Navigating second-line therapy after immunotherapy in advanced HCC☆

In recent years, systemic treatment options for hepatocellular carcinoma have expanded significantly, with pivotal phase III trials reporting unprecedented improvements in survival and response outcomes. However, these advances have largely focused on first-line strategies, challenging existing treatment sequences and raising questions about the optimal therapeutic approach following disease progression. Several therapeutic options are available in second and later lines - including immunotherapies, tyrosine kinase inhibitors, and local therapies - but so far comprehensive head-to-head comparisons to establish the ideal treatment sequence are lacking. Consequently, most evidence guiding second-line therapy has been derived from post hoc analyses, real-world data, and select prospective studies, primarily based on phase II designs. In clinical practice, treatment decisions integrate this evolving evidence base with patient-specific factors such as prior treatment response, liver function, and performance status, often within the constraints of regulatory and accessibility considerations. Ongoing research is investigating novel approaches, including the continuation of immunotherapy following progression, the application of CAR T cells, and targeted treatments against specific markers like fibroblast growth factor 19 and glypican-3. This review summarises the current evidence for second-line and subsequent therapies, explores key considerations in treatment sequencing, and highlights emerging strategies that may further refine the therapeutic landscape for hepatocellular carcinoma. (c) 2025 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).