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 firstline 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, ORIENT32, 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. (c) 2026 The Author(s). Published by Elsevier B.V. on behalf of Editrice Gastroenterologica Italiana S.r.l. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )