Immune checkpoint blockade and transarterial chemoembolization in liver-limited hepatocellular carcinoma: new questions at the dawn of a new era.

Anti-programed cell death protein-1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies combined with anti-vascular endothelial growth factor (VEGF) or anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are now standard therapeutic options for patients with treatment-naïve, advanced stage, hepatocellular carcinoma. Given the observed efficacy in the advanced setting, the unmet need for therapies for intermediate stage liver cancer, and compelling preclinical rationale for combination with liver-directed therapies, such as transarterial chemoembolization, immunotherapies have quickly moved into earlier stages of the disease. Several phase 1/2 clinical trials have collectively verified the safety of immune checkpoint blockade with regional therapy for intermediate stage, liver-limited, hepatocellular carcinoma. Recently, two global, randomized, double-blind, placebo-controlled studies have demonstrated superior efficacy, based on the surogate of progession free survial, for transarterial chemoembolization plus combination immunotherapy over chemoembolization alone. In this issue of the Journal, Li and colleagues present data for an anti-PD-1 inhibitor with chemoembolization in liver-limited hepatocellular carcinoma (HCC). This study, along with the status of the field, provides the opportunity to highlight key issues for implementation of combinatorial approaches in patients with liver-limited liver cancer, which are discussed in this Commentary. Regional treatment with immune checkpoint inhibition combinations for intermediate stage disease is now rightly at the forefront of HCC drug development, though specific biologic factors, ideal patient characteristics, and optimal combinations require deeper investigation prior to routine use for all patients.