts in blood	 2019 Oct	Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study.	 J Oncol Pharm Pract	PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count.METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test.RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24-month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival.CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed.
CANIT0003149	30400750	Clinical research	97 patients with advanced malign melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	97	N/A	Retrospective analysis	Bone metastasis was significantly related to survival.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Bone metastasis	Disease status	 2019 Oct	Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study.	 J Oncol Pharm Pract	PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count.METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test.RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24-month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival.CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed.
CANIT0003150	30400750	Clinical research	97 patients with advanced malign melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	97	N/A	Retrospective analysis	The number of metastatic sites was significantly related to survival.	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Number of metastatic sites	Disease status	 2019 Oct	Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study.	 J Oncol Pharm Pract	PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count.METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test.RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24-month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival.CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed.
CANIT0003151	30400750	Clinical research	97 patients with advanced malign melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	97	N/A	Retrospective analysis	RECIST response was significantly related to survival.	N/A	N/A	N/A	RECIST response ()	RECIST response	Disease status	 2019 Oct	Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study.	 J Oncol Pharm Pract	PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count.METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test.RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24-month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival.CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed.
CANIT0003152	30400750	Clinical research	97 patients with advanced malign melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	97	N/A	Retrospective analysis	LDH-high group was associated with decreased OS as compared to LDH-normal group (median OS was 8.5 months (95% CI: 3.1¨C13.9) versus 10 months (95% CI: 5.9¨C14.8), p: 0.035).	N/A	N/A	N/A	LDH (P00338); 	Serum lactate dehydrogenase levels	Gene expression signature in serum	 2019 Oct	Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study.	 J Oncol Pharm Pract	PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count.METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test.RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24-month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival.CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed.
CANIT0003153	30400750	Clinical research	97 patients with advanced malign melanoma	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	97	N/A	Retrospective analysis	Univariate analysis of ECOG PS revealed no significant association with OS.	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Oct	Prognostic factors for survival in patients with metastatic malign melanoma treated with ipilimumab: Turkish Oncology Group study.	 J Oncol Pharm Pract	PURPOSE: Studies in the last decade show survival improvement with checkpoint blocker therapy in patients with metastatic malign melanoma. Our purpose was to define the efficacy of ipilimumab according to the patient's baseline characteristics including absolute lymphocytes count.METHODS: We collected the data of 97 patients with advanced malign melanoma treated with ipilimumab (3 mg/kg, q3w) retrospectively. Log-rank test was used to analyze the univariate effects of patient's characteristics (age, gender, metastatic sites, ECOG PS, type of melanoma, lactic dehydrogenase levels, anemia, lymphocytes (L), neutrophils (N), N/L ratio), c-kit and BRAF status. Survival analyses were estimated with Kaplan-Meier method. Cox regression analysis was used to assess the possible factors identified with log-rank test.RESULTS: The median age was 58, and 58% were male and 90% of patients had at least one prior systemic therapy. The median survival was 9.7 months for all patients; and the 12- and 24-month survival rates were 43% and 19%, respectively. Absolute lymphocytes count, lactic dehydrogenase level, bone metastasis, the number of metastatic sites, and RECIST response were significantly related to survival. After Cox regression analysis, RECIST response (complete or partial response), absolute lymphocytes count (more than 1500/mm3) and the number of metastatic sites (less than three sites) remained as significant independent prognostic factors for longer survival.CONCLUSION: Ipilimumab improved survival of patients with metastatic malign melanoma. However, patients with fewer metastatic sites and higher absolute lymphocytes count have a significantly better benefit. To determine if these markers could be used to direct patient therapy, further validation analysis is needed.
CANIT0003154	30413900	Case report	An HIV patient with refractory Hodgkin lymphoma	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	Nivolumab as a safe and effective treatment in an HIV patient with refractory Hodgkin lymphoma	N/A	N/A	N/A	HIV (NCIT:C161395); 	HIV infection	Microbiota	 2019 Jun	Nivolumab as a safe and effective treatment in an HIV patient with refractory Hodgkin lymphoma.	 Ann Hematol	Unable to provide
CANIT0003155	30415456	Clinical research	3 patients diagnosed with recurrent IDHwt GBM with variable MGMT methylation status 	Glioblastoma multiforme	EFO:0000519	Brain	IDO1 (P14902); 	IDO1; 	Indoximod plus temozolomide	N/A	Immune checkpoint therapy	Indoximod (DB12827); temozolomide (DB00853); 	3	N/A	Phase I/II	Regional intratumoral variability of AMT within enhancing and non-enhancing tumor was noted at baseline. On treatment imaging revealed decreased regional uptake suggesting IDO1 pathway modulation with treatment.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Jan	Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod.	 J Neurooncol	INTRODUCTION: Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the central nervous system, accounting for over 50% of all primary malignant gliomas arising in the adult brain. Even after surgical resection, adjuvant radiotherapy (RT) and temozolomide (TMZ) chemotherapy, as well as tumor-treating fields, the median survival is only 15-20 months. We have identified a pathogenic mechanism that contributes to the tumor-induced immunosuppression in the form of increased indoleamine 2,3 dioxygenase 1 (IDO1) expression; an enzyme that metabolizes the essential amino acid, tryptophan (Trp), into kynurenine (Kyn). However, real-time measurements of IDO1 activity has yet to become mainstream in clinical protocols for assessing IDO1 activity in GBM patients.METHODS: Pre-treatment and on-treatment a-[11C]-methyl-L-Trp (AMT) positron emission tomography (PET) with co-registered MRI was performed on patients with recurrent GBM treated with the IDO1 pathway inhibitor indoximod (D1-MT) and TMZ.RESULTS: Regional intratumoral variability of AMT within enhancing and non-enhancing tumor was noted at baseline. On treatment imaging revealed decreased regional uptake suggesting IDO1 pathway modulation with treatment.CONCLUSIONS: Here, we have validated the ability to use PET of the Trp probe, AMT, for use in visualizing and quantifying intratumoral Trp uptake in GBM patients treated with an IDO1 pathway inhibitor. These data serve as rationale to utilize AMT-PET imaging in the future evaluation of GBM patients treated with IDO1 enzyme inhibitors.
CANIT0003156	30442730	Case report	Two patients	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	This report provides additional insight into the heterogeneous patterns of disease response to anti-PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy.	Adrenal gland as a potential sanctuary site 	N/A	N/A	N/A	N/A	N/A	 2018 Nov	The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series.	 J Natl Compr Canc Netw	Therapeutic agents targeting the PD-1/PD-L1 axis have shown durable clinical responses in patients with various cancer types. Although objective responses are common, intrapatient heterogeneous responses have been described, and the mechanism for the different organ responses remains unknown. We present a series of patients in whom a lack of response was noted solely in the adrenal glands. This is the first case series describing 3 patients with heterogeneous patterns of response to pembrolizumab with progression of adrenal metastatic disease despite objective response (complete or partial response) in all other sites of metastatic disease. Two patients, one with melanoma and one with uterine carcinosarcoma, underwent robotic adrenalectomy for enlarging adrenal metastases. An additional patient with melanoma underwent laparotomy with attempted resection, but infiltration of the adrenal tumor into the inferior vena cava prohibited safe excision. This report provides additional insight into the heterogeneous patterns of disease response to anti-PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy. These cases display the potential benefit of early surgical resection in this scenario and the pitfalls of delaying referral to a surgeon for assessment of operative intervention.
CANIT0003157	30442730	Case report	Two patients	Uterine carcinosarcoma	EFO:1000613	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	This report provides additional insight into the heterogeneous patterns of disease response to anti-PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy.	Adrenal gland as a potential sanctuary site 	N/A	N/A	N/A	N/A	N/A	 2018 Nov	The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series.	 J Natl Compr Canc Netw	Therapeutic agents targeting the PD-1/PD-L1 axis have shown durable clinical responses in patients with various cancer types. Although objective responses are common, intrapatient heterogeneous responses have been described, and the mechanism for the different organ responses remains unknown. We present a series of patients in whom a lack of response was noted solely in the adrenal glands. This is the first case series describing 3 patients with heterogeneous patterns of response to pembrolizumab with progression of adrenal metastatic disease despite objective response (complete or partial response) in all other sites of metastatic disease. Two patients, one with melanoma and one with uterine carcinosarcoma, underwent robotic adrenalectomy for enlarging adrenal metastases. An additional patient with melanoma underwent laparotomy with attempted resection, but infiltration of the adrenal tumor into the inferior vena cava prohibited safe excision. This report provides additional insight into the heterogeneous patterns of disease response to anti-PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy. These cases display the potential benefit of early surgical resection in this scenario and the pitfalls of delaying referral to a surgeon for assessment of operative intervention.
