Etiology-Based Treatment for Unresectable/Advanced Hepatocellular Carcinoma: Focus on Viral Hepatitis and Metabolic Dysfunction-Associated Steatohepatitis.

Background: Immune checkpoint inhibitors (ICI) are a keystone in advanced hepatocellular carcinoma (aHCC) therapy. However, preclinical evidence suggests that mice with pure metabolic dysfunction-associated steatohepatitis (MASH)-related HCCs may not benefit from ICIs. This has tremendous implications for both therapy selection and future drug development. Summary: Viral and MASH-HCCs differ in molecular pathogenesis and immune microenvironment. Preclinical evidence has shown impaired immune surveillance and ICI-induced auto-aggressive T cells in pure MASH-HCC. Phase 3 clinical trials and meta-analyses have conflicting outcomes. For single-ICI regimens with anti-programmed-death 1/L1 (anti-PD1/L1), there was no apparent difference in the overall survival for patients with non-viral HCCs in the CheckMate-459, IMbrave150, COSMIC-312, and KEYNOTE-240 trials for ICI over tyrosine-kinase inhibitors or placebo, while patients with viral hepatitis seemed to have benefited more. Meanwhile, comparable outcomes were seen for patients with viral and non-viral HCCs in the HIMALAYA, RATIONALE-301, LEAP-002, and CARES-310 trials. There was no consistent difference in outcomes between patients with HBV or HCV-HCCs. For dual-ICI regimens with anti-PD1/L1 and anti-cytotoxic T-lymphocyte associated protein-4 (anti-CTLA-4), the HIMALAYA and CheckMate-9DW trials showed similar efficacy for ICI combinations across all etiologies. Important caveats in interpreting current evidence exist. All trial data are from unplanned subgroup analyses only, limiting the level of clinical evidence available. "Non-viral HCCs" are also a heterogenous entity, the composition of which varies from trial to trial. Fundamentally, defining HCC etiologies, especially in mutually exclusive terms, is challenging: Occult hepatitis B infections are inconsistently tested and reported; hence, viral HCCs may be underreported. HCCs are often multifactorial, with steatosis frequently co-existing and interacting with viral hepatitis, creating difficulty in translating findings from pure MASH-HCC mouse models. Key Messages: Current evidence is insufficient to support individualizing aHCC treatment based on etiology. Preclinical evidence for a lesser benefit with ICIs in MASH-HCCs exists, while data from clinical trials are mixed but limited. Major gaps in knowledge remain, and further studies are required to clarify this important subject.