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Published on: September 30, 2021
Etiology-Based Treatment for Unresectable/Advanced Hepatocellular Carcinoma: Focus on Viral Hepatitis and Metabolic
Frances Sze Kei Sun1, Jeffrey Sum Lung Wong1, Lung-Yi Mak1
1Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR.
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.
Insights
Metabolic dysfunction-associated steatohepatitis (MASH)-related liver cancer (HCC) may not respond well to immune checkpoint inhibitors (ICIs). Clinical trial data are mixed, highlighting the need for further research to guide therapy selection for diverse HCC etiologies.
Area of Science:
- Hepatocellular carcinoma (HCC) research
- Immunotherapy
- Metabolic dysfunction-associated steatohepatitis (MASH)
Background:
- Immune checkpoint inhibitors (ICIs) are a standard treatment for advanced HCC.
- Preclinical models suggest MASH-related HCC may exhibit limited response to ICIs.
- This raises critical questions for therapy selection and drug development in HCC.
Purpose of the Study:
- To evaluate the efficacy of ICIs in MASH-related HCC compared to viral HCC.
- To analyze conflicting clinical trial outcomes regarding ICI effectiveness across different HCC etiologies.
- To identify knowledge gaps in understanding ICI response based on HCC pathogenesis.
Main Methods:
- Review of Phase 3 clinical trials and meta-analyses investigating ICI regimens (single and dual) in HCC.
- Analysis of subgroup data comparing outcomes in viral versus non-viral HCC, including MASH-related cases.
- Assessment of limitations in current evidence, such as unplanned subgroup analyses and heterogeneous HCC classifications.
Main Results:
- Single-ICI regimens showed no significant overall survival difference for non-viral HCC in some trials, while viral hepatitis patients appeared to benefit more.
- Other trials reported comparable outcomes for viral and non-viral HCC with single or dual ICI regimens.
- No consistent differences were observed between patients with hepatitis B virus (HBV) or hepatitis C virus (HCV)-HCC.
Conclusions:
- Current evidence is insufficient to personalize advanced HCC treatment based on etiology.
- Preclinical data suggest a potentially reduced benefit of ICIs in MASH-HCC, but clinical trial data are inconclusive and limited.
- Further research is essential to clarify ICI efficacy across different HCC etiologies and inform clinical practice.
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