Phase I trial of extended-dose anti-PD-1 antibody BMS-936558 with a multipeptide vaccine for previously treated stage IV melanoma.

Abstract

8582 Background: BMS-936558, a fully human IgG4 anti-PD-1 antibody, has shown clinical activity in melanoma and renal cancer. Methods: 30 HLA A*0201 positive patients with unresectable, previously treated stage IV melanoma received MART-1/gp100/NY-ESO-1 peptides with adjuvant Montanide ISA 51 injected subcutaneously with BMS-936558 at 1, 3 or 10 mg/kg intravenously every 2 weeks for 24 weeks, followed by BMS-936558 alone every 3 months. No patient had prior ipilimumab. Endpoints were toxicity, correlative studies of immunity measured by ELISPOT and T-cell phenotype assays, and response by RECIST. Results: Median age was 62, with 14 men and 16 women. 73% of patients had M1c disease. One patient had dose limiting optic neuritis; one patient had dose limiting grade 3 interstitial pneumonitis. Of 10 patients at 1 mg/kg, 2 had confirmed partial responses (PR), both one year from initiation of study. 13 patients were treated at the 3 mg/kg cohort; 3 patients did not complete more than 3 doses secondary to progressive disease and one withdrew consent. Of 12 evaluable patients, 3 had confirmed PRs and 2 unconfirmed PRs. In the 10 mg/kg cohort, thus far 6 patients completed one cycle with 2 unconfirmed PRs and one patient stable. Only 2 of the 9 responders after one cycle have progressed with a median follow-up of 7 months. 2/6 patients failing BMS-936558 responded to ipilimumab. At week 12, patients in all cohorts had decreased PD-1 on CD4 and CD8 T-cells (p<0.0001), increased CD4 CTLA-4 levels (p=0.01) and dose related decreases in CD8 T-cells whereas CD4 T-cells increased (both p<0.05). ELISPOT assays showed that patients at all doses had no increased responses in fresh PBMC to MART-1/gp100, but showed dose related decreased responses to viral (CMV, EBV, FLU) peptides over time (p=0.04). Conclusions: BMS-936558 in combination with a peptide vaccine is well tolerated at 1 and 3mg/kg. Accural to the 10mg/kg cohort is on-going. Responses have been observed at all dose levels. PD-1 levels on T-cells decreased, and CTLA-4 levels increased in CD4 T cells in all cohorts. There was a dose-related decrease in CD8 T-cells and in viral-specific T-cells. Further study of BM-936558 is warranted to determine its optimal dose.