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  • Review article
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Evolving therapeutic landscape of advanced hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology volume 20, pages 203–222 (2023)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide. A large proportion of patients with HCC are diagnosed at advanced stages and are only amenable to systemic therapies. We have witnessed the evolution of systemic therapies from single-agent targeted therapy (sorafenib and lenvatinib) to the combination of a checkpoint inhibitor plus targeted therapy (atezolizumab plus bevacizumab therapy). Despite remarkable advances, only a small subset of patients can obtain durable clinical benefit, and therefore substantial therapeutic challenges remain. In the past few years, emerging systemic therapies, including new molecular-targeted monotherapies (for example, donafenib), new immuno-oncology monotherapies (for example, durvalumab) and new combination therapies (for example, durvalumab plus tremelimumab), have shown encouraging results in clinical trials. In addition, many novel therapeutic approaches with the potential to offer improved treatment effects in patients with advanced HCC, such as sequential combination targeted therapy and next-generation adoptive cell therapy, have also been proposed and developed. In this Review, we summarize the latest clinical advances in the treatment of advanced HCC and discuss future perspectives that might inform the development of more effective therapeutics for advanced HCC.

Key points

  • Therapeutic advances have dramatically changed the systemic treatment landscape of advanced hepatocellular carcinoma (HCC).

  • Many molecular-targeted or immuno-oncology agents are being investigated as stand-alone therapies with potential predictive biomarkers for advanced HCC.

  • Combination therapies have become the current focus of treatment investigation in advanced HCC, and show remarkable therapeutic potential.

  • There has been an urgent need to develop effective biomarkers to select patients who would be most likely to benefit from well-established therapies for advanced HCC.

  • A number of innovative therapeutic approaches have been proposed, including some fascinating combination strategies involving targeted therapies and immunotherapies that provide new treatment opportunities for HCC.

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Fig. 1: Evolving systemic therapeutics for advanced HCC.
Fig. 2: Classifications of combination approaches in HCC.
Fig. 3: Immunomodulatory effects of molecular-targeted agents.
Fig. 4: Emerging targeted therapy-based strategies with therapeutic potential in HCC.
Fig. 5: Emerging immunotherapy-based strategies with therapeutic potential in HCC.

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Acknowledgements

The research of the authors was funded by grants from the European Research Council (ERC 787925 to R.B.), the National Natural Science Foundation of China (81920108025 (W.Q.), 81874229 (C.W.), 82072633 (C.W.) and 82122047 (C.W.)) and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZLCX20211602 (C.W.)). The authors apologize to those researchers whose work was not included in this Review due to space constraints.

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  1. These authors contributed equally: Chen Yang, Hailin Zhang.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Chen Yang, Hailin Zhang, Linmeng Zhang, René Bernards, Wenxin Qin & Cun Wang

  2. Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Andrew X. Zhu

  3. Jiahui International Cancer Center, Jiahui Health, Shanghai, China

    Andrew X. Zhu

  4. Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands

    René Bernards

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Yang, C., Zhang, H., Zhang, L. et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 20, 203–222 (2023). https://doi.org/10.1038/s41575-022-00704-9

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