Risk of liver adverse events with nivolumab/ipilimumab combination therapy for hepatocellular carcinoma: A disproportionality analysis based on the Food and Drug Administration Adverse Event Reporting System data base.

The combination of nivolumab and ipilimumab represents a major therapeutic advance for hepatocellular carcinoma (HCC), yet its real-world hepatic safety profile remains insufficiently characterized. To address this, we conducted a disproportionality analysis using adverse event reports from the US Food and Drug Administration Adverse Event Reporting System submitted between the first quarter of 2004 and the third quarter of 2025, specifically for patients with HCC receiving this dual immunotherapy. Disproportionality signals were assessed using 4 complementary methods: the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. A total of 128 liver adverse event reports were identified, spanning 2 primary system organ classes with the majority classified under hepatobiliary disorders, and 5 significant disproportionality signals for specific liver adverse events were detected across these methods. Collectively, these findings highlight the critical need for vigilant monitoring of hepatic function in patients with HCC treated with nivolumab/ipilimumab in routine clinical practice. SIGNIFICANCE STATEMENT: The study specifically focuses on the hepatic safety of dual immune checkpoint inhibitor therapy in patients with HCC, addressing the gap in real-world hepatic safety data, and successfully identifies 5 specific liver adverse event signals that provide clear directions for clinical monitoring of liver injury.