CANIT0003158	30447078	Clinical research	The melanoma patients into three groups according to the locations of their tumors. Accordingly, our study included 24 mucosal melanomas (MCM) (17 cases with visceral metastases and 7 cases without visceral metastases), 16 acral lentiginous melanomas (ALM) (13 cases with visceral metastases and 3 cases without visceral metastases), and 28 cutaneous melanomas (24 cases with visceral metastases and 4 cases without visceral metastases)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	68	N/A	Retrospective analysis	Nivolumab monotherapy is less effective in Japanese melanoma patients than in Caucasian melanoma patients, apparently because of the tendency for the response rates of acral lentiginous melanomas (ALM) and mucosal melanomas (MCM), which account for a high percentage of Japanese melanoma cases, to be low	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2019 May	Efficacy of nivolumab monotherapy against acral lentiginous melanoma and mucosal melanoma in Asian patients.	 Br J Dermatol	Unable to provide
CANIT0003159	30447078	Clinical research	The melanoma patients into three groups according to the locations of their tumors. Accordingly, our study included 24 mucosal melanomas (MCM) (17 cases with visceral metastases and 7 cases without visceral metastases), 16 acral lentiginous melanomas (ALM) (13 cases with visceral metastases and 3 cases without visceral metastases), and 28 cutaneous melanomas (24 cases with visceral metastases and 4 cases without visceral metastases)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	68	N/A	Retrospective analysis	There was no significant difference in OS or PFS among the BRAF mutation-positive and BRAF mutation-negative cases. Nivolumab monotherapy is less effective in Japanese melanoma patients than in Caucasian melanoma patients, apparently because of the tendency for the response rates of acral lentiginous melanomas (ALM) and mucosal melanomas (MCM), which account for a high percentage of Japanese melanoma cases, to be low	N/A	N/A	N/A	BRAF (P15056); 	BRAF mutational status	Mutational status	 2019 May	Efficacy of nivolumab monotherapy against acral lentiginous melanoma and mucosal melanoma in Asian patients.	 Br J Dermatol	Unable to provide
CANIT0003160	30447078	Clinical research	The melanoma patients into three groups according to the locations of their tumors. Accordingly, our study included 24 mucosal melanomas (MCM) (17 cases with visceral metastases and 7 cases without visceral metastases), 16 acral lentiginous melanomas (ALM) (13 cases with visceral metastases and 3 cases without visceral metastases), and 28 cutaneous melanomas (24 cases with visceral metastases and 4 cases without visceral metastases)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	68	N/A	Retrospective analysis	Nivolumab monotherapy is less effective in Japanese melanoma patients than in Caucasian melanoma patients, apparently because of the tendency for the response rates of acral lentiginous melanomas (ALM) and mucosal melanomas (MCM), which account for a high percentage of Japanese melanoma cases, to be low	N/A	N/A	N/A	Gender (NCIT:C17357); 	Gender	Personal feature	 2019 May	Efficacy of nivolumab monotherapy against acral lentiginous melanoma and mucosal melanoma in Asian patients.	 Br J Dermatol	Unable to provide
CANIT0003161	30447078	Clinical research	The melanoma patients into three groups according to the locations of their tumors. Accordingly, our study included 24 mucosal melanomas (MCM) (17 cases with visceral metastases and 7 cases without visceral metastases), 16 acral lentiginous melanomas (ALM) (13 cases with visceral metastases and 3 cases without visceral metastases), and 28 cutaneous melanomas (24 cases with visceral metastases and 4 cases without visceral metastases)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	68	N/A	Retrospective analysis	Nivolumab monotherapy is less effective in Japanese melanoma patients than in Caucasian melanoma patients, apparently because of the tendency for the response rates of acral lentiginous melanomas (ALM) and mucosal melanomas (MCM), which account for a high percentage of Japanese melanoma cases, to be low	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Visceral metastasis	Disease status	 2019 May	Efficacy of nivolumab monotherapy against acral lentiginous melanoma and mucosal melanoma in Asian patients.	 Br J Dermatol	Unable to provide
CANIT0003162	30447078	Clinical research	The melanoma patients into three groups according to the locations of their tumors. Accordingly, our study included 24 mucosal melanomas (MCM) (17 cases with visceral metastases and 7 cases without visceral metastases), 16 acral lentiginous melanomas (ALM) (13 cases with visceral metastases and 3 cases without visceral metastases), and 28 cutaneous melanomas (24 cases with visceral metastases and 4 cases without visceral metastases)	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	68	N/A	Retrospective analysis	Nivolumab monotherapy is less effective in Japanese melanoma patients than in Caucasian melanoma patients, apparently because of the tendency for the response rates of acral lentiginous melanomas (ALM) and mucosal melanomas (MCM), which account for a high percentage of Japanese melanoma cases, to be low	N/A	N/A	N/A	Tumor burden (NCIT:C28384); 	Tumor location	Disease status	 2019 May	Efficacy of nivolumab monotherapy against acral lentiginous melanoma and mucosal melanoma in Asian patients.	 Br J Dermatol	Unable to provide
CANIT0003163	30456528	Case report	A 61-year-old woman	Colorectal cancer	EFO:0005842	Intestines	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab plus nivolumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); nivolumab (DB09035); 	1	N/A	Case	A case of severe necrotizing myositis which occurred in a patient treated with Nivolumab plus ipilimumab (N + I) combination for metastatic colorectal cancer microsatellite instability-high (MSI-H).	Proximal muscles weakness associated with diffuse erythematous rash with grade 2/5 strength on abdominal, dorsal, and proximal limb muscles and impressive muscular edema.	N/A	N/A	Microsatellite instability (NCIT:C36318); 	Microsatellite instability	Mutational status	 2019 Feb	Severe necrotizing myositis associated with long term anti-neoplastic efficacy following nivolumab plus ipilimumab combination therapy.	 Clin Rheumatol	Immune-related adverse events (irAEs), have been reported under immune checkpoint inhibitors. Nivolumab plus ipilimumab (N + I) demonstrated meaningful improvements in key patient-reported outcomes, in patients with pretreated microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We report a case of severe necrotizing myositis which occurred in a patient treated with N + I combination for mCRC MSI-H. A 61-year-old woman was diagnosed with mCRC MSI-H and BRAFV600E mutated with synchronous liver, pleural, and lymph nodes metastases. After she failed to respond to standard chemotherapy (two lines with 5-fluorouracil, oxaliplatin, and irinotecan + bevacizumab), she received in a clinical trial (CheckMate 142), nivolumab 3 mg/kg, and ipilumumab 1 mg/kg every 3 weeks [4]. One week after the second infusion, she developed rapidly extending proximal muscles weakness associated with diffuse erythematous rash with grade 2/5 strength on abdominal, dorsal, and proximal limb muscles and impressive muscular edema. The creatine kinase level was at 14827 U/L (0-160 U/L), without any detectable autoantibodies. The electromyogram showed a severe myogenic syndrome, and muscular histological analysis demonstrated extensive muscular necrosis, with scarce lymphocytic infiltrates and pathological expression of class I HLA and C5b9 complement deposits with severe endomysial edema. N-I therapy was discontinued. Intravenous methylprednisolone was initiated for 3 days followed by 1 mg/kg/day orally, combined with intravenous immunoglobulins (2 g/kg/day for 2 days). At 3 years of first infusion of N + I, patient is without any new progressive disease, in partial response on the liver, pleural, and nodes metastasis, with only persistent minor psoas weakness.
CANIT0003164	30474878	Case report	A patient	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	CD8+ T lymphocytes may have a crucial role both in tumor reduction and liver toxicity in this case	Liver toxicity	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8(+) T lymphocytes	Gene expression signature on/in immune cell	 2019 May	Dramatic effect of nivolumab against melanoma and immune-related liver toxicity: A detailed histopathological and immunohistochemical analysis of nivolumab-induced liver toxicity.	 J Dermatol	Unable to provide
CANIT0003165	30478475	Clinical research	41 patients with unresectable metastatic melanoma 	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab	N/A	Immune checkpoint therapy	Ipilimumab (DB06186); 	41	N/A	N/A	10% patients in the interim or late PET/CT showed 'sarcoid-like lymphadenopathy' as response to treatment. All these patients showed disease control, implying a relation between the appearance of sarcoid-like lymphadenopathy and the clinical benefit of anti-CTLA-4 therapy. On the other hand, quantitative 18F-FDG PET analysis of the spleen showed a poor performance in predicting clinical benefit to ipilimumab	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Can benign lymphoid tissue changes in (18)F-FDG PET/CT predict response to immunotherapy in metastatic melanoma 	 Cancer Immunol Immunother	BACKGROUND: An association between immune-related adverse events (irAEs) caused by immunotherapeutic agents and the clinical benefit of immunotherapy has been suggested. We retrospectively evaluated by means of 18F-FDG PET/CT lymphoid tissue changes in the mediastinal/hilar lymph nodes and the spleen in response to ipilimumab administration in metastatic melanoma.METHODS: A total of 41 patients with unresectable metastatic melanoma underwent 18F-FDG PET/CT before the start of ipilimumab (baseline PET/CT), after two cycles (interim PET/CT) and at the end of treatment (late PET/CT). Data analysis was focused on the mediastinal/hilar lymph nodes and the spleen. The patients' best clinical response (BCR) was used as reference.RESULTS: According to the BCR reference, 31 patients showed disease control (DC) and 10 patients showed progressive disease (PD). Mediastinal/hilar lymph node evaluation revealed that in total 4 patients in the interim or late PET/CT (10%) demonstrated a 'sarcoid-like lymphadenopathy' as response to treatment (LN-positive). All LN-positive patients responded to ipilimumab with DC. On the other hand, no significant differences between the DC and PD groups regarding both semi-quantitative and quantitative 18F-FDG PET spleen-related parameters at baseline and as response to treatment were detected.CONCLUSION: Based on our findings, 10% patients in the interim or late PET/CT showed 'sarcoid-like lymphadenopathy' as response to treatment. All these patients showed disease control, implying a relation between the appearance of sarcoid-like lymphadenopathy and the clinical benefit of anti-CTLA-4 therapy. On the other hand, quantitative 18F-FDG PET analysis of the spleen showed a poor performance in predicting clinical benefit to ipilimumab.
CANIT0003166	30482243	Case report	 a patient with CSCC with nodal involvement and pulmonary metastases	Cutaneous squamous cell carcinoma	EFO:1001927	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	The case of patient with metastatic CSCC, refractory, received immunotherapy and evolved with atypical pattern of response	Atypical response with bone pseudoprogression	N/A	N/A	N/A	N/A	N/A	 2018 Nov 27	Atypical response with bone pseudoprogression in a patient receiving nivolumab for advanced cutaneous squamous cell carcinoma.	 J Immunother Cancer	Currently, there is no established standard of care for patients with metastatic CSCC. Based on the mechanisms of CSCC carcinogenesis has been postulated that these tumors may be amenable to PD-1/PD-L1 blockade.This case illustrates a patient with CSCC with nodal involvement and pulmonary metastases, refractory to two lines of platinum-based regimens and salvage surgery, for whom treatment with nivolumab was recommended. His clinical course was marked by an atypical pattern of response, with initial reduction of soft tissue/visceral lesions, yet development of new bone findings, followed by overall improvement in subsequent scans and sustained disease control upon treatment continuation.The case of patient with metastatic CSCC, refractory, received immunotherapy and evolved with atypical pattern of response.
