Immunotherapy in hepatocellular carcinoma: Combination strategies

Abstract

Liver cancer is one of the most common causes of cancer death globally, and its incidence in the United States is increasing. Patients with advanced hepatocellular carcinoma (HCC) who are not candidates for surgical resection, liver transplant, or locoregional therapies can be treated with systemic therapies. Multiple agents, including sorafenib, lenvatinib, and regorafenib are approved for use as either first- or second-line therapy in this patient population, but all have relatively modest survival benefits. HCC is potentially susceptible to therapy with checkpoint inhibitors, including agents such as nivolumab and pembrolizumab, which are both approved by the Food and Drug Administration for patients previously treated with sorafenib but have not demonstrated superior overall survival in phase III trials. It is clear that more effective approaches are needed to potentiate the effects of checkpoint inhibitors in patients with HCC. This review will outline and appraise the current literature on the use of checkpoint inhibitors in HCC as part of a combination treatment involving an additional mode of therapy. The list of agents that can be paired with checkpoint inhibitors includes an additional checkpoint inhibitor, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors, tyrosine kinase inhibitors, OX-40 agonists, and PT-112 inhibitors. The main non-pharmacologic therapies currently being studied for inclusion in a combination strategy include radiation therapy, trans-arterial chemoembolization, and ablation.

Keywords: Hepatocellular carcinoma, Liver neoplasms, Antineoplastic agents, Immunological, Protein kinase inhibitors, Angiogenesis inhibitors

Core tip: Immunotherapy remains a viable option for the systemic treatment of patients with unresectable hepatocellular carcinoma, although nivolumab and pembrolizumab failed to meet their endpoints in phase III studies. Combining immunotherapy with other treatment modalities may improve treatment responses. Multiple clinical trials are evaluating the safety and efficacy of these new combination strategies, which involve pairing PD-1 or PD-L1 inhibitors with CTLA-4 inhibitors, or pairing checkpoint inhibitors with alternative agents or non-pharmacologic therapies.