The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) is emerging as a promising first-line treatment for patients with unresectable hepatocellular carcinoma (HCC), offering improved overall survival and response rates compared to standard tyrosine kinase inhibitors. Data from the phase 3 CheckMate 9DW trial, presented at the 2025 Gastrointestinal Cancers Symposium, highlight the clinical benefits of this immunotherapy combination in a challenging patient population.
Improved Overall Survival
The CheckMate 9DW trial (NCT04039607) compared nivolumab plus ipilimumab to investigator's choice of lenvatinib (Lenvima) or sorafenib (Nexavar) in patients with previously untreated, unresectable HCC. The results demonstrated a significant improvement in median overall survival (OS) with the combination therapy, reaching 23.7 months (95% CI, 18.8-29.4) compared to 20.6 months (95% CI, 17.5-22.5) with lenvatinib or sorafenib (HR, 0.79; 95% CI, 0.65-0.96; P = .018).
Enhanced Response Rates and Duration
In addition to improved survival, nivolumab plus ipilimumab also demonstrated a significantly higher objective response rate (ORR) of 36% (95% CI, 31%-42%) compared to 13% (95% CI, 10%-17%) with lenvatinib or sorafenib (P < .0001). The median duration of response (DOR) was also significantly longer with the combination therapy, at 30.4 months (95% CI, 21.2-not evaluable) versus 12.9 months (95% CI, 10.2-13.2) for lenvatinib or sorafenib.
Safety and Tolerability
The safety profile of nivolumab and ipilimumab in the CheckMate 9DW trial was consistent with previous studies. Treatment-related adverse events (TRAEs) occurred in 84% of patients in the combination arm and 91% in the lenvatinib/sorafenib arm. Grade 3 or 4 TRAEs were reported in 41% and 42% of patients, respectively. Serious TRAEs were experienced by 28% and 14% of patients, respectively. Notably, 12 treatment-related deaths occurred in the nivolumab plus ipilimumab arm versus 3 in the control arm, with most deaths in the combination arm occurring in patients with severe underlying liver disease.
Regulatory Progress
In August 2024, the FDA accepted a supplemental biologics license application for nivolumab plus ipilimumab as a first-line treatment for unresectable HCC, with a Prescription Drug User Fee Act (PDUFA) target action date of April 21, 2025.