CANIT0003167	30514390	Clinical research	Seventeen patients	Prostate cancer	MONDO:0008315	Prostate	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab plus olaparib	N/A	Immune checkpoint therapy plus Target therapy	Durvalumab (DB11714); olaparib (DB09074); 	17	N/A	Phase II single-institution, single-arm, open-label	Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DNA damage repair (DDR) mutations.	Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17)	N/A	N/A	Defective Mismatch Repair (NCIT:C8494); 	DNA mismatch repair-deficient	Mutational status	 2018 Dec 4	Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations.	 J Immunother Cancer	BACKGROUND: Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations.METHODS: Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations.RESULTS: Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5-16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7-72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8-18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response.CONCLUSIONS: Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02484404 .
CANIT0003168	30522700	Clinical research	Twenty-six patients (median age, 57.5 years) with PD-L1-positive advanced metastatic ovarian	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	26	N/A	Phase Ib KEYNOTE-028 trial	Pembrolizumab conferred durable antitumor activity with manageable safety and toxicity in patients with advanced PD-L1-positive ovarian cancer and is under further investigation in an ongoing phase II trial, KEYNOTE-100.	Treatment-related AEs (TRAEs) occurred in 19 (73.1%) patients, most commonly arthralgia (19.2%), nausea (15.4%), and pruritus (15.4%). One grade 3 TRAE (increased plasma transaminase level) occurred. No deaths and no treatment discontinuations due to TRAEs occurred.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb	Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028.	 Gynecol Oncol	OBJECTIVE: To evaluate safety, tolerability, and antitumor activity of pembrolizumab monotherapy in patients with programmed death ligand 1 (PD-L1)-expressing advanced ovarian cancer enrolled in the multicohort, phase Ib KEYNOTE-028 trial.METHODS: Key inclusion criteria were age >=18 years; advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of previous therapy; and tumor PD-L1 positivity. Patients received pembrolizumab (10 mg/kg every 2 weeks) for <=24 months or until disease progression/intolerable toxicity. Tumor response was assessed per RECIST v1.1 (investigator review). Adverse events (AEs) were graded using CTCAE version 4.0. Primary end point was confirmed objective response rate (ORR) per RECIST v1.1 (investigator review); data cutoff date was February 20, 2017.RESULTS: Twenty-six patients (median age, 57.5 years) with PD-L1-positive advanced metastatic ovarian cancer received pembrolizumab; 38.5% had metastatic disease, and 73.1% previously received >=3 lines of therapy. Treatment-related AEs (TRAEs) occurred in 19 (73.1%) patients, most commonly arthralgia (19.2%), nausea (15.4%), and pruritus (15.4%). One grade 3 TRAE (increased plasma transaminase level) occurred. No deaths and no treatment discontinuations due to TRAEs occurred. After a median follow-up duration of 15.4 months, ORR was 11.5% (1 complete response, 2 partial responses); 7 patients (26.9%) achieved stable disease. Median progression-free and overall survival were 1.9 (95% CI, 1.8-3.5) and 13.8 (95% CI, 6.7-18.8) months, respectively.CONCLUSION: Pembrolizumab conferred durable antitumor activity with manageable safety and toxicity in patients with advanced PD-L1-positive ovarian cancer and is under further investigation in an ongoing phase II trial, KEYNOTE-100.
CANIT0003169	30528699	Clinical research	Advanced urothelial carcinoma of the bladder	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Docetaxel	Immune checkpoint therapy	Pembrolizumab (DB09037); 	N/A	N/A	N/A	Pembrolizumab was not cost-effective in either strategy based on a $100,000/quality-adjusted life-year willingness-to-pay threshold. Using PD-L1 testing to select for patients who may have better associated outcomes may improve the affordability of pembrolizumab	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Mar	Effect of PD-L1 testing on the cost-effectiveness and budget impact of pembrolizumab for advanced urothelial carcinoma of the bladder in the United States.	 Urol Oncol	PURPOSE: Our purpose was to evaluate the effect of PD-L1 testing on the cost-effectiveness of pembrolizumab for second-line treatment of advanced urothelial carcinoma in the bladder from the U.S. societal perspective.MATERIALS AND METHODS: We developed a microsimulation model to compare 3 treatment strategies: (1) treat all patients with standard-of-care chemotherapy, (2) treat all patients with pembrolizumab, and (3) treat patients with PD-L1-positive tumors at a >=1% expression threshold with pembrolizumab, and all others with standard-of-care chemotherapy. Additionally, we performed a budget impact analysis based on the projected number of urothelial carcinoma patients eligible for second-line pembrolizumab treatment.RESULTS: Treating all patients with chemotherapy resulted in a mean cost of $17,232 and mean effect of 0.43 quality-adjusted life-years. The PD-L1 test strategy was the most efficient strategy, with an incremental cost-effectiveness ratio of $122,933/quality-adjusted life-year. Treating all patients with pembrolizumab resulted in an incremental cost-effectiveness ratio of $197,383/quality-adjusted life-year compared to the PD-L1 test strategy. The PD-L1 test strategy would produce an incremental budget impact of $14.9 million in the first year of use compared to chemotherapy, increasing to $16.5 million in the fifth year of use. Treating all patients with pembrolizumab would produce an incremental budget impact of $19.6 million compared to the PD-L1 test strategy in its first year of use, increasing to $20.9 million by year 5.CONCLUSIONS: Pembrolizumab was not cost-effective in either strategy based on a $100,000/quality-adjusted life-year willingness-to-pay threshold. Using PD-L1 testing to select for patients who may have better associated outcomes may improve the affordability of pembrolizumab.
CANIT0003170	30528699	Clinical research	Advanced urothelial carcinoma of the bladder	Bladder cancer	EFO:0000292	Bladder	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Paclitaxel	Immune checkpoint therapy	Pembrolizumab (DB09037); 	N/A	N/A	N/A	Pembrolizumab was not cost-effective in either strategy based on a $100,000/quality-adjusted life-year willingness-to-pay threshold. Using PD-L1 testing to select for patients who may have better associated outcomes may improve the affordability of pembrolizumab	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Mar	Effect of PD-L1 testing on the cost-effectiveness and budget impact of pembrolizumab for advanced urothelial carcinoma of the bladder in the United States.	 Urol Oncol	PURPOSE: Our purpose was to evaluate the effect of PD-L1 testing on the cost-effectiveness of pembrolizumab for second-line treatment of advanced urothelial carcinoma in the bladder from the U.S. societal perspective.MATERIALS AND METHODS: We developed a microsimulation model to compare 3 treatment strategies: (1) treat all patients with standard-of-care chemotherapy, (2) treat all patients with pembrolizumab, and (3) treat patients with PD-L1-positive tumors at a >=1% expression threshold with pembrolizumab, and all others with standard-of-care chemotherapy. Additionally, we performed a budget impact analysis based on the projected number of urothelial carcinoma patients eligible for second-line pembrolizumab treatment.RESULTS: Treating all patients with chemotherapy resulted in a mean cost of $17,232 and mean effect of 0.43 quality-adjusted life-years. The PD-L1 test strategy was the most efficient strategy, with an incremental cost-effectiveness ratio of $122,933/quality-adjusted life-year. Treating all patients with pembrolizumab resulted in an incremental cost-effectiveness ratio of $197,383/quality-adjusted life-year compared to the PD-L1 test strategy. The PD-L1 test strategy would produce an incremental budget impact of $14.9 million in the first year of use compared to chemotherapy, increasing to $16.5 million in the fifth year of use. Treating all patients with pembrolizumab would produce an incremental budget impact of $19.6 million compared to the PD-L1 test strategy in its first year of use, increasing to $20.9 million by year 5.CONCLUSIONS: Pembrolizumab was not cost-effective in either strategy based on a $100,000/quality-adjusted life-year willingness-to-pay threshold. Using PD-L1 testing to select for patients who may have better associated outcomes may improve the affordability of pembrolizumab.
