Systemic therapy for hepatocellular carcinoma (HCC) used to be limited to patients with advanced diseases and multi-kinase inhibitors targeting tumor angiogenesis the major approach of developing new treatment options. In the past 3 years, new data from trials of both molecular targeted therapy and immune checkpoint inhibitors (ICI) provided many new options of first- and second-line treatment for advanced HCC. Most notably, combination of ICI targeting the program cell death-1 (PD-1) pathway with other novel agents or conventional anti-cancer therapy may further improve treatment efficacy in different clinical settings. In this paper updated data of clinical trials of systemic therapy in the first- and second-line settings for advanced HCC were reviewed and the following issues were discussed: (1) lessons of trial design learned from positive and negative trials; (2) the balance between efficacy and safety in clinical practice; and (3) impact on future multi-disciplinary management of HCC.
Keywords: Accelerated approval; Adverse events; Anti-angiogenesis; Combination therapy; Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4); Immune checkpoint inhibitor; Molecular targeted therapy; Multi-disciplinary management; Program cell death-1 (PD-1); Randomized control trials.