Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial

BACKGROUND: Patients with unresectable hepatocellular carcinoma have a poor prognosis, and treatments with long-term benefits are needed. We report results from the preplanned interim analysis of the CheckMate 9DW trial assessing nivolumab plus ipilimumab versus lenvatinib or sorafenib for unresectable hepatocellular carcinoma in the first-line setting. METHODS: This open-label, randomised, phase 3 trial enrolled patients aged 18 years or older with unresectable hepatocellular carcinoma without previous systemic therapy at 163 hospitals and cancer centres across 25 countries in Asia, Australia, Europe, North America, and South America. Patients had at least one measurable untreated lesion per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, a Child-Pugh score of 5 or 6, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive response technology system to receive nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) intravenously every 3 weeks for up to four doses, followed by nivolumab 480 mg every 4 weeks or investigator's choice of either oral lenvatinib (8 mg or 12 mg mg daily depending on bodyweight) or oral sorafenib (400 mg twice daily). Randomisation was stratified by aetiology; the presence of macrovascular invasion, extrahepatic spread, or both; and baseline alpha-fetoprotein concentration. The primary endpoint was overall survival, which was assessed in all randomly assigned patients; safety was an exploratory endpoint and was assessed in all randomly assigned patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04039607 (ongoing). FINDINGS: Between Jan 6, 2020, and Nov 8, 2021, 668 patients were randomly assigned to nivolumab plus ipilimumab (n=335) or lenvatinib or sorafenib (n=333). Early crossing of the overall survival Kaplan-Meier curves reflected a higher number of deaths during the first 6 months after randomisation with nivolumab plus ipilimumab (hazard ratio 1·65 [95% CI 1·12-2·43]) but was followed by a sustained separation of the curves thereafter in favour of nivolumab plus ipilimumab (0·61 [0·48-0·77]). After a median follow-up of 35·2 months (IQR 31·1-39·9), overall survival was significantly improved with nivolumab plus ipilimumab versus lenvatinib or sorafenib (median 23·7 months [95% CI 18·8-29·4] vs 20·6 months [17·5-22·5]; hazard ratio 0·79 [0·65-0·96]; two-sided stratified log-rank p=0·018); respective overall survival rates were 49% (95% CI 44-55) versus 39% (34-45) at 24 months and 38% (32-43) versus 24% (19-30) at 36 months. Overall, 137 (41%) of 332 patients receiving nivolumab plus ipilimumab and 138 (42%) of 325 patients receiving lenvatinib or sorafenib had grade 3-4 treatment-related adverse events. 12 deaths were attributed to treatment with nivolumab plus ipilimumab and three were attributed to treatment with lenvatinib or sorafenib. INTERPRETATION: Nivolumab plus ipilimumab showed a significant overall survival benefit versus lenvatinib or sorafenib and manageable safety in patients with previously untreated unresectable hepatocellular carcinoma. These results support nivolumab plus ipilimumab as a first-line treatment in this setting. FUNDING: Bristol Myers Squibb.