1 National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: firstname.lastname@example.org.
2 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan; Center of Precision Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: email@example.com.
3 State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, Institute of Digestive Disease, The Chinese University of Hong Kong, China.
4 National Cancer Center, Singapore.
5 Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Immune checkpoint inhibitor (ICI) therapy targeting anti-programmed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is the backbone of numerous combination regimens aimed at improving the objective response and survival of patients with hepatocellular carcinoma (HCC). Clinical trials of immuno-oncology regimens in other cancer types have shed light on issues of study design, including how to choose candidate regimens based on early-phase trial results, statistical considerations in trials with multiple primary endpoints, and the importance of predictive biomarkers. In this review, the updated data from early-phase trials of combination immunotherapy for HCC are summarised. Since the most extensively tested combination regimens for advanced HCC comprise anti-PD-1/anti-PD-L1 agents plus antiangiogenic agents, the relative benefit and antitumor mechanism of antiangiogenic multikinase inhibitors versus specific VEGF/VEGFR inhibitors are discussed. Other critical issues in the development of combination immunotherapy, including optimal management of immune-related adverse events and the value of ICI therapy in combination with locoregional treatment for HCC, are also explored.