S. Agrawal, A. Roy, Y. Feng, G. Bajaj, S. Saeger, J. Park, I. Waxman, M. Gupta; Bristol-Myers Squibb, Princeton, NJ

BACKGROUND: Nivolumab, a fully human monoclonal IgG4 antibody targeting the programmed death-1 receptor, is currently under development for immunotherapy of multiple cancer types. This evaluation aimed to assess the immunogenicity of nivolumab and its impact on PK and safety in subjects with solid tumors treated with nivolumab monotherapy.
METHODS: The occurrence of anti-drug antibody (ADA) after nivolumab treatment was assessed from serum samples of three studies (phase I, n=1; phase II, n=1; phase III, n=1). Samples were collected at regular intervals and ≤100 days after the last dose and analyzed by validated electrochemiluminescence assays. Confirmed positive samples from phase II or III studies were further tested for presence of neutralizing antibodies (NAb). The effect of ADA on nivolumab clearance (CL) was assessed as a time-varying covariate in population PK (PPK) analysis. The impact of ADA on safety was assessed in persistent positive (subject with 2 consecutive positive samples ≥8 weeks apart) and neutralizing positive subjects.
RESULTS: Of 524 nivolumab-treated subjects with available baseline and post-baseline ADA assessment, 4 (0.8%) subjects were persistent positive for the presence of ADA. Of 281 subjects, 2 were positive for NAb. The impact of immunogenicity on nivolumab CL was minimal (1.16; 90% CI, 0.9-1.3) as determined by PPK analysis. No acute infusion reactions, hypersensitivity events, or new or additional adverse events were observed in subjects with persistent or neutralizing antibodies.
CONCLUSION: The immunogenic potential of nivolumab was minimal, with low persistent positive rates and low incidences of NAb. There was minimal impact of immunogenicity on nivolumab CL, with no evidence of an altered safety profile with ADA development.