CANIT0003171	30536371	Case report	Melanocytic nevi	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We report a case of regression of multiple melanocytic nevi in a patient with metastatic melanoma showing a complete response to nivolumab	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Nov	Regression of multiple melanocytic nevi associated with nivolumab treatment for metastatic melanoma.	 Int J Dermatol	Unable to provide
CANIT0003172	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Anal squamous cell carcinoma	EFO:1000081	Anus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003173	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Anal squamous cell carcinoma	EFO:1000081	Anus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003174	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Anal squamous cell carcinoma	EFO:1000081	Anus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003175	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Biliary tract adenocarcinoma	DOID:4607	Bilie duct	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003176	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Biliary tract adenocarcinoma	DOID:4607	Bilie duct	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003177	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Biliary tract adenocarcinoma	DOID:4607	Bilie duct	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003178	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003179	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003180	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Breast cancer	MONDO:0007254	Breast	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003181	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003182	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003183	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Cancer	EFO:0000311	Other	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003184	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Cervical squamous cell carcinoma	EFO:1000172	Cervix	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003185	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Cervical squamous cell carcinoma	EFO:1000172	Cervix	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003186	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Cervical squamous cell carcinoma	EFO:1000172	Cervix	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003187	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003188	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003189	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Colorectal cancer	EFO:0005842	Intestines	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003190	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003191	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003192	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003193	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Esophageal adenocarcinoma	EFO:0000478; 	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003194	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Esophageal adenocarcinoma	EFO:0000478; 	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003195	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Esophageal adenocarcinoma	EFO:0000478; 	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003196	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Esophageal squamous cell carcinoma; 	EFO:0005922	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003197	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Esophageal squamous cell carcinoma; 	EFO:0005922	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003198	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Esophageal squamous cell carcinoma; 	EFO:0005922	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003199	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003200	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003201	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Glioblastoma multiforme	EFO:0000519	Brain	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003202	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Leiomyosarcoma	EFO:0000564	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003203	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Leiomyosarcoma	EFO:0000564	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003204	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Leiomyosarcoma	EFO:0000564	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003205	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Mesothelioma	EFO:0000588	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003206	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Mesothelioma	EFO:0000588	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003207	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Mesothelioma	EFO:0000588	Soft tissue	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	25	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003208	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003209	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003210	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Nasopharyngeal carcinoma	EFO:1000058	Head and neck	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	27	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003211	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Neuroendocrine carcinoma	MONDO:0002120	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003212	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Neuroendocrine carcinoma	MONDO:0002120	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003213	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Neuroendocrine carcinoma	MONDO:0002120	Nervous system	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	16	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003214	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	26	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003215	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	26	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003216	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Ovarian carcinoma	EFO:0001075	Ovary	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	26	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003217	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Prostate adenocarcinoma	EFO:0000673	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003218	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Prostate adenocarcinoma	EFO:0000673	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003219	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Prostate adenocarcinoma	EFO:0000673	Prostate	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	23	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003220	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Salivary gland carcinoma	MONDO:0004669	Salivary gland	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	26	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003221	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Salivary gland carcinoma	MONDO:0004669	Salivary gland	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	26	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003222	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Salivary gland carcinoma	MONDO:0004669	Salivary gland	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	26	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003223	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003224	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003225	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Small cell lung carcinoma	EFO:0000702	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	24	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003226	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Thyroid cancer	MONDO:0002108	Thyroid	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	22	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003227	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Thyroid cancer	MONDO:0002108	Thyroid	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	22	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003228	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Thyroid cancer	MONDO:0002108	Thyroid	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	22	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003229	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Vulvar cancer	EFO:1000624	Vulvar	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	18	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003230	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Vulvar cancer	EFO:1000624	Vulvar	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	18	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	T-Lymphocyte (NCIT:C12476); Tumor infiltrate (NCIT:C12546); 	Higher T-cell -inflamed GEP on tumor	Tumor-infiltrating immune cell	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003231	30557521	Clinical research	475 patients with PD-L1-positive advanced solid tumors	Vulvar cancer	EFO:1000624	Vulvar	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	18	N/A	Phase Ib 	A T-cell--inflamed gene-expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.	Safety was similar and consistent with prior pembrolizumab reports.	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Feb 1	T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.	 J Clin Oncol	PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.RESULTS: ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.CONCLUSION: A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.
CANIT0003232	30562710	Clinical research	850 patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-L1 (Q9NZQ7); 	PD-L1; 	Atezolizumab	Docetaxel	Immune checkpoint therapy	Atezolizumab (DB11595); 	425	425	Randomised phase III OAK study	After >2 years of follow-up, atezolizumab continued to provide durable survival benefit versus docetaxel, with tolerable safety. Atezolizumab-arm LTSs were enriched for patients with high PD-L1 expression and included PD-L1-negative patients. Long-term survival was not limited to responders.	 The most frequently occurring TRAEs in atezolizumab-arm LTSs were grade 1-2 and included diarrhoea (14%), fatigue (12%) and pruritus (12%) . Atezolizumab-arm LTSs had an irAE rate of 30% ; most of these irAEs were grade 1-2 . The most frequently reported irAEs in both populations were changes in liver function test results (14%, LTSs; 6%, non-LTSs) and hypothyroidism (9%, LTSs; 4%, non-LTSs)	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jan	Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study.	 Eur J Cancer	BACKGROUND: Atezolizumab (anti-programmed death-ligand 1 [PD-L1]) received approval from the US Food and Drug Administration and European Medicines Agency for previously treated advanced non-small-cell lung cancer based on OAK-a randomised, phase III trial that showed significantly improved survival with atezolizumab versus docetaxel regardless of PD-L1 expression. With longer follow-up, we summarised the characteristics of long-term survivors (LTSs).METHODS: In OAK (NCT02008227), patients were randomised 1:1 to receive atezolizumab or docetaxel until loss of clinical benefit or disease progression, respectively. Overall survival was evaluated after a 26-month minimum follow-up, including in patient subgroups defined by best overall response (BOR). LTSs were defined as patients who lived >=24 months since randomisation. Non-LTSs died within 24 months, and patients censored before 24 months were excluded from the analysis. The baseline characteristics, including biomarkers, BOR, subsequent non-protocol therapy (NPT) and safety, are reported.RESULTS: Survival benefit with atezolizumab was observed across all patient subgroups defined by BOR. More atezolizumab-treated patients were LTSs versus those treated with docetaxel (28% versus 18%). Most atezolizumab responders were LTSs (77%) versus only 48% of docetaxel responders. However, 21% of atezolizumab-arm LTSs had progressive disease (PD) as BOR, and more atezolizumab-arm LTSs than non-LTSs continued treatment post-PD. Fifty-two percent of docetaxel-arm LTSs received immunotherapy as subsequent NPT. Despite extended treatment duration in atezolizumab-arm LTSs (median, 18 months), atezolizumab was well tolerated.CONCLUSIONS: After >2 years of follow-up, atezolizumab continued to provide durable survival benefit versus docetaxel, with tolerable safety. Atezolizumab-arm LTSs were enriched for patients with high PD-L1 expression and included PD-L1-negative patients. Long-term survival was not limited to responders.
CANIT0003233	30563577	Case report	 A 79-year-old man	Prostate cancer	MONDO:0008315	Prostate	PD-1 (Q15116); 	PD-1; 	Nivolumab plus PROSTVAC	N/A	Immune checkpoint therapy plus Tumor vaccine 	Nivolumab (DB09035); PROSTVAC (); 	1	N/A	Case	This is the first case of myocarditis in a patient with mCRPC receiving simultaneous treatment with an immune checkpoint inhibitor and a prostate cancer vaccine. Our experience highlights the importance of suspicion and early intervention in patients who present with cardiac abnormalities after receiving cancer immunotherapy.	Myocarditis	N/A	N/A	N/A	N/A	N/A	 2018 Dec 18	Myocarditis in a patient treated with Nivolumab and PROSTVAC: a case report.	 J Immunother Cancer	Unable to provide
CANIT0003234	30570649	Clinical research	121 patients had advanced, metastatic esophageal cancer 	Esophageal carcinoma	EFO:0002916	Stomach	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	121	N/A	Phase II KEYNOTE-180 study	Pembrolizumab provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer.	Overall, 15 patients (12.4%) had treatment-related grade 3 to 5 adverse events. Only 5 patients (4.1%) discontinued treatment because of adverse events. There was 1 treatment-related death from pneumonitis.	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Apr 1	Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-180 Study.	 JAMA Oncol	IMPORTANCE: Effective treatment options are limited for patients with advanced, metastatic esophageal cancer progressing after 2 or more lines of systemic therapy.OBJECTIVE: To evaluate the efficacy and safety of pembrolizumab for patients with advanced, metastatic esophageal squamous cell carcinoma (ESCC) or advanced, metastatic adenocarcinoma of the esophagus and gastroesophageal junction that progressed after 2 or more lines of systemic therapy.DESIGN, SETTING, AND PARTICIPANTS: This phase 2, open-label, interventional, single-arm study, KEYNOTE-180, enrolled 121 patients from January 12, 2016, to March 21, 2017, from 57 sites in 10 countries. Patients had advanced, metastatic esophageal cancer that progressed after 2 or more lines of therapy and had evaluable tumor samples for biomarkers.INTERVENTIONS: Pembrolizumab, 200 mg, was administered intravenously every 3 weeks until disease progression, unacceptable toxic effects, or study withdrawal, for up to 2 years.MAIN OUTCOMES AND MEASURES: Primary end point was objective response rate per the Response Evaluation Criteria in Solid Tumors by central imaging review for all patients.RESULTS: As of September 18, 2017, of 121 enrolled patients (100 men and 21 women; median age, 65 years [range, 33-87 years]), 18 (14.9%) had undergone 3 or more prior therapies, 63 (52.1%) had ESCC, and 58 (47.9%) had tumors positive for programmed death ligand-1 (PD-L1), defined as a combined positive score of 10 or higher assessed by immunohistochemistry. Median duration of follow-up was 5.8 months (range, 0.2-18.3 months). Objective response rate was 9.9% (95% CI, 5.2%-16.7%) among all patients (12 of 121), and median duration of response was not reached (range, 1.9-14.4 months). Objective response rate was 14.3% (95% CI, 6.7%-25.4%) among patients with ESCC (9 of 63), 5.2% (95% CI, 1.1%-14.4%) among patients with adenocarcinoma (3 of 58), 13.8% (95% CI, 6.1%-25.4%) among patients with PD-L1-positive tumors (8 of 58), and 6.3% (95% CI, 1.8%-15.5%) among patients with PD-L1-negative tumors (4 of 63). Overall, 15 patients (12.4%) had treatment-related grade 3 to 5 adverse events. Only 5 patients (4.1%) discontinued treatment because of adverse events. There was 1 treatment-related death from pneumonitis.CONCLUSIONS AND RELEVANCE: Where effective treatment options are an unmet need, pembrolizumab provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer. Phase 3 studies evaluating pembrolizumab vs standard therapy for patients with esophageal cancer progressing after first-line therapy or in combination with chemotherapy as first-line therapy for patients with locally advanced unresectable or metastatic esophageal cancer are ongoing.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02559687.
CANIT0003235	30591549	Clinical research	The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	1,344	N/A	Retrospective analysis	Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome.	N/A	N/A	N/A	ALK (Q9UM73); 	ALK rearrangement	Mutational status	 2019 May	Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.	 Oncologist	BACKGROUND: Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval.MATERIALS AND METHODS: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded.RESULTS: Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS.CONCLUSION: This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies.IMPLICATIONS FOR PRACTICE: This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.
CANIT0003236	30591549	Clinical research	The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	1,344	N/A	Retrospective analysis	Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome.	N/A	N/A	N/A	EGFR (P00533); 	EGFR mutational status	Mutational status	 2019 May	Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.	 Oncologist	BACKGROUND: Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval.MATERIALS AND METHODS: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded.RESULTS: Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS.CONCLUSION: This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies.IMPLICATIONS FOR PRACTICE: This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.
