Long-term Survival and Cure Fraction in Patients with Advanced Hepatocellular Carcinoma under Immunotherapy in Randomized Controlled Trials and Real-world Data

초록

Purpose: Immune checkpoint inhibitors (ICI) can induce long-term survival and even cancer cure in several cancers. Mixture cure models (MCM) estimate the fraction of long-term survivors and cured patients but have not been applied in hepatocellular carcinoma (HCC).Experimental Design: We identified phase III randomized trials of first-line ICI in advanced HCC with mature follow-up (>= 30 months) and analyzed a cohort of patients with HCC treated with atezolizumab-bevacizumab. After reconstructing Kaplan-Meier curves, MCMs estimated the long-term survivors' fraction [overall survival (OS)] and cure fractions [progression-free survival (PFS)].Results: In HIMALAYA (median follow-up of 60 months), long-term survival was 12.8% [95% confidence interval (CI), 8.5%-18.6%] with durvalumab-tremelimumab versus 5.2% (95% CI, 2.6%-10.2%) with sorafenib; the cure fraction was not assessable. In CheckMate 9DW (median follow-up: 35.2 months), long-term survival was 8.7% (95% CI, 0.2%-81.3%) versus 4.1% (95% CI, 0.1%-66.1%), and cure fractions were 17.8% (95% CI, 12%-25.8%) versus 3.5% (95% CI, 0.7%-16.7%) for nivolumab-ipilimumab and sorafenib/lenvatinib, respectively, with long-term OS estimates remaining exploratory due to limited late numbers at risk. In RATIONALE-301, long-term survival was 25.2% (95% CI, 19.2-32.2) with tislelizumab versus 15.4% (95% CI, 10-22.8) with sorafenib. The IMbrave150 trial was not analyzed due to insufficient follow-up (15.6 months). Among a clinical cohort of 1,581 patients treated with atezolizumab-bevacizumab (median follow-up: 34.7 months), long-term survival was 12.3% (95% CI, 9.3%-16.1%), and the cure fraction was 7.9% (95% CI, 6.3%-9.8%). In 1,187 patients meeting IMbrave150 criteria, long-term survival reached 15.4% (95% CI, 10.6%-18.5%), and the cure fraction was 9.1% (95% CI, 7.3%-11.4%). Albumin-bilirubin score and hepatitis C predicted long-term survival, and albumin and hepatitis C predicted cure.Conclusions: Across trials and real-world data, ICI combinations achieve long-term survival in 10% to 15% of patients with advanced HCC, with cure fractions of 7% to 9%.

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