On April 11, 2025, the U.S. Food and Drug Administration (FDA) approved nivolumab (Opdivo) with ipilimumab (Yervoy) for the first-line treatment of adults with unresectable or metastatic hepatocellular carcinoma. (See here for details on approval of this combination immunotherapy for colorectal cancer.)
Efficacy was evaluated in CheckMate 9DW (ClinicalTrials.gov identifier NCT04039607), an open-label trial in 668 adults with unresectable or metastatic hepatocellular carcinoma. Patients had histologically confirmed hepatocellular carcinoma, Child-Pugh class A, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior systemic therapy for advanced disease. Patients were randomly assigned to receive either nivolumab at 1 mg/kg as an intravenous (IV) infusion with ipilimumab at 3 mg/kg IV every 3 weeks for a maximum of four doses, followed by single-agent nivolumab at 480 mg IV every 4 weeks or investigator’s choice of lenvatinib or sorafenib.
The primary efficacy outcome measure was overall survival. Overall response rate, based on Response Evaluation Criteria in Solid Tumors, version 1.1, assessed by blinded independent central review, was an additional efficacy outcome measure.
Median overall survival was 23.7 months (95% confidence interval [CI] = 18.8–29.4 months) with nivolumab plus ipilimumab and 20.6 months (95% CI = 17.5–22.5 months) with lenvatinib or sorafenib (hazard ratio = 0.79 [95% CI = 0.65–0.96] P < .0180). Overall response rates were 36.1% (95% CI = 31.0%–41.5%) and 13.2% (95% CI = 9.8%–17.3%) in the respective arms (P < .0001).
The most common adverse reactions (> 20%) were rash, pruritus, fatigue, and diarrhea.
The recommended nivolumab dose is 1 mg/kg IV with ipilimumab at 3 mg/kg IV every 3 weeks for a maximum of four doses, followed by nivolumab 240 mg IV every 2 weeks or nivolumab at 480 mg IV as a single agent every 4 weeks.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with Health Canada and Switzerland’s Swissmedic. This review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant, to facilitate the FDA’s assessment.