CANIT0003237	30591549	Clinical research	The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	1,344	N/A	Retrospective analysis	Age at PD-1 inhibitor initiation or line of therapy did not impact OS. This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome.	N/A	N/A	N/A	Age (NCIT:C25150); 	Age	Personal feature	 2019 May	Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.	 Oncologist	BACKGROUND: Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval.MATERIALS AND METHODS: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded.RESULTS: Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS.CONCLUSION: This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies.IMPLICATIONS FOR PRACTICE: This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.
CANIT0003238	30600107	Case report	A 63-year-old Japanese man 	Ameloblastic carcinoma	EFO:1000078	Bone	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	We present a rare case of an ameloblastic carcinoma with multiple metastases in a 63-year-old Japanese man that was treated in several different ways, including chemoradiotherapy and immunotherapy.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Huge ameloblastic carcinoma of the mandible with metastases treated in several different ways.	 Br J Oral Maxillofac Surg	Ameloblastic carcinoma is an extremely rare, aggressive, malignant tumour that is most common in the mandible. Because of its rarity there is no general approach to treatment. We present a rare case of an ameloblastic carcinoma with multiple metastases in a 63-year-old Japanese man that was treated in several different ways, including chemoradiotherapy and immunotherapy.
CANIT0003239	30604316	Case report	A patient with Hodgkin's lymphoma after allogeneic HSCT	Hodgkins lymphoma	EFO:0000183	Blood and lymph nodes	PD-1 (Q15116); 	PD-1; 	Allogeneic hematopoietic stem cell transplantation followed by Nivolumab	N/A	Cell immunotherapy FOllowed by Immune checkpoint therapy	Nivolumab (DB09035); 	1	N/A	Case	These findings provide new insights into nivolumab-induced irAE pathogenesis and suggest possible optimal treatments for immune-related adverse events.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Relationship between clinical course of nivolumab-related myositis and immune status in a patient with Hodgkin's lymphoma after allogeneic hematopoietic stem cell transplantation.	 Int J Hematol	Although programmed cell death (PD)-1 blockade induces immune-related adverse events (irAEs), little is known about the safety of PD-1 blockade after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we describe immune system changes during nivolumab-related myositis in a patient with Hodgkin's lymphoma after allogeneic HSCT; to our knowledge, this is the first such report in the literature. At the onset of myositis, the patient lost lower limb mobility against gravity, and had an activated immune profile with increased cytotoxic CD107a and granzyme B expression, as well as pro-inflammatory cytokines, interferon-¦Ã, tumor necrosis factor-a, interleukin-2 in T and NK cells compared to healthy donor. Pulse steroid therapy decreased creatine kinase levels and induced PD-1 expression and regulatory T cells, but did not improve myositis; previously activated markers remained high. Four-week corticosteroid therapy decreased previously activated markers and the myositis improved. These findings provide new insights into nivolumab-induced irAE pathogenesis and suggest possible optimal treatments for irAEs.
CANIT0003240	30614355	Clinical research	Seven patients who had measurable metastatic lesions and had received at least two cycles of CP therapy were included in this study; we excluded two cases who had only one course of CP therapy without response evaluation. Carboplatin (area under the curve 4 or 5, Calvert formula) plus paclitaxel (175mg/m2) were administered intravenously once every four weeks.	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); 	CTLA-4; 	Ipilimumab followed by carboplatin plus paclitaxel	N/A	Immune checkpoint therapy followed by Chemotherapy	Ipilimumab (DB06186); carboplatin (DB00958); paclitaxel (DB01229)	7	N/A	Retrospective analysis	The mean duration from last ICI administration to first CP therapy was 31.4 days (range: 14¨C81 days). As the best response to the CP therapy, two of the seven patients achieved partial response (PR), two of the seven patients had stable disease (SD) and three of the seven patients had PD. The mean OS and PFS were 7.6 months (range: 4.4¨C14.8 months) and 5.0 months (range: 1.2¨C10.9 months), respectively. Of the four mucosal melanoma patients in this study, one achieved PR and two had SD as the best response. Furthermore, the mean OS and PFS were 9.5 and 7.3 months, respectively	Neutropenia,drug-induced lung injury,neuropathy,alopecia	N/A	N/A	N/A	N/A	N/A	 2019 Mar	The efficacy of platinum-based chemotherapy for immune checkpoint inhibitor-resistant advanced melanoma.	 Acta Oncol	Unable to provide
CANIT0003241	30614355	Clinical research	Seven patients who had measurable metastatic lesions and had received at least two cycles of CP therapy were included in this study; we excluded two cases who had only one course of CP therapy without response evaluation. Carboplatin (area under the curve 4 or 5, Calvert formula) plus paclitaxel (175mg/m2) were administered intravenously once every four weeks.	Melanoma	EFO:0000756	Skin	CTLA-4 (P16410); PD-1 (Q15116); 	CTLA-4; PD-1	Ipilimumab or nivolumab followed by carboplatin plus paclitaxel	N/A	Immune checkpoint therapy followed by Chemotherapy	Ipilimumab (DB06186); nivolumab (DB09035); carboplatin (DB00958); paclitaxel (DB01229)	7	N/A	Retrospective analysis	The mean duration from last ICI administration to first CP therapy was 31.4 days (range: 14¨C81 days). As the best response to the CP therapy, two of the seven patients achieved partial response (PR), two of the seven patients had stable disease (SD) and three of the seven patients had PD. The mean OS and PFS were 7.6 months (range: 4.4¨C14.8 months) and 5.0 months (range: 1.2¨C10.9 months), respectively. Of the four mucosal melanoma patients in this study, one achieved PR and two had SD as the best response. Furthermore, the mean OS and PFS were 9.5 and 7.3 months, respectively	Neutropenia,rush,neuropathy,alopecia	N/A	N/A	N/A	N/A	N/A	 2019 Mar	The efficacy of platinum-based chemotherapy for immune checkpoint inhibitor-resistant advanced melanoma.	 Acta Oncol	Unable to provide
CANIT0003242	30614355	Clinical research	Seven patients who had measurable metastatic lesions and had received at least two cycles of CP therapy were included in this study; we excluded two cases who had only one course of CP therapy without response evaluation. Carboplatin (area under the curve 4 or 5, Calvert formula) plus paclitaxel (175mg/m2) were administered intravenously once every four weeks.	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Nivolumab followed by carboplatin plus paclitaxel	N/A	Immune checkpoint therapy followed by Chemotherapy	Nivolumab (DB09035); carboplatin (DB00958); paclitaxel (DB01229)	7	N/A	Retrospective analysis	The mean duration from last ICI administration to first CP therapy was 31.4 days (range: 14¨C81 days). As the best response to the CP therapy, two of the seven patients achieved partial response (PR), two of the seven patients had stable disease (SD) and three of the seven patients had PD. The mean OS and PFS were 7.6 months (range: 4.4¨C14.8 months) and 5.0 months (range: 1.2¨C10.9 months), respectively. Of the four mucosal melanoma patients in this study, one achieved PR and two had SD as the best response. Furthermore, the mean OS and PFS were 9.5 and 7.3 months, respectively	Neutropenia,nausea,neuropathy,alopecia	N/A	N/A	N/A	N/A	N/A	 2019 Mar	The efficacy of platinum-based chemotherapy for immune checkpoint inhibitor-resistant advanced melanoma.	 Acta Oncol	Unable to provide
CANIT0003243	30616523	Clinical research	Cohort 1 included 18 patients treated with nivolumab or pembrolizumab. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy.	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	20	N/A	N/A	For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs. The brain metastases (BM) of lung cancer did not respond well to ICIs. Immunohistochemical analysis revealed a decreased infiltration of PD-1+ tumor infiltrating lymphocytes(TILs) in BM compared to primary lung cancer. These findings demonstrate that decreased PD-1+ of TILs could be one of the potential causative reasons for a poor intracranial response to ICIs.	N/A	N/A	N/A	CD3 (P07766); T-Lymphocyte (NCIT:C12476); 	CD3 expression on tumor infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Jan 7	Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.	 BMC Cancer	BACKGROUND: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway.METHODS: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells.RESULTS: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs.CONCLUSIONS: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM.
CANIT0003244	30616523	Clinical research	Cohort 1 included 18 patients treated with nivolumab or pembrolizumab. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy.	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	20	N/A	N/A	For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs. The brain metastases (BM) of lung cancer did not respond well to ICIs. Immunohistochemical analysis revealed a decreased infiltration of PD-1+ tumor infiltrating lymphocytes(TILs) in BM compared to primary lung cancer. These findings demonstrate that decreased PD-1+ of TILs could be one of the potential causative reasons for a poor intracranial response to ICIs.	N/A	N/A	N/A	CD4 (P01730); T-Lymphocyte (NCIT:C12476); 	CD4 expression on tumor infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Jan 7	Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.	 BMC Cancer	BACKGROUND: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway.METHODS: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells.RESULTS: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs.CONCLUSIONS: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM.
CANIT0003245	30616523	Clinical research	Cohort 1 included 18 patients treated with nivolumab or pembrolizumab. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy.	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	20	N/A	N/A	For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs. The brain metastases (BM) of lung cancer did not respond well to ICIs. Immunohistochemical analysis revealed a decreased infiltration of PD-1+ tumor infiltrating lymphocytes(TILs) in BM compared to primary lung cancer. These findings demonstrate that decreased PD-1+ of TILs could be one of the potential causative reasons for a poor intracranial response to ICIs.	N/A	N/A	N/A	CD8 (P01732); T-Lymphocyte (NCIT:C12476); 	CD8 expression on tumor infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Jan 7	Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.	 BMC Cancer	BACKGROUND: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway.METHODS: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells.RESULTS: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs.CONCLUSIONS: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM.
