Trial watch: immunotherapeutic strategies on the horizon for hepatocellular carcinoma

ABSTRACT

The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25–30% of the patients with advanced HCC treated with atezolizumab-bevacizumab or tremelimumab-durvalumab (STRIDE) respond initially, and mechanistic biomarkers and novel treatment strategies are urgently needed for patients who present with or acquire resistance to first-line ICI-based therapies. The recent approval of the STRIDE regimen has also engendered new questions, such as patient selection factors (e.g. portal hypertension and history of variceal bleed) and biomarkers, and the optimal combination and sequencing of ICI-based regimens. Triumphs in the setting of advanced HCC have also galvanized considerable interest in the broader application of ICIs to early- and intermediate-stage diseases, including clinical combination of ICIs with locoregional therapies. Among these clinical contexts, the role of ICIs in liver transplantation – which is a potentially curative strategy unique to HCC management – as a bridge to liver transplant in potential candidates or in the setting of post-transplant recurrence, warrants investigation in view of the notable theoretical risk of allograft rejection. In this review, we summarize and chart the landscape of seminal immuno-oncology trials in HCC and envision future clinical developments.

KEYWORDS:

• Hepatocellular carcinoma
• immune checkpoint blockade
• Neoadjuvant immunotherapy
• precision immunotherapy
• transplant oncology
• tumor microenvironment
• viral hepatitis

Acknowledgments

All authors have made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted. No writing assistance was obtained in the preparation of the manuscript. The manuscript, including related data, figures, and tables, has not been previously published and that the manuscript is not under consideration elsewhere.

Disclosure statement

Cheng Han Ng has served as a consultant to Boxer Capital

Mark Muthiah has served as a consultant to Boxer Capital

Thomas Yau has received research or consulting fees from Bristol Myers-Squibb, Eisai, Merck, Bayer, Novartis, EMD Sereon, Exelixis, Ipsen, AbbVie, Pfizer, Sirtex, Sillajen, New B Innovation, Sirtex, OrigiMed, and Taiho.

Wei Peng Yong has received Honoraria and consulting fees from AbbVie/Genentech, Amgen, AstraZeneca, Bristol Myers Squibb, Ipsen, Novartis, Bayer, Eisai, Lilly, MSD, Sanofi/Aventis, and Taiho Pharmaceutical.

All other authors disclose no conflicts of interests.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Author contributions

All authors approve the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethical Statement

The study was conducted in accordance with the Declaration of Helsinki. The study was exempt from IRB review because no confidential patient information was involved.

Additional information

Funding

Daniel Q Huang has served as an advisory board member for Eisai and receives funding support from Singapore Ministry of Health’s National Medical Research Council under its NMRC Research Training Fellowship (MOH-000595-01)