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Hepatobiliary Disease

Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular CarcinomaA Review

To identify the key insights or developments described in this article

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JAMA Oncology

Published Online: August 3, 2023

Review

Article Information and Disclosures

Sarah Cappuyns, MD^1,2;

Virginia Corbett, MD¹;

Mark Yarchoan, MD³;

Richard S. Finn, MD⁴;

Josep M. Llovet, MD, PhD^1,5,6

Author Affiliations

¹Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
²Digestive Oncology, Department of Gastroenterology, Universitair Ziekenhuis Leuven/Katholieke Universiteit Leuven, Leuven, Belgium
³Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
⁴Department of Medicine, Hematology/Oncology, Geffen School of Medicine at UCLA (University of California, Los Angeles), Los Angeles
⁵Liver Cancer Translational Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
⁶Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain

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Abstract

Importance The combination of immune checkpoint inhibitors with antiangiogenic agents has revolutionized the treatment landscape of advanced hepatocellular carcinoma (HCC). However, due to rapid publication of new studies that attained their predefined primary end points, a lack of robust cross-trial comparison of first-line therapies, and diverging clinical guidelines, no clear-cut treatment flowchart and sequence of therapies are available. This critical analysis of the recommendations for the management of advanced HCC from the main scientific societies in the US and Europe adopted an integrated approach to provide information on the clinical benefit (overall survival and progression-free survival) and safety profile of these therapies using the European Society for Medical Oncology (ESMO)–Magnitude of Clinical Benefit Scale (MCBS) score and an ad hoc network meta-analysis.

Observations There is a major consensus among guidelines that atezolizumab plus bevacizumab has a primacy as the recommended first-line treatment of choice in advanced HCC. On progression after immunotherapy-containing regimens and for patients with contraindications for immunotherapies, most guidelines maintain the established treatment hierarchy, recommending lenvatinib or sorafenib as the preferred options, followed by either regorafenib, cabozantinib, or ramucirumab. Thus far, the first-line immune-based regimen of tremelimumab plus durvulumab has been integrated only in the American Association for the Study of Liver Diseases guidance document and the latest National Comprehensive Cancer Network guidelines and is recommended for patients with a high risk of gastrointestinal bleeding. Overall, in the first-line setting, both atezolizumab plus bevacizumab and sintilimab plus IBI305 (a bevacizumab biosimilar) received the highest ESMO-MCBS score of 5, indicating a substantial magnitude of clinical benefit. In a network meta-analysis, no significant differences in overall survival were found among the various combination regimens. However, the newly reported combination of camrelizumab plus rivoceranib was associated with a significantly higher risk of treatment-related adverse events compared with atezolizumab plus bevacizumab (relative risk, 1.59; 95% CI, 1.25-2.03; P < .001).

Conclusions and Relevance This narrative review found that atezolizumab plus bevacizumab is regarded as the primary standard of care for advanced HCC in the first-line setting. These findings from integrating the recommendations from scientific societies’ guidelines for managing advanced HCC along with new data from cross-trial comparisons may aid clinicians in decision-making and guide them through a rapidly evolving and complex treatment landscape.

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Article Information

Accepted for Publication: February 21, 2023.

Published Online: August 3, 2023. doi:10.1001/jamaoncol.2023.2677

Corresponding Author: Josep M. Llovet, MD, PhD, Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Madison Ave 1425, 11F-70, Box 1123, New York, NY 10029 (josep.llovet@mountsinai.org).

Author Contributions: Dr Llovet had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Corbett, Yarchoan, Llovet.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Cappuyns, Finn, Llovet.

Administrative, technical, or material support: Corbett, Yarchoan, Finn.

Supervision: Llovet.

Conflict of Interest Disclosures: Dr Cappuyns reported receiving a research fellowship from Research Foundation–Flanders (1S95221N) and a postdoctoral fellowship from the Belgian American Educational Foundation during the conduct of the study. Dr Corbett reported previously owning equity in Pfizer, Bristol Myers Squibb, Seagen, and Viatris. Dr Yarchoan reported receiving grants and personal fees from Genentech, grants from Bristol Myers Squibb, grants and personal fees from Exelixis, grants from Incyte, and personal fees from Eisai, AstraZeneca, and Hepion outside the submitted work as well as being a co-founder and officer of and holding equity in Adventris Pharmaceuticals. Dr Finn reported receiving personal fees from AstraZeneca, Bayer, Eisai, Eli Lilly, CStone, Exelixis, Hengrui, Merck, Pfizer, Roche, and Genentech and institutional grants from Bayer, Eisai, Eli Lilly, Merck, Pfizer, Roche, Genentech, and Adaptimmune during the conduct of the study. Dr Llovet reported receiving grants from Bayer, Eisai, Bristol Myers Squibb, Boehringer Ingelheim, and Ipsen and personal fees from Bayer, Eisai, Bristol Myers Squibb, Ipsen, Merck, Eli Lilly, Roche, Genentech, Glycotest, AstraZeneca, Omega Therapeutics, Mina Alpha, Boston Scientific, Exelixis, Bluejay, and Captor Therapeutics outside the submitted work. No other disclosures were reported.

Funding/Support: Dr Llovet was supported by grants RO1DK56621 and RO1DK128289 from the National Institutes of Health, Cancer Research UK, Fondazione AIRC, grant C9380/A26813 from Fundación Científica de la Asociación Española Contra el Cáncer (Hepatocellular Carcinoma Network [HUNTER]), Samuel Waxman Cancer Research Foundation, grant SGR-1358 from the Generalitat de Catalunya (Agencia de Gestión de Ayudas Universitarias y de Investigación [AGAUR]), and grant PID2019-105378RB-I00 from the Spanish National Health Institute (Ministerio de Ciencia e Innovación [MICINN]).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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