Treatment of pd-l1-negative melanoma using an anti-pd-1 antibody and an anti-ctla-4 antibody

Abstract

The invention provides a method of treating a melanoma comprising (i) identifying a patient having a PD-L1-negative melanoma and (ii) administering to the patient a combination of an anti-PD-1 antibody or an antigen-binding portion thereof and an anti-CTLA-4 antibody or an antigen-binding portion thereof. The methods of the invention can extend progression-free survival for over 8 months and/or reduces the tumor size at least about 10%, about 20%, about 30%, about 40%, or about 50% compared to the tumor size prior to the administration.

1 . (canceled) 
     
     
         2 . A method for treating a melanoma comprising administering to a patient afflicted with a melanoma tumor
 an anti-PD-1 antibody or an antigen-binding portion thereof that binds specifically to a human PD-1 (“anti-PD-1 antibody”) at a flat dose of 240 mg once every two weeks or 480 mg once every four weeks.   
     
     
         3 . The method of  claim 2  further comprising administering to the patient an anti-CTLA-4 antibody or an antigen-binding portion thereof that binds specifically to a human CTLA-4 (“anti-CTLA-4 antibody”). 
     
     
         4 - 7 . (canceled) 
     
     
         8 . The method of  claim 2 , wherein the patient is characterized by (i) extended progression-free survival for over 8 months, (ii) tumor size reduction at least about 10%, about 20%, about 30%, about 40%, or about 50% compared to the tumor size prior to the administration, or (iii) both. 
     
     
         9 - 13 . (canceled) 
     
     
         14 . The method of  claim 2 , further comprising measuring a PD-L1 expression on the melanoma tumor prior to the administration. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 14 , wherein the measuring comprises providing a test tissue sample obtained from the patient, the test tissue sample comprising tumor cells and/or tumor-infiltrating inflammatory cells. 
     
     
         17 . The method of  claim 16 , wherein the measuring further comprises assessing the proportion of cells in the test tissue sample that express PD-L1 on the cell surface. 
     
     
         18 . The method of  claim 17 , wherein the test tissue sample is a formalin-fixed paraffin-embedded (FFPE) tissue sample, and wherein the presence of PD-L1 is determined using an automated IHC assay. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 18 , wherein the IHC assay is performed using an anti-PD-L1 monoclonal antibody that specifically binds to the PD-L1 and wherein the anti-PD-L1 monoclonal antibody comprises a variable heavy chain region comprising the amino acid sequence set forth in SEQ ID NO: 1 and a variable light region comprising the amino acid sequence set forth in SEQ ID NO: 2. 
     
     
         21 . The method of  claim 2 , wherein the PD-L1-positive melanoma tumor is characterized by having at least about 5% of tumor cells showing binding to the anti-PD-L1 antibody or an antigen-binding portion thereof. 
     
     
         22 - 24 . (canceled) 
     
     
         25 . The method of  claim 2 , wherein the anti-PD-1 antibody is nivolumab or pembrolizumab. 
     
     
         26 - 31 . (canceled) 
     
     
         32 . The method of  claim 3 , wherein the anti-CTLA-4 antibody is ipilimumab. 
     
     
         33 . (canceled) 
     
     
         34 . The method of  claim 3 , wherein the anti-CTLA-4 antibody is administered once every 2, 3 or 4 weeks. 
     
     
         35 . The method of  claim 34 , wherein the anti-CTLA-4 antibody is administered at a dose of 1 or 3 mg/kg body weight once every 3 weeks. 
     
     
         36 . The method of  claim 34 , wherein the anti-CTLA-4 antibody is administered at a flat dose of about 80 mg, about 160 mg, or about 240 mg. 
     
     
         37 . The method of  claim 3 , wherein the anti-PD-1 antibody is administered concurrently with the anti-CTLA-4 antibody. 
     
     
         38 . The method of  claim 3 , wherein the anti-PD-1 antibody is administered prior to or after the anti-CTLA-4 antibody. 
     
     
         39 - 45 . (canceled) 
     
     
         46 . The method of  claim 3 , further comprising administering an anti-cancer agent. 
     
     
         47 . (canceled) 
     
     
         48 . The method of  claim 3 , wherein the anti-PD-1 antibody is administered at a flat dose of 240 mg once every two weeks. 
     
     
         49 . The method of  claim 3 , wherein the anti-PD-1 antibody is administered at a flat dose of 480 mg once every four weeks. 
     
     
         50 . A method for treating a melanoma in a patient afflicted with a melanoma tumor, comprising administering to the patient nivolumab as a monotherapy at a flat dose of 240 mg once every two weeks or 480 mg once every four weeks, wherein the patient is identified as having a PD-L1-positive melanoma tumor prior to the administration.