Navigating the new landscape of second‐line treatment in advanced hepatocellular carcinoma

Sorafenib and lenvatinib are approved for first‐line treatment of patients with advanced hepatocellular carcinoma (HCC), and the efficacy of atezolizumab plus bevacizumab has been demonstrated versus sorafenib. Over time, first‐line treatment frequently fails, and regorafenib, cabozantinib, ramucirumab (for patients with alpha fetoprotein ≥400 ng/mL), nivolumab, pembrolizumab and ipilimumab plus nivolumab are approved for use after sorafenib (but not lenvatinib) treatment in advanced HCC. Given the considerable complexity in the therapeutic landscape, the objective of this review was to summarize the clinical evidence for second‐line agents and provide practical guidance for selecting the best sequential treatment approach. The timing and sequencing of treatment switches are key to optimizing patient outcomes in advanced HCC, and decisions should be informed by reasons for discontinuation of previous therapy and disease progression. It is important not to switch too soon, because sequential treatment benefit may then be lost, nor should switching be delayed too long. Effectiveness, safety and tolerability, patient quality of life, route of administration, dosing regimen, drug class, molecular target and individual patients’ characteristics, including comorbidities, inform the selection of second‐line systemic treatment, independently of the aetiology of HCC, tumour stage and the response to previous treatment. Biomarkers predictive of treatment effectiveness are of great value, but currently biomarker‐driven patient selection is possible only in the case of ramucirumab. The approval of new combination therapies for advanced HCC in the first‐line setting will further increase the complexity of decision‐making. However, the important factors will remain the individual patient’s characteristics and preferences.