Nivolumab dose escalation and expansion in patients with advanced hepatocellular carcinoma (HCC): The CheckMate 040 study.

226 Background: HCC diagnosed at advanced stages has a poor prognosis. Patients who progress on sorafenib have few options. Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), has demonstrated clinical and survival benefit in a number of tumor types. Here we report updated interim analyses of safety, efficacy, and exploratory biomarkers in patients with advanced HCC treated with nivolumab in the CheckMate 040 study (NCT01658878). Methods: Patients enrolled had advanced HCC with or without hepatitis C or B virus (HCV or HBV) infection. Prior sorafenib was allowed. Phase 1 dose-escalation evaluated nivolumab (0.1–10 mg/kg) Q2W. Phase 2 dose-expansion was initiated in 4 cohorts: sorafenib naïve/intolerant, sorafenib progressors, HCV infected, and HBV infected. All cohorts received nivolumab 3 mg/kg Q2W. The primary endpoint in the dose-escalation phase was safety/tolerability, and the primary endpoint in the dose-expansion phase was objective response rate (ORR) by RECIST v1.1 (central review). Secondary endpoints included duration of response (DOR), disease control rate (DCR), and overall survival (OS). Biomarkers within pre-treatment tumors were assessed. Results: Across dose escalation and expansion phases, 262 patients have been treated. Grade 3/4 treatment-related adverse events occurred in 20%. No maximum tolerated dose was reached during dose escalation (n = 48). The ORR (investigator-assessed) was 20% (95% CI 15–26) in 214 patients treated in the dose expansion phase with a median DoR of 9.9 months; DCR was 64% (95% CI 58–71). Responses were observed across etiologies and regardless of tumor PD-L1 expression. ORRs of 23% (95% CI 13–36) and 21% (95% CI 11–34) were observed in the uninfected sorafenib-naive and -treated patients, respectively. The 9-month overall survival rate in the expansion phase was 74% (95% CI 67–79). Association between immune-cell biomarkers and clinical outcomes will be presented. Conclusions: In this heavily pretreated population, responses to nivolumab were durable with encouraging overall survival. Safety was manageable and consistent with that observed in other solid tumors with no new safety signals. Clinical trial information: NCT01658878.