Therapeutic and diagnostic methods for cancer

Abstract

The present invention provides therapeutic and diagnostic methods and compositions for cancer, for example, bladder cancer. The invention provides methods of treating bladder cancer, methods of determining whether a patient suffering from bladder cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist, methods of predicting responsiveness of a patient suffering from bladder cancer to treatment comprising a PD-L1 axis binding antagonist, and methods of selecting a therapy for a patient suffering from bladder cancer, based on expression levels of a biomarker of the invention (e.g., PD-L1 expression levels in tumor-infiltrating immune cells in a tumor sample obtained from the patient) and/or based on the determination of a tumor sample subtype.

What is claimed is: 
     
         1 . A method of treating a patient suffering from a bladder cancer, the method comprising administering to the patient a therapeutically effective amount of a PD-L1 axis binding antagonist, wherein a tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more of the tumor sample. 
     
     
         2 . The method of  claim 1 , wherein the median overall survival time of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is at least 8 months. 
     
     
         3 . The method of  claim 1  or  2 , wherein the median overall survival time of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is at least about 8.8 months. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the objective response rate of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is at least about 12%. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the objective response rate of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is at least about 21%. 
     
     
         6 . The method of any one of  claims 1 - 4 , wherein the objective response rate of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is about 18%. 
     
     
         7 . The method of  claim 1 , wherein the tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 5% or more of the tumor sample. 
     
     
         8 . The method of  claim 7 , wherein the median overall survival time of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is at least 9 months. 
     
     
         9 . The method of  claim 7  or  8 , wherein the median overall survival time of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is at least about 11 months. 
     
     
         10 . The method of any one of  claims 7 - 9 , wherein the objective response rate of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is at least about 14%. 
     
     
         11 . The method of any one of  claims 7 - 10 , wherein the objective response rate of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is at least about 25%. 
     
     
         12 . The method of any one of  claims 7 - 11 , wherein the objective response rate of a patient administered a therapeutically effective amount of a PD-L1 axis binding antagonist is about 27%. 
     
     
         13 . The method of  claim 7 , wherein the tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 10% or more of the tumor sample. 
     
     
         14 . The method of any one of  claims 1 - 13 , wherein the tumor sample obtained from the patient has been determined to be a luminal subtype tumor. 
     
     
         15 . A method of treating a patient suffering from a bladder cancer, the method comprising administering to the patient a therapeutically effective amount of a PD-L1 axis binding antagonist, wherein a tumor sample obtained from the patient has been determined to be a luminal subtype tumor. 
     
     
         16 . The method of  claim 14  or  15 , wherein:
 (a) the expression level of at least one of CDKN2A, GATA3, FOXA1, and ERBB2 in the tumor sample obtained from the patient has been determined to be increased relative to a reference level of the at least one gene, and/or 
 (b) the expression level of at least one of FGFR3, KRT5, KRT14, and EGFR in the tumor sample obtained from the patient has been determined to be decreased relative to a reference level of the at least one gene. 
 
     
     
         17 . The method of  claim 16 , wherein:
 (a) the expression levels of CDKN2A, GATA3, FOXA1, and ERBB2 in the tumor sample obtained from the patient have been determined to be increased relative to reference levels of the genes, and/or   (b) the expression levels of FGFR3, KRT5, KRT14, and EGFR in the tumor sample obtained from the patient have been determined to be decreased relative to reference levels of the genes.   
     
     
         18 . The method of  claim 17 , wherein:
 (a) the expression levels of CDKN2A, GATA3, FOXA1, and ERBB2 in the tumor sample obtained from the patient have been determined to be increased relative to reference levels of the genes, and   (b) the expression levels of FGFR3, KRT5, KRT14, and EGFR in the tumor sample obtained from the patient have been determined to be decreased relative to reference levels of the genes.   
     
     
         19 . The method of any one of  claims 14 - 18 , wherein the expression level of miR-99a-5p or miR100-5p in the tumor sample obtained from the patient has been determined to be increased relative to a reference level of the microRNA (miRNA). 
     
     
         20 . The method of  claim 19 , wherein the expression levels of miR-99a-5p and miR100-5p in the tumor sample obtained from the patient have been determined to be increased relative to reference levels of the miRNAs. 
     
