Use of ezh2 inhibitors for treating cancer

Abstract

The disclosure provides methods of treating, identifying and/or selecting for treatment a subject having a cancer in which an immune checkpoint protein is upregulated. In certain embodiments, the methods for treating cancer in a subject in need thereof comprise administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor and (b) a therapeutically effective amount of an immune checkpoint inhibitor. In certain embodiments of the methods of the disclosure, the EZH2 inhibitor is tazemetostat.

1 . A method for treating a subject having a cancer that is positive for a T-cell marker comprising:
 (a) identifying a subject for treatment based on:
 (i) detecting a reference level of expression of PD-L1 in a subject having cancer, wherein the subject has not been administered an enhancer of zeste homolog 2 (EZH2) inhibitor, or a pharmaceutically acceptable salt thereof, then 
 (ii) detecting a level of expression of PD-L1 in the subject after the subject has been administered tazemetostat or the pharmaceutically acceptable salt thereof, and comparing the level of expression to the reference level of expression; and 
   (b) administering to the subject having a cancer, wherein the PD-L1 expression is increased after administration of tazemetostat or the pharmaceutically acceptable salt thereof:
 (i) 
   
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salt thereof; and
   (ii) a PD-1 inhibitor; and/or   (iii) a PD-L1 inhibitor,   
 wherein the PD-1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, Avelumab, BMS-936559, AMP-224, MEDI-0680, TSR-042, BGB-108, STI-1014, KY-1003, ALN-PDL, BGB-A317, KD-033, REGN-2810, PDR-001, SHR-1210, MGD-013, PF-06801591, CX-072, or a combination thereof, and 
 wherein the PD-L1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, Avelumab, BMS-936559, AMP-224, MEDI-0680, TSR-042, BGB-108, STI-1014, KY-1003, ALN-PDL, BGB-A317, KD-033, REGN-2810, PDR-001, SHR-1210, MGD-013, PF-06801591, CX-072, or a combination thereof. 
 
     
     
         2 . The method of  claim 1 , further comprising detecting a T-cell marker in the cancer of the subject. 
     
     
         3 . The method of  claim 1 , wherein the cancer is positive for a T-cell marker after administration of the EZH2 inhibitor. 
     
     
         4 . The method of  claim 2 , wherein the T-cell marker comprises CD4. 
     
     
         5 . The method of  claim 2 , wherein the T-cell marker comprises CD8. 
     
     
         6 . The method of  claim 1 , wherein the PD-1 inhibitor and/or the PD-L1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, and Durvalumab. 
     
     
         7 . The method of  claim 1 , wherein the cancer is bladder cancer or transitional cell cancer. 
     
     
         8 . The method of  claim 1 , wherein the cancer is head and neck cancer or squamous neck cancer. 
     
     
         9 . The method of  claim 1 , wherein the cancer is squamous cell carcinoma. 
     
     
         10 . The method of  claim 1 , wherein the cancer is a solid tumor. 
     
     
         11 . The method of  claim 1 , wherein the cancer is a soft tissue sarcoma. 
     
     
         12 . The method of  claim 1 , wherein the cancer is colorectal cancer or pancreatic cancer. 
     
     
         13 . The method of  claim 12 , wherein the pancreatic cancer is selected from ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, and mucinous cystadenocarcinoma. 
     
     
         14 . The method of  claim 1 , wherein the cancer is breast cancer. 
     
     
         15 . The method of  claim 1 , wherein the cancer is lung cancer.