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Efficacy of Nivolumab plus Ipilimumab in Advanced Hepatocellular Carcinoma with and without High-Risk Features: An International Multicenter Study

Year: 2026

Type: article

Abstract: Introduction: The phase 1/2 CheckMate-040 and the phase 3 CheckMate-9DW trials consistently demonstrated meaningful activity of nivolumab plus ipilimumab (Nivo/Ipi) in previously treated and treatment-naïve patients with advanced HCC. However, patients with ≥50% liver involvement, Vp4 portal vein tumor thrombosis (PVTT), or bile duct invasion were excluded from these trials. We aimed to assess the real-world efficacy and safety of Nivo/Ipi in this high-risk population. Methods: This international, multicenter, retrospective study was conducted in patients with advanced HCC who received Nivo/Ipi at six hospitals in Korea, Hong Kong, Singapore, and Taiwan between 2016 and 2024. Patients with Child-Pugh B/C or ECOG >2 were excluded. Results: = 7) and 101 as non-high risk. Baseline characteristics were comparable, aside from differences in liver function and high-risk features. Nivo/Ipi was administered as third-line or later-line therapy in 76.6% of patients. The high-risk group exhibited a significantly lower objective response rate (ORR) (12.8% vs. 34.3%) and shorter median progression-free survival (PFS) (1.2 vs. 2.9 months) and overall survival (OS) (3.6 vs. 16.5 months). Among the high-risk features, ≥50% liver involvement was strongly associated with inferior ORR, PFS, and OS, whereas Vp4 PVTT and bile duct invasion alone were not significantly associated with outcomes. A higher intrahepatic tumor burden was also inversely associated with treatment response and survival. Adverse events were more frequent in high-risk patients, particularly hyperbilirubinemia (36.4% vs. 13.9%; grade ≥3: 11.4% vs. 1.0%). On multivariable analysis, ≥50% liver involvement and prior immune-checkpoint inhibitor exposure independently predicted shorter PFS and OS. Conclusion: Extensive liver involvement emerged as the key predictor of poor prognosis, whereas Vp4 PVTT and bile duct invasion were not associated with significantly worse outcomes.

Source: Liver Cancer

DOI: 10.1159/000551631