CANIT0003246	30616523	Clinical research	Cohort 1 included 18 patients treated with nivolumab or pembrolizumab. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy.	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	20	N/A	N/A	For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs. The brain metastases (BM) of lung cancer did not respond well to ICIs. Immunohistochemical analysis revealed a decreased infiltration of PD-1+ tumor infiltrating lymphocytes(TILs) in BM compared to primary lung cancer. These findings demonstrate that decreased PD-1+ of TILs could be one of the potential causative reasons for a poor intracranial response to ICIs.	N/A	N/A	N/A	FOXP3 (Q9BZS1); T-Lymphocyte (NCIT:C12476); 	FOXP3 expression on tumor infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Jan 7	Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.	 BMC Cancer	BACKGROUND: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway.METHODS: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells.RESULTS: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs.CONCLUSIONS: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM.
CANIT0003247	30616523	Clinical research	Cohort 1 included 18 patients treated with nivolumab or pembrolizumab. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy.	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	20	N/A	N/A	The brain metastases (BM) of lung cancer did not respond well to ICIs. Immunohistochemical analysis revealed a decreased infiltration of PD-1+ tumor infiltrating lymphocytes(TILs) in BM compared to primary lung cancer. These findings demonstrate that decreased PD-1+ of TILs could be one of the potential causative reasons for a poor intracranial response to ICIs.	N/A	N/A	N/A	PD-1 (Q15116); T-Lymphocyte (NCIT:C12476); 	PD-1 expression on tumor infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Jan 7	Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.	 BMC Cancer	BACKGROUND: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway.METHODS: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells.RESULTS: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs.CONCLUSIONS: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM.
CANIT0003248	30616523	Clinical research	Cohort 1 included 18 patients treated with nivolumab or pembrolizumab. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy.	Lung carcinoma	EFO:0001071	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab or nivolumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); nivolumab (DB09035); 	20	N/A	N/A	The brain metastases (BM) of lung cancer did not respond well to ICIs. Immunohistochemical analysis revealed a decreased infiltration of PD-1+ tumor infiltrating lymphocytes(TILs) in BM compared to primary lung cancer. These findings demonstrate that decreased PD-1+ of TILs could be one of the potential causative reasons for a poor intracranial response to ICIs.	N/A	N/A	N/A	PD-L1 (Q9NZQ7); T-Lymphocyte (NCIT:C12476); 	PD-L1 expression on tumor infiltrating lymphocytes	Gene expression signature on/in immune cell	 2019 Jan 7	Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients: therapeutic implications for immune checkpoint inhibitors.	 BMC Cancer	BACKGROUND: We aimed to compare intra- and extracranial responses to immune checkpoint inhibitors (ICIs) in lung cancer with brain metastases (BM), and to explore tumor microenvironments of the brain and lungs focusing on the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway.METHODS: Two cohorts of lung cancer patients with BM were analyzed. Cohort 1 included 18 patients treated with nivolumab or pembrolizumab, and intra- and extracranial responses were assessed. Cohort 2 comprised 20 patients who underwent both primary lung surgery and brain metastasectomy. Specimens from cohort 2 were subjected to immunohistochemical analysis for the following markers: CD3, CD4, CD8, FOXP3, and PD-1 on tumor infiltrating lymphocytes (TIL) and PD-L1 on tumor cells.RESULTS: Seven patients (38.9%) in cohort 1 showed progressive disease in both primary and intracranial lesions. Although the other 11 patients exhibited a partial response or stable disease in the primary lesion, eight showed a progression in BM. Interestingly, PD-1+ TILs were significantly decreased in BM (P = 0.034). For fifteen patients with adenocarcinoma, more distinctive patterns were observed in CD3+ (P = 0.078), CD8+ (P = 0.055), FOXP3+ (P = 0.016), and PD-1+ (P = 0.016) TILs.CONCLUSIONS: There may be discordant responses to an ICI of lung cancer between primary lung lesion and BM based on discrepancies in the tumor microenvironment. The diminished infiltration of PD-1+ TILs in tumor tissue within the brain may be one of the major factors that hinder the response to anti-PD-1 antibody in BM.
CANIT0003249	30627987	Clinical research	62 AGC patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	N/A	Hyperprogressive disease (HPD) was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in absolute neutrophil count (ANC) and C-reactive protein (CRP) levels upon treatment might indicate HPD.	N/A	N/A	N/A	C-reactive protein (P02741); 	Serum c-reactive protein levels	Gene expression signature in serum	 2019 Jul	Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer.	 Gastric Cancer	BACKGROUND: Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC).METHODS: Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as >= two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.RESULTS: Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.CONCLUSIONS: HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.
CANIT0003250	30627987	Clinical research	62 AGC patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	N/A	Liver metastases (77% vs. 41%) was significantly associated with Hyperprogressive disease (HPD).	N/A	N/A	N/A	Metastasis (NCIT:C19151); 	Liver metastasis	Disease status	 2019 Jul	Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer.	 Gastric Cancer	BACKGROUND: Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC).METHODS: Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as >= two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.RESULTS: Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.CONCLUSIONS: HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.
CANIT0003251	30627987	Clinical research	62 AGC patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	N/A	Hyperprogressive disease (HPD) was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in absolute neutrophil count (ANC) and C-reactive protein (CRP) levels upon treatment might indicate HPD.	N/A	N/A	N/A	Neutrophil counts (NCIT:C12533); 	Neutrophil counts	Cell percentage/counts in blood	 2019 Jul	Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer.	 Gastric Cancer	BACKGROUND: Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC).METHODS: Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as >= two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.RESULTS: Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.CONCLUSIONS: HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.
CANIT0003252	30627987	Clinical research	62 AGC patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	N/A	A large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) was significantly associated with Hyperprogressive disease (HPD).	N/A	N/A	N/A	Number of Lesions (NCIT:C174277); 	A large sum of target lesion diameters at baseline(median 104.2 mm vs. 44.9 mm) 	Disease status	 2019 Jul	Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer.	 Gastric Cancer	BACKGROUND: Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC).METHODS: Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as >= two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.RESULTS: Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.CONCLUSIONS: HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.
CANIT0003253	30627987	Clinical research	62 AGC patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	N/A	Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%) was significantly associated with Hyperprogressive disease (HPD).	N/A	N/A	N/A	Performance status (NCIT:C20641); 	ECOG performance status	Disease status	 2019 Jul	Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer.	 Gastric Cancer	BACKGROUND: Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC).METHODS: Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as >= two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.RESULTS: Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.CONCLUSIONS: HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.
CANIT0003254	30627987	Clinical research	62 AGC patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	62	N/A	N/A	Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with Hyperprogressive disease (HPD) than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001).	N/A	N/A	N/A	Performance status (NCIT:C20641); 	Hyperprogressive disease (HPD)	Disease status	 2019 Jul	Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer.	 Gastric Cancer	BACKGROUND: Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC).METHODS: Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as >= two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.RESULTS: Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.CONCLUSIONS: HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.
CANIT0003255	30642453	Case report	A 41-year-old woman diagnosed with an unresectable locally advanced L-LCNEC	Lung large-cell neuroendocrine carcinoma	MONDO:0002120	Nervous system	PD-1 (Q15116); 	PD-1; 	Palliative thoracic radiotherapy followed by Nivolumab	N/A	Radiotherapy followed by Immune checkpoint therapy	Nivolumab (DB09035); radiotherapy (NCIT:C15313); 	1	N/A	Case	We report the case of a 41-year-old woman diagnosed with an unresectable locally advanced L-LCNEC who presented an impressive tumor response to immunotherapy with nivolumab after non-curative thoracic radiotherapy. Salvage surgery was then performed, and pathologic analysis of the resected piece revealed the absence of residual viable tumor cells.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Feb	Complete tumor response of a locally advanced lung large-cell neuroendocrine carcinoma after palliative thoracic radiotherapy and immunotherapy with nivolumab.	 Lung Cancer	Lung large-cell neuroendocrine carcinoma (L-LCNEC) is a rare subset of lung carcinoma associated with poor overall survival. Due to its rarity, little has been established about its optimal treatment in the advanced stage. We report the case of a 41-year-old woman diagnosed with an unresectable locally advanced L-LCNEC who presented an impressive tumor response to immunotherapy with nivolumab after non-curative thoracic radiotherapy. Salvage surgery was then performed, and pathologic analysis of the resected piece revealed the absence of residual viable tumor cells. Based on this case report, we discuss the literature regarding the efficacy of inhibitors of programmed death-1 protein (PD-1) in L-LCNEC and their use in association with radiotherapy and in the neoadjuvant setting.
CANIT0003256	30663147	Case report	A 62-year-old Japanese man	Squamous cell lung carcinoma	EFO:0000708	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We describe a case of adult ashy dermatosis developing in a patient with squamous cell carcinoma of the lung, which was resolved by the administration of pembrolizumab in parallel with multiple vitiligo.	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Mar	Pembrolizumab resolves adult ashy dermatosis developing in patients with squamous cell carcinoma of the lung.	 J Dermatol	Ashy dermatosis is a rare cutaneous disorder of unknown etiology. We describe a case of adult ashy dermatosis developing in a patient with squamous cell carcinoma of the lung, which was resolved by the administration of pembrolizumab in parallel with multiple vitiligo. Interestingly, immunohistochemical staining revealed that lesional skin of the ashy dermatosis contained cytotoxic T cells and programmed death ligand 1 expressing cells. To our knowledge, this is the first case of adult ashy dermatosis resolved by pembrolizumab.
