Association of immune-mediated hepatitis with immune checkpoint inhibitor regimens in advanced hepatocellular carcinoma.

Abstract

e16200 Background: Immune checkpoint inhibitors (ICIs) are standard for unresectable/advanced hepatocellular carcinoma (HCC); however, immune-mediated hepatitis (IMH) remains a clinically relevant toxicity in patients with underlying liver disease. Prior safety analyses often pool heterogeneous tumor types or report nonspecific transaminase elevations, limiting HCC- and regimen-specific risk estimation. We evaluated IMH across contemporary ICI regimens in advanced HCC. Methods: Phase II–III trials and relevant meta-analyses of ICI-containing regimens in unresectable/advanced HCC were reviewed. IMH was defined as trial-reported immune-related hepatitis or hepatic adverse events of special interest managed under immune-toxicity frameworks (when specified). Outcomes included any-grade and grade ≥3 IMH, corticosteroid use, treatment discontinuation, and fatal IMH. Regimens were categorized as ICI monotherapy, dual immune checkpoint blockade (IO–IO), or ICI plus anti-VEGF or tyrosine kinase inhibitor therapy (IO–VEGF/IO–TKI). Results: Across meta-analyses focused on primary liver cancers, pooled IMH incidence was ~2.0% (any grade) and ~1.3% (grade ≥3). Trial-level immune-hepatic toxicity reporting was most detailed for IO–IO and IO–VEGF/IO–TKI regimens. In HIMALAYA (STRIDE; IO–IO; n = 388), IMH occurred in 7.5%, with grade ≥3 events in 4.4%; corticosteroids were required in reported IMH cases, 2.3% discontinued therapy, and 0.8% experienced fatal IMH. Additional first-line trials informing regimen-class risk included IO–IO (CheckMate 9DW), IO–VEGF (IMbrave150; ORIENT-32; camrelizumab plus rivoceranib), IO–TKI (COSMIC-312; LEAP-002), and ICI monotherapy (CheckMate 459; RATIONALE-301; KEYNOTE studies). Overall patterns suggest higher IMH risk with IO–IO, intermediate risk with IO–VEGF/IO–TKI, and lower risk with monotherapy; however, cross-trial comparisons are limited by heterogeneity in immune attribution. Conclusions: IMH risk in advanced HCC appears regimen-class dependent, with the most clinically significant signal observed with dual checkpoint blockade. Standardized reporting of immune-attributed hepatic events is needed to support actionable risk stratification. Immune-mediated hepatitis across ICI regimens in advanced hepatocellular carcinoma. Regimen Key trials Any-grade IMH (%) Grade ≥3 IMH (%) Notes IO–IO HIMALAYA; CheckMate 9DW 7.5 / NR 4.4 / NR Steroids; 2.3% d/c; 0.8% fatal IO–VEGF IMbrave150; ORIENT-32; camrelizumab+rivoceranib NR NR Immune attribution variable IO–TKI COSMIC-312; LEAP-002 NR NR IMH not consistently separated ICI mono CheckMate 459; RATIONALE-301 Low Low Lower immune-hepatic toxicity Abbreviations: IMH = immune-mediated hepatitis; IO–IO = dual immune checkpoint blockade; IO–VEGF = ICI + anti-VEGF; IO–TKI = ICI + tyrosine kinase inhibitor; NR = not reported; d/c = discontinuation.