Advancing Systemic Treatment beyond First Line for Advanced Hepatocellular Carcinoma

PURPOSE OF REVIEW: Hepatocellular carcinoma (HCC) ranks among the most prevalent solid malignancies worldwide. A substantial proportion of patients are diagnosed at advanced stages, making systemic therapies the primary treatment option. In recent years, treatment strategies have shifted from single-agent targeted therapies, such as sorafenib and lenvatinib, to combination regimens incorporating immune checkpoint inhibitors, with or without antiangiogenic agents. This evolving treatment paradigm has led to an increasing number of patients receiving second-line and subsequent therapies. However, clinical guidelines for treatment selection remain lacking. RECENT FINDINGS: Currently, available salvage therapies include various molecularly targeted agents, immune checkpoint inhibitors, and combination regimens. Nonetheless, evidence supporting their efficacy and patient selection for specific strategies in this setting remains scarce. This review summarizes recent clinical advancements and explores emerging strategies to optimize systemic treatment options beyond first-line therapy in the increasingly complex landscape of advanced HCC.