CANIT0003257	30666395	Clinical research	1302 patients with solid tumors, including 387 patients with GC/GEJC who had received nivolumab 3 mg/kg once every 2 weeks (Q2W). 	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1302	N/A	N/A	Nivolumab clearance (CL) was increased in gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) relative tonon-small cell lung cancer (NSCLC) in second line or subsequent lines of treatment (2L+). Higher nivolumab exposures achieved with 240 mg Q2W in Asian patients are predicted to be below the acceptable safety margin, supporting the use of a flat dose in both patient populations	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Population pharmacokinetics analysis of nivolumab in Asian and non-Asian patients with gastric and gastro-esophageal junction cancers.	 Cancer Chemother Pharmacol	PURPOSE: Nivolumab monotherapy provided clinically meaningful antitumor activity in Asian and non-Asian patients with chemotherapy-refractory gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) in the ATTRACTION-2 and CheckMate 032 studies, respectively. This analysis assessed the population pharmacokinetics (PopPK) of nivolumab, the impact of covariates on pharmacokinetics (PK), and the PK of nivolumab flat dosing in GC/GEJC using samples from these studies.METHODS: PopPK analyses were conducted using data from 1302 patients with solid tumors, including 387 patients with GC/GEJC who had received nivolumab 3 mg/kg once every 2 weeks (Q2W). The impact of covariates on nivolumab PK was assessed in the full model. Nivolumab exposures following a flat dose of 240 mg Q2W in patients with GC/GEJC were simulated and compared with those of 3 mg/kg Q2W.RESULTS: Nivolumab PK was described using a 2-compartment, zero-order intravenous infusion and time-varying clearance (CL) model. Baseline CL in patients with GC/GEJC was ~ 33% greater than in patients with non-small cell lung cancer (NSCLC) in second line or subsequent lines of treatment (2L+). The effect of race was not clinically relevant (< 20% difference). Nivolumab exposures following 240 mg Q2W were similar to 3 mg/kg Q2W in non-Asian patients and 46% higher in Asian patients due to lower body weight.CONCLUSIONS: Nivolumab CL was increased in GC/GEJC relative to NSCLC 2L+. Higher nivolumab exposures achieved with 240 mg Q2W in Asian patients are predicted to be below the acceptable safety margin, supporting the use of a flat dose in both patient populations.
CANIT0003258	30666395	Clinical research	1302 patients with solid tumors, including 387 patients with GC/GEJC who had received nivolumab 3 mg/kg once every 2 weeks (Q2W). 	Gastric-oesophageal junction cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	1302	N/A	N/A	Nivolumab clearance (CL) was increased in gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) relative tonon-small cell lung cancer (NSCLC) in second line or subsequent lines of treatment (2L+). Higher nivolumab exposures achieved with 240 mg Q2W in Asian patients are predicted to be below the acceptable safety margin, supporting the use of a flat dose in both patient populations	N/A	N/A	N/A	N/A	N/A	N/A	 2019 Apr	Population pharmacokinetics analysis of nivolumab in Asian and non-Asian patients with gastric and gastro-esophageal junction cancers.	 Cancer Chemother Pharmacol	PURPOSE: Nivolumab monotherapy provided clinically meaningful antitumor activity in Asian and non-Asian patients with chemotherapy-refractory gastric cancer (GC) or gastro-esophageal junction cancer (GEJC) in the ATTRACTION-2 and CheckMate 032 studies, respectively. This analysis assessed the population pharmacokinetics (PopPK) of nivolumab, the impact of covariates on pharmacokinetics (PK), and the PK of nivolumab flat dosing in GC/GEJC using samples from these studies.METHODS: PopPK analyses were conducted using data from 1302 patients with solid tumors, including 387 patients with GC/GEJC who had received nivolumab 3 mg/kg once every 2 weeks (Q2W). The impact of covariates on nivolumab PK was assessed in the full model. Nivolumab exposures following a flat dose of 240 mg Q2W in patients with GC/GEJC were simulated and compared with those of 3 mg/kg Q2W.RESULTS: Nivolumab PK was described using a 2-compartment, zero-order intravenous infusion and time-varying clearance (CL) model. Baseline CL in patients with GC/GEJC was ~ 33% greater than in patients with non-small cell lung cancer (NSCLC) in second line or subsequent lines of treatment (2L+). The effect of race was not clinically relevant (< 20% difference). Nivolumab exposures following 240 mg Q2W were similar to 3 mg/kg Q2W in non-Asian patients and 46% higher in Asian patients due to lower body weight.CONCLUSIONS: Nivolumab CL was increased in GC/GEJC relative to NSCLC 2L+. Higher nivolumab exposures achieved with 240 mg Q2W in Asian patients are predicted to be below the acceptable safety margin, supporting the use of a flat dose in both patient populations.
CANIT0003259	30704511	Clinical research	80 patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	80	N/A	Prospective study 	Some features (tumor mutational burden, EBV-infection, PD-L1 expression levels on tumor cells, DNA mismatch repair deficient) were associated with favorable response to nivolumab for advanced gastric cancer (AGC). Combining these features might be useful to predict efficacy	N/A	N/A	N/A	DNA mismatch repair-deficient (NCIT:C136712); 	DNA mismatch repair-deficient	Mutational status	 2019 Jan 31	Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer.	 J Immunother Cancer	BACKGROUND: Clinicopathological and molecular features of responders to nivolumab for advanced gastric cancer (AGC) are not well understood.METHODS: Patients (pts) with AGC who were treated with nivolumab after two or more chemotherapy regimens in a single institution from September 2017 to May 2018 were enrolled in this study. PD-L1 expression in tumor cells (TC) and mismatch repair (MMR) were analyzed by immunohistochemistry. Epstein-Barr virus (EBV) was detected by in situ hybridization. Cancer genome alterations were evaluated by a next-generation sequencing-based panel. High tumor mutation burden (TMB) was defined as more than 10 mutations/megabase.RESULTS: A total of 80 pts were analyzed in this study. Tumor response was evaluated in 72 pts with measurable lesions and 14 pts (19%) had an objective response. Overall response rate (ORR) was significantly higher in pts with ECOGPS 0 in those with PS 1 or 2, MMR-deficient (MMR-D) in those with MMR-proficient (MMR-P), PD-L1+ in TC in those with PD-L1- in TC and PIK3CA mutation in those with PIK3CA wild-type. ORR was 31% in pts with at least one of the following factors; MMR-D, high TMB, EBV+ and PD-L1+ in TC vs. 0% in those without these factors. Progression-free survival was significantly longer in pts with PS 0 than in those with PS 1 or 2, MMR-D than in those with MMR-P, and PD-L1+ in TC than in those with PD-L1- in TC.CONCLUSIONS: Some features were associated with favorable response to nivolumab for AGC. Combining these features might be useful to predict efficacy.
CANIT0003260	30704511	Clinical research	80 patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	80	N/A	Prospective study 	Some features (tumor mutational burden, EBV-infection, PD-L1 expression levels on tumor cells, DNA mismatch repair deficient) were associated with favorable response to nivolumab for advanced gastric cancer (AGC). Combining these features might be useful to predict efficacy	N/A	N/A	N/A	EBV (NCIT:C14204); 	EBV-positive	Microbiota	 2019 Jan 31	Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer.	 J Immunother Cancer	BACKGROUND: Clinicopathological and molecular features of responders to nivolumab for advanced gastric cancer (AGC) are not well understood.METHODS: Patients (pts) with AGC who were treated with nivolumab after two or more chemotherapy regimens in a single institution from September 2017 to May 2018 were enrolled in this study. PD-L1 expression in tumor cells (TC) and mismatch repair (MMR) were analyzed by immunohistochemistry. Epstein-Barr virus (EBV) was detected by in situ hybridization. Cancer genome alterations were evaluated by a next-generation sequencing-based panel. High tumor mutation burden (TMB) was defined as more than 10 mutations/megabase.RESULTS: A total of 80 pts were analyzed in this study. Tumor response was evaluated in 72 pts with measurable lesions and 14 pts (19%) had an objective response. Overall response rate (ORR) was significantly higher in pts with ECOGPS 0 in those with PS 1 or 2, MMR-deficient (MMR-D) in those with MMR-proficient (MMR-P), PD-L1+ in TC in those with PD-L1- in TC and PIK3CA mutation in those with PIK3CA wild-type. ORR was 31% in pts with at least one of the following factors; MMR-D, high TMB, EBV+ and PD-L1+ in TC vs. 0% in those without these factors. Progression-free survival was significantly longer in pts with PS 0 than in those with PS 1 or 2, MMR-D than in those with MMR-P, and PD-L1+ in TC than in those with PD-L1- in TC.CONCLUSIONS: Some features were associated with favorable response to nivolumab for AGC. Combining these features might be useful to predict efficacy.
CANIT0003261	30704511	Clinical research	80 patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	80	N/A	Prospective study 	Some features (tumor mutational burden, EBV-infection, PD-L1 expression levels on tumor cells, DNA mismatch repair deficient) were associated with favorable response to nivolumab for advanced gastric cancer (AGC). Combining these features might be useful to predict efficacy	N/A	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Jan 31	Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer.	 J Immunother Cancer	BACKGROUND: Clinicopathological and molecular features of responders to nivolumab for advanced gastric cancer (AGC) are not well understood.METHODS: Patients (pts) with AGC who were treated with nivolumab after two or more chemotherapy regimens in a single institution from September 2017 to May 2018 were enrolled in this study. PD-L1 expression in tumor cells (TC) and mismatch repair (MMR) were analyzed by immunohistochemistry. Epstein-Barr virus (EBV) was detected by in situ hybridization. Cancer genome alterations were evaluated by a next-generation sequencing-based panel. High tumor mutation burden (TMB) was defined as more than 10 mutations/megabase.RESULTS: A total of 80 pts were analyzed in this study. Tumor response was evaluated in 72 pts with measurable lesions and 14 pts (19%) had an objective response. Overall response rate (ORR) was significantly higher in pts with ECOGPS 0 in those with PS 1 or 2, MMR-deficient (MMR-D) in those with MMR-proficient (MMR-P), PD-L1+ in TC in those with PD-L1- in TC and PIK3CA mutation in those with PIK3CA wild-type. ORR was 31% in pts with at least one of the following factors; MMR-D, high TMB, EBV+ and PD-L1+ in TC vs. 0% in those without these factors. Progression-free survival was significantly longer in pts with PS 0 than in those with PS 1 or 2, MMR-D than in those with MMR-P, and PD-L1+ in TC than in those with PD-L1- in TC.CONCLUSIONS: Some features were associated with favorable response to nivolumab for AGC. Combining these features might be useful to predict efficacy.
