Treatment of PD-L1-negative melanoma using an anti-PD-1 antibody and an anti-CTLA-4 antibody

1. A method for treating a melanoma tumor in a human patient in need thereof comprising:

(i) identifying a patient having a PD-L1-negative melanoma tumor; and

(ii) administering to the patient:

(a) about 1 mg/kg of an antibody or an antigen-binding portion thereof that binds specifically to a human PD-1 (“an anti-PD-1 antibody”) and a dose of an antibody or an antigen-binding portion thereof that binds specifically to a human CTLA-4 (“an anti-CTLA-4 antibody”) every three weeks for about 4 doses; followed by

(b) a dose of the anti-PD-1 antibody,

wherein the dose in (b) is a flat dose of about 240 mg or about 480 mg.

2. A method for treating a melanoma tumor in a human patient in need thereof comprising administering to the patient:

(a) about 1 mg/kg of an antibody or an antigen-binding portion thereof that binds specifically to a human PD-1 (“an anti-PD-1 antibody”) and a dose of an antibody or an antigen-binding portion thereof that binds specifically to a human CTLA-4 (“an anti-CTLA-4 antibody”) every three weeks for about 4 doses; followed by

(b) a dose of the anti-PD-1 antibody,

wherein the dose in (b) is a flat dose of about 240 mg or about 480 mg.

3. The method of claim 2 , wherein the patient is characterized by (i) extended progression-free survival for over 8 months following the administration, (ii) tumor size reduction at least about 10% compared to the tumor size prior to the administration, or (iii) both (i) and (ii).

4. The method of claim 2 , further comprising measuring a PD-L1 expression on the melanoma tumor prior to the administration.

5. The method of claim 4 , 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.

6. The method of claim 5 , wherein the measuring further comprises assessing the proportion of cells in the test tissue sample that express PD-L1 on the cell surface.

7. The method of claim 6 , 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.

8. The method of claim 7 , 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 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.

9. The method of claim 2 , wherein less than about 5% of tumor cells show binding to an anti-PD-L1 antibody or an antigen-binding portion thereof.

10. The method of claim 2 , wherein the anti-PD-1 antibody is nivolumab.

11. The method of claim 2 , wherein the dose of the anti-PD-1 antibody in (b) is about 240 mg administered once every two weeks.

12. The method of claim 2 , wherein the dose of the anti-PD-1 antibody in (b) is about 480 mg administered once every four weeks.

13. The method of claim 2 , wherein the anti-CTLA-4 antibody is ipilimumab.

14. The method of claim 2 , wherein the dose of the anti-CTLA-4 antibody is from 0.1 mg/kg to 10.0 mg/kg.

15. The method of claim 14 , wherein the dose of the anti-CTLA-4 antibody is 3 mg/kg.

16. The method of claim 2 , further comprising administering an anti-cancer agent.

17. The method of claim 1 , wherein the dose of the anti-PD-1 antibody in (b) is about 240 mg administered once every two weeks.

18. The method of claim 1 , wherein the dose of the anti-PD-1 antibody in (b) is about 480 mg administered once every four weeks.

19. The method of claim 1 , wherein the dose of the anti-CTLA-4 antibody is 3 mg/kg.

20. The method of claim 1 , wherein the anti-PD-1 antibody is nivolumab.