Post-immunotherapy second-line strategies for hepatocellular carcinoma: State of the art and ongoing trials

The treatment landscape of hepatocellular carcinoma (HCC) has significantly evolved following the introduction of immune checkpoint inhibitors (ICIs), which are now the standard of care in first-line systemic therapy. However, as more patients experience progression after ICI-based combinations, the optimal second-line treatment strategy remains undefined. Currently approved agents, such as regorafenib, cabozantinib, and ramucirumab, have not been specifically tested in the post-ICI setting, and their efficacy in this context remains uncertain. This review provides a comprehensive and critical analysis of systemic second-line treatment strategies in patients with unresectable HCC after progression to frontline immunotherapy. We summarize the available evidence from early-phase studies and retrospective series and describe the rationale, efficacy signals, and development status of ongoing clinical trials. Therapeutic approaches include tyrosine kinase inhibitors, novel ICI-based combinations, bispecific antibodies, T-cell therapies (chimeric antigen receptor-T and T-cell receptor-T), and other emerging strategies such as liver-targeted prodrugs and microbiota modulation. While current data are still limited, several trials are ongoing and reflect compelling biological hypotheses. Their diversity highlights both the complexity and the opportunity of this therapeutic space. Future research should focus on identifying predictive biomarkers, optimizing safety, and developing individualized sequencing strategies to enhance outcomes in this rapidly expanding patient population.