Complementary evaluation of phase III immunotherapy trials in advanced HCC using the survival-inferred fragility index

BACKGROUND: Hepatocellular carcinoma (HCC) represents a major health burden, historically treated with tyrosine kinase inhibitors (TKIs). The advent of immune checkpoint inhibitors (ICIs) has reshaped treatments, with pivotal trials (IMbrave150 and HIMALAYA) establishing ICI-based combinations as first-line therapy. Traditional statistical metrics may not fully capture the robustness of trial outcomes. The Survival-Inferred Fragility Index (SIFI) quantifies trial stability as the minimum number of additional survival events required to lose statistical significance. METHODS: We systematically searched PubMed, Embase, Scopus for phase III randomized controlled trials comparing ICIs and TKIs in HCC published up to 31 May 2025. Trials reporting statistically significant time-to-event outcomes were included. Individual survival data were reconstructed from Kaplan-Meier curves using validated methods, SIFI was calculated using specific R algorithms. RESULTS: Six trials (4570 patients) were included for primary analysis (IMbrave150, COSMIC-312, ORIENT-32, CARES-310, HIMALAYA; CheckMate 9DW analyzed separately for its heterogeneous control arm). Median SIFI was 10 (range 5-18) for overall survival, 8 (range 6-19) for progression-free survival. SIFI corresponded to <1% of enrolled patients in most trials. Asian- trials (ORIENT-32, CARES-310) showed higher stability (SIFI 16-20) compared to global trials. CONCLUSIONS: SIFI analysis revealed heterogeneous stability across pivotal HCC trials. Incorporating fragility metrics with conventional statistics may improve interpretation and support balanced interpretation of trial outcomes.