CANIT0003262	30704511	Clinical research	80 patients	Gastric cancer	MONDO:0001056	Stomach	PD-1 (Q15116); 	PD-1; 	Nivolumab	N/A	Immune checkpoint therapy	Nivolumab (DB09035); 	80	N/A	Prospective study 	Some features (tumor mutational burden, EBV-infection, PD-L1 expression levels on tumor cells, DNA mismatch repair deficient) were associated with favorable response to nivolumab for advanced gastric cancer (AGC). Combining these features might be useful to predict efficacy	N/A	N/A	N/A	Tumor mutational burden (NCIT:C150128); 	Tumor mutational burden	Mutational status	 2019 Jan 31	Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer.	 J Immunother Cancer	BACKGROUND: Clinicopathological and molecular features of responders to nivolumab for advanced gastric cancer (AGC) are not well understood.METHODS: Patients (pts) with AGC who were treated with nivolumab after two or more chemotherapy regimens in a single institution from September 2017 to May 2018 were enrolled in this study. PD-L1 expression in tumor cells (TC) and mismatch repair (MMR) were analyzed by immunohistochemistry. Epstein-Barr virus (EBV) was detected by in situ hybridization. Cancer genome alterations were evaluated by a next-generation sequencing-based panel. High tumor mutation burden (TMB) was defined as more than 10 mutations/megabase.RESULTS: A total of 80 pts were analyzed in this study. Tumor response was evaluated in 72 pts with measurable lesions and 14 pts (19%) had an objective response. Overall response rate (ORR) was significantly higher in pts with ECOGPS 0 in those with PS 1 or 2, MMR-deficient (MMR-D) in those with MMR-proficient (MMR-P), PD-L1+ in TC in those with PD-L1- in TC and PIK3CA mutation in those with PIK3CA wild-type. ORR was 31% in pts with at least one of the following factors; MMR-D, high TMB, EBV+ and PD-L1+ in TC vs. 0% in those without these factors. Progression-free survival was significantly longer in pts with PS 0 than in those with PS 1 or 2, MMR-D than in those with MMR-P, and PD-L1+ in TC than in those with PD-L1- in TC.CONCLUSIONS: Some features were associated with favorable response to nivolumab for AGC. Combining these features might be useful to predict efficacy.
CANIT0003263	30711649	Clinical research	1034 patients	Non-small cell lung carcinoma	EFO:0003060	Lung	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	Docetaxel	Immune checkpoint therapy	Pembrolizumab (DB09037); 	768	266	Phase II/III KEYNOTE-010	These findings suggest that health-related quality of life (HRQoL) and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population	N/A	N/A	N/A	N/A	N/A	N/A	 2019 May	Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1-Expressing NSCLC.	 J Thorac Oncol	INTRODUCTION: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score >= 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here.METHODS: Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks or docetaxel 75 mg/m2 every 3 weeks. HRQoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30 (C30), EORTC QLQ-Lung Cancer 13 (LC13), and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain.RESULTS: Patient reported outcomes compliance was high across all three instruments. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or tumor proportion score status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had deteriorated status and more had improved status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true time to deterioration for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided p = 0.03), but not for the 2-mg/kg dose.CONCLUSIONS: These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population.
CANIT0003264	30715153	Clinical research	655 patients with melanoma	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	655	N/A	Phase Ib KEYNOTE-001 study	This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma	Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE	N/A	N/A	N/A	N/A	N/A	 2019 Apr 1	Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.	 Ann Oncol	BACKGROUND: Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.PATIENTS AND METHODS: Patients aged >=18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017).RESULTS: KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.CONCLUSIONS: This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT01295827.
CANIT0003265	30731276	Clinical research	Sixty-two patients were enrolled and evaluable	Head and neck squamous cell carcinoma	EFO:0000181	Head and neck	PD-L1 (Q9NZQ7); 	PD-L1; 	Durvalumab	N/A	Immune checkpoint therapy	Durvalumab (DB11714); 	62	N/A	Phase I/II expansion cohort	Durvalumab safety in HNSCC was manageable and consistent with other cohorts of the study. OS rate was 62% at 6 months and 38% at 12 months (42% for PD-L1 >=25%, 36% for <25%).	All-causality adverse events (AEs) occurred in 98.4%; drug-related AEs occurred in 59.7% and were grade III-IV in 9.7%. There were no drug-related discontinuations or deaths. 	N/A	N/A	PD-L1 (Q9NZQ7); 	PD-L1 expression levels on tumor cells	Gene expression signature on/in tumor cell	 2019 Mar	Safety and efficacy of durvalumab in patients with head and neck squamous cell carcinoma: results from a phase I/II expansion cohort.	 Eur J Cancer	INTRODUCTION: Durvalumab selectively blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1. Encouraging clinical activity and manageable safety were reported in urothelial carcinoma, non-small-cell lung cancer (NSCLC), hepatocellular carcinoma (HC) and small-cell lung cancer (SCLC) in a multicenter phase I/II study. Safety and clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) were evaluated in the expansion phase.METHODS: Patients received 10 mg/kg of durvalumab intravenously every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. The primary objective was safety; clinical activity was a secondary objective.RESULTS: Sixty-two patients were enrolled and evaluable (received first dose >=24 weeks before data cutoff). Median age was 57 years; 40.3% were human papillomavirus (HPV)-positive; 32.3% had tumour cell PD-L1 expression >=25%, and 62.9% were current/former smokers. They had a median of 2 prior systemic treatments (range, 1-13). All-causality adverse events (AEs) occurred in 98.4%; drug-related AEs occurred in 59.7% and were grade III-IV in 9.7%. There were no drug-related discontinuations or deaths. Objective response rate (blinded independent central review) was 6.5% (15.0% for PD-L1 >=25%, 2.6% for <25%). Median time to response was 2.7 months (range, 1.2-5.5); median duration was 12.4 months (range, 3.5-20.5+). Median progression-free survival was 1.4 months; median overall survival (OS) was 8.4 months. OS rate was 62% at 6 months and 38% at 12 months (42% for PD-L1 >=25%, 36% for <25%).CONCLUSIONS: Durvalumab safety in HNSCC was manageable and consistent with other cohorts of the study. Early, durable responses in these heavily pretreated patients warrant further investigation; phase III monotherapy and combination therapy studies are ongoing. CLINICAL TRIAL REGISTRY: clinicaltrials.gov NCT01693562; MedImmune study 1108.
CANIT0003266	30739840	Case report	A metastatic melanoma patient 	Melanoma	EFO:0000756	Skin	PD-1 (Q15116); 	PD-1; 	Pembrolizumab	N/A	Immune checkpoint therapy	Pembrolizumab (DB09037); 	1	N/A	Case	We report the occurrence of successive haematologic adverse events in a patient treated with pembrolizumab for a metastatic melanoma including an immune-mediated pure red cell aplasia (PRCA) followed by an immune thrombocytopaenia (IT)	Haematologic adverse events	N/A	N/A	N/A	N/A	N/A	 2019 Mar	A case of immune thrombocytopaenia induced by pembrolizumab in a metastatic melanoma patient with a history of immune-mediated pure red cell aplasia.	 Eur J Cancer	Unable to provide
CANIT0003267	30808517	Basic research	4400 patients£¬ 800 patients were assumed to have MSI-H tumors	Endometrial cancer	MONDO:0011962	Uterus	PD-1 (Q15116); VEGFR1 (P17948); 	PD-1; VEGFR1	Pembrolizumab	Pegylated liposomal doxorubicin or bevacizumab	Immune checkpoint therapy	Pembrolizumab (DB09037); bevacizumab (DB00112); pegylated liposomal doxorubicin (DB00997); 	4400	N/A	Basic research	For patients with Microsatellite instability-high (MSI-H) recurrent endometrial cancers who have failed first-line chemotherapy, pembrolizumab is cost-effective relative to other single agent drugs. To be cost-effective in non-MSI-H patients, the cost of pembrolizumab should decrease substantially	 Anemia	N/A	N/A	Microsatellite instability (NCIT:C36318); 	Microsatellite instability	Mutational status	 2019 May	Pembrolizumab in advanced recurrent endometrial cancer: A cost-effectiveness analysis.	 Gynecol Oncol	OBJECTIVE: To determine the cost-effectiveness of pembrolizumab in patients with recurrent endometrial cancer that have failed first-line chemotherapy.METHODS: We created a model to evaluate the cost-effectiveness of pembrolizumab compared to pegylated liposomal doxorubicin (PLD) or bevacizumab for the treatment of women with recurrent endometrial cancer who have failed carboplatin and paclitaxel. Microsatellite instability-high (MSI-H) and non-microsatellite instability-high (non-MSI-H) tumors were evaluated. We included 4400 patients in the model; 800 patients were assumed to have MSI-H tumors. Drug costs were calculated using 2016-2017 wholesale acquisition costs, and cost of Grade III-IV toxicities was estimated from clinical experience. Effectiveness was calculated as 2-year overall survival (OS). We calculated incremental cost-effectiveness ratios (ICERs) to determine the cost per 2-year survivor. Univariate sensitivity analyses were performed. The willingness to pay threshold was $100,000 per year of OS.RESULTS: The cost of therapy with PLD and bevacizumab were $33.2 million (M) and $167.9 M, respectively. The cost of pembrolizumab therapy was $318.3 M for non-MSI-H patients compared to $57.9 M for MSI-H patients. For non-MSI-H patients, bevacizumab was cost-effective relative to PLD with an ICER of $153,028, while pembrolizumab was not cost-effective relative to bevacizumab with an ICER of $341,830. For MSI-H patients, pembrolizumab was cost-effective compared to PLD with an ICER of $147,249, while bevacizumab was subjected to extended dominance. Sensitivity analysis revealed that for non-MSI-H patients, one cycle of pembrolizumab would need to cost $7253 or less to be cost-effective.CONCLUSIONS: For patients with MSI-H recurrent endometrial cancers who have failed first-line chemotherapy, pembrolizumab is cost-effective relative to other single agent drugs. To be cost-effective in non-MSI-H patients, the cost of pembrolizumab should decrease substantially.