The Evolving Landscape of Checkpoint Inhibitor Combination Therapy in the Treatment of Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers and a main cause of cancer-associated death worldwide. Even with the successful launch of sorafenib for the clinical treatment of HCC in 2007, the long-term survival for patients with HCC is still suboptimal, largely due to the occurrence of primary or acquired drug resistance. With an improved understanding of the molecular pathophysiology and tumor heterogeneity of HCC, therapeutic options have been evolving rapidly in recent years. While lenvatinib, cabozantinib, regorafenib, and the monoclonal antibody ramucirumab, as well as the immune checkpoint inhibitors (ICIs) atezolizumab, nivolumab, and pembrolizumab, have all shown promise in clinical trials, ICIs, especially when administered in combination with molecular-targeted drugs or cytotoxic drugs, have drawn increased attention. Recently, ample relevant clinical studies have surfaced, particularly related to the use of ICIs and exploring the therapeutic potential of ICI combination strategies. A more thorough knowledge of novel treatment strategies should help in decision making for advanced HCC therapy. The present review summarizes the mechanisms of HCC tumorigenesis, relevant trial results for approved HCC therapies, future perspectives, and major challenges for the overall treatment of HCC.