     
         21 . The method of any one of  claims 14 - 20 , wherein the expression level of at least one of CD8A, GZMA, GZMB, IFNG, CXCL9, CXCL10, PRF1, and TBX21 in the tumor sample obtained from the patient has been determined to be increased relative to a reference level of the at least one gene. 
     
     
         22 . The method of  claim 21 , wherein the expression levels of at least CXCL9 and CXCL10 in the tumor sample obtained from the patient have been determined to be increased relative to reference levels of the genes. 
     
     
         23 . The method of any one of  claims 14 - 22 , wherein the luminal subtype tumor is a luminal cluster II subtype tumor. 
     
     
         24 . A method for determining whether a patient suffering from a bladder cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist, the method comprising:
 determining the expression level of PD-L1 in tumor-infiltrating immune cells in a tumor sample obtained from the patient,   wherein a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more of the tumor sample indicates that the patient is likely to respond to treatment comprising a PD-L1 axis binding antagonist.   
     
     
         25 . A method for predicting responsiveness of a patient suffering from a bladder cancer to treatment comprising a PD-L1 axis binding antagonist, the method comprising:
 determining the expression level of PD-L1 in tumor-infiltrating immune cells in a tumor sample obtained from the patient,   wherein a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more of the tumor sample indicates that the patient is likely to respond to treatment comprising a PD-L1 axis binding antagonist.   
     
     
         26 . A method for selecting a therapy for a patient suffering from a bladder cancer, the method comprising:
 determining the expression level of PD-L1 in tumor-infiltrating immune cells in a tumor sample obtained from the patient, and   selecting a therapy comprising a PD-L1 axis binding antagonist for the patient based on a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more of the tumor sample.   
     
     
         27 . The method of any one of  claims 24 - 26 , wherein the tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 5% or more of the tumor sample. 
     
     
         28 . The method of  claim 27 , wherein the tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating cells that comprise at least about 10% of the tumor sample. 
     
     
         29 . A method for determining whether a patient suffering from a bladder cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist, the method comprising:
 determining from a tumor sample obtained from the patient the subtype of the tumor, wherein a luminal subtype tumor indicates that the patient is likely to respond to treatment comprising a PD-L1 axis binding antagonist.   
     
     
         30 . A method for predicting responsiveness of a patient suffering from a bladder cancer to treatment comprising a PD-L1 axis binding antagonist, the method comprising:
 determining from a tumor sample obtained from the patient the subtype of the tumor,   wherein a luminal subtype tumor indicates that the patient is likely to respond to treatment comprising a PD-L1 axis binding antagonist.   
     
     
         31 . A method for selecting a therapy for a patient suffering from a bladder cancer, the method comprising:
 determining from a tumor sample obtained from the patient the subtype of the tumor, and   selecting a therapy comprising a PD-L1 axis binding antagonist for the patient based on the determination that the tumor is a luminal subtype tumor.   
     
     
         32 . The method of any one of  claims 24 - 31 , further comprising administering to the patient a therapeutically effective amount of a PD-L1 axis binding antagonist based on the expression level of PD-L1 in tumor-infiltrating immune cells in the tumor sample. 
     
     
         33 . The method of any one of  claims 1 - 32 , wherein the PD-L1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. 
     
     
         34 . The method of  claim 33 , wherein the PD-L1 axis binding antagonist is a PD-L1 binding antagonist. 
     
     
         35 . The method of  claim 34 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. 
     
     
         36 . The method of  claim 35 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1. 
     
     
         37 . The method of  claim 35 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1. 
     
     
         38 . The method of any one of  claims 35 - 37 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. 
     
     
         39 . The method of any one of  claims 34 - 38 , wherein the PD-L1 binding antagonist is an antibody. 
     
     
         40 . The method of  claim 39 , wherein the antibody is selected from the group consisting of atezolizumab (MPDL3280A), YW243.55.S70, MDX-1105, MEDI4736 (durvalumab), and MSB0010718C (avelumab). 
     
