Combination of a pd-1 antagonist and a vegfr inhibitor for treating cancer

Abstract

The present disclosure describes combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1) and a VEGFR inhibitor, and the use of the combination therapies for the treatment of cancer, and in particular for treating cancers that express PD-L 1.

1 . A method for treating a cancer in an individual comprising administering to the individual a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) and a vascular endothelial growth factor receptor (VEGFR) inhibitor, wherein the PD-1 antagonist is an anti-PD-1 monoclonal antibody which comprises a heavy chain and a light chain, wherein the heavy and light chains comprise SEQ ID NO:21 and SEQ ID NO:22, respectively, and further wherein the VEGFR inhibitor is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide or a pharmaceutically acceptable salt thereof, wherein the cancer tested positive for Programmed Death Ligand 1 (PD-L1) expression by an immunohistochemical (IHC) assay. 
     
     
         2 . The method of  claim 1 , wherein the individual is a human. 
     
     
         3 . The method of  claim 1 , wherein the cancer is a solid tumor. 
     
     
         4 . The method of  claim 1 , wherein the cancer is renal cell carcinoma. 
     
     
         5 . The method of  claim 1 , wherein the PD-1 antagonist is pembrolizumab and the VEGFR inhibitor is axitinib. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the cancer is bladder cancer, breast cancer, clear cell kidney cancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small-cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL). 
     
     
         18 . The method of  claim 17 , wherein the cancer is advanced renal cell carcinoma. 
     
     
         19 . A method for treating a human individual diagnosed with a cancer, comprising administering to the individual a combination therapy which comprises pembrolizumab and axitinib, wherein (a) axitinib is administered at a dose of 5 mg twice daily (BID) and pembrolizumab is administered at a dose selected from the group consisting of 1 mg/kg every three weeks (Q3W), 2 mg/kg Q3W and 200 mg Q3W or (b) axitinib is administered at a dose of 3 mg BID and pembrolizumab is administered at a dose selected from the group consisting of 1 mg/kg Q3W, 2 mg/kg Q3W and 200 mg Q3W, wherein a tissue section of the cancer removed from the individual prior to administration of the combination therapy tested positive for PD-L1 expression. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the PD-1 antagonist is pembrolizumab. 
     
     
         22 . The method of  claim 1 , wherein at least 1% of total tumor cells in a tissue section of the cancer exhibited histologic evidence of cell-surface membrane staining. 
     
     
         23 . The method of  claim 1 , wherein at least 5% of total tumor cells in a tissue section of the cancer exhibited histologic evidence of cell-surface membrane staining. 
     
     
         24 . The method of  claim 19 , wherein the cancer is renal cell carcinoma. 
     
     
         25 . The method of  claim 19 , wherein said pembrolizumab is provided at a dose of 200 mg Q3W. 
     
     
         26 . The method of  claim 19 , comprising administering to the individual a combination therapy which comprises pembrolizumab and axitinib, wherein axitinib is administered at a dose of 5 mg twice daily (BID) and pembrolizumab is administered at a dose of 1 mg/kg every three weeks (Q3W). 
     
     
         27 . The method of  claim 19 , comprising administering to the individual a combination therapy which comprises pembrolizumab and axitinib, wherein axitinib is administered at a dose of 5 mg twice daily (BID) and pembrolizumab is administered at a dose of 2 mg/kg Q3W. 
     
     
         28 . The method  claim 19 , comprising administering to the individual a combination therapy which comprises pembrolizumab and axitinib, wherein axitinib is administered at a dose of 5 mg twice daily (BID) and pembrolizumab is administered at a dose of 200 mg Q3W. 
     
     
         29 . The method of  claim 19 , comprising administering to the individual a combination therapy which comprises pembrolizumab and axitinib, wherein axitinib is administered at a dose of 3 mg twice daily (BID) and pembrolizumab is administered at a dose of 1 mg/kg every three weeks (Q3W). 
     
     
         30 . The method of  claim 19 , comprising administering to the individual a combination therapy which comprises pembrolizumab and axitinib, wherein axitinib is administered at a dose of 3 mg twice daily (BID) and pembrolizumab is administered at a dose of 2 mg/kg Q3W. 
     
     
         31 . The method of  claim 19 , comprising administering to the individual a combination therapy which comprises pembrolizumab and axitinib, wherein axitinib is administered at a dose of 3 mg twice daily (BID) and pembrolizumab is administered at a dose of 200 mg Q3W. 
     
     
         32 . The method of  claim 19 , wherein at least 1% of total tumor cells in the tissue section of the cancer exhibited histologic evidence of cell-surface membrane staining. 
     
     
         33 . The method of  claim 19 , wherein at least 5% of total tumor cells in the tissue section of the cancer exhibited histologic evidence of cell-surface membrane staining.