     
         41 . The method of  claim 39 , wherein the antibody comprises a heavy chain comprising HVR-H1 sequence of SEQ ID NO:19, HVR-H2 sequence of SEQ ID NO:20, and HVR-H3 sequence of SEQ ID NO:21; and a light chain comprising HVR-L1 sequence of SEQ ID NO:22, HVR-L2 sequence of SEQ ID NO:23, and HVR-L3 sequence of SEQ ID NO:24. 
     
     
         42 . The method of  claim 39 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:26 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4. 
     
     
         43 . The method of  claim 33 , wherein the PD-L1 axis binding antagonist is a PD-1 binding antagonist. 
     
     
         44 . The method of  claim 43 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners. 
     
     
         45 . The method of  claim 44 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. 
     
     
         46 . The method of  claim 44 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. 
     
     
         47 . The method of any one of  claims 44 - 46 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. 
     
     
         48 . The method of any one of  claims 43 - 47 , wherein the PD-1 binding antagonist is an antibody. 
     
     
         49 . The method of  claim 48 , wherein the antibody is selected from the group consisting of: MDX-1106 (nivolumab), MK-3475 (pembrolizumab), CT-011 (pidilizumab), MEDI-0680 (AMP-514), PDR001, REGN2810, and BGB-108. 
     
     
         50 . The method of any one of  claims 33 - 47 , wherein the PD-1 binding antagonist is an Fc-fusion protein. 
     
     
         51 . The method of  claim 50 , wherein the Fc-fusion protein is AMP-224. 
     
     
         52 . The method of any one of  claims 1 - 23  and  32 - 51 , further comprising administering to the patient an effective amount of a second therapeutic agent. 
     
     
         53 . The method of  claim 52 , wherein the second therapeutic agent is selected from the group consisting of a cytotoxic agent, a growth-inhibitory agent, a radiation therapy agent, an anti-angiogenic agent, and combinations thereof. 
     
     
         54 . The method of any one of  claims 1 - 53 , wherein the bladder cancer is an urothelial bladder cancer. 
     
     
         55 . The method of  claim 54 , wherein the urothelial bladder cancer is a metastatic urothelial bladder cancer. 
     
     
         56 . The method of  claim 54 , wherein the urothelial bladder cancer is a locally advanced urothelial bladder cancer. 
     
     
         57 . The method of any one of  claims 1 - 56 , wherein the patient has progressed following treatment with a platinum-based chemotherapeutic agent. 
     
     
         58 . The method of any one of  claims 1 - 57 , wherein the tumor sample is a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample. 
     
     
         59 . The method of any one of  claims 1 - 14 ,  16 - 28 , and  52 - 58 , wherein the expression level of PD-L1 is a protein expression level. 
     
     
         60 . The method of  claim 59 , wherein the protein expression level of PD-L1 is determined using a method selected from the group consisting of immunohistochemistry (IHC), immunofluorescence, flow cytometry, and Western blot. 
     
     
         61 . The method of  claim 60 , wherein the protein expression level of PD-L1 is determined using IHC. 
     
     
         62 . The method of  claim 60  or  61 , wherein the protein expression level of PD-L1 is detected using an anti-PD-L1 antibody. 
     
     
         63 . The method of any one of  claims 1 - 14 ,  16 - 28 , and  52 - 58 , wherein the expression level of PD-L1 is an mRNA expression level. 
     
     
         64 . The method of  claim 63 , wherein the mRNA expression level of PD-L1 is determined using a method selected from the group consisting of quantitative polymerase chain reaction (qPCR), reverse transcription qPCR (RT-qPCR), RNA sequencing, microarray analysis, in situ hybridization, and serial analysis of gene expression (SAGE). 
     
     
         65 . A PD-L1 axis binding antagonist for use in treating a patient suffering from a bladder cancer, wherein a tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more of the tumor sample. 
     
     
         66 . Use of an effective amount of a PD-L1 axis binding antagonist in the manufacture of a medicament for use in treating a patient suffering from a bladder cancer, wherein a tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more of the tumor sample. 
     
     
         67 . A composition comprising an effective amount of a PD-L1 axis binding antagonist for use in a method of treating a patient suffering from a bladder cancer, wherein a tumor sample obtained from the patient has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more of the tumor sample.