The COSMIC-312 study: will it shape future combination therapies for advanced hepatocellular carcinoma?

Thomas Yau and colleagues' final analysis of the COSMIC-312 trial, 1 Yau T Kaseb A Cheng A-L et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 study. Lancet Gastroenterol Hepatol. 2024; (published online Feb 13.)https://doi.org/10.1016/S2468-1253(23)00454-5 Google Scholar a phase 3 randomised controlled trial aiming to assess the efficacy of a TKI-based immunotherapy doublet as first-line systemic treatment, in The Lancet Gastroenterology & Hepatology, adds to our knowledge about the use tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI) combinations for treatment of advanced hepatocellular carcinoma. Although the role of ICI plus the VEGF-targeted agent bevacizumab or the combination of two ICIs is well established in advanced hepatocellular carcinoma, 2 Cheng AL Qin S Ikeda M et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022; 76: 862-873 Summary Full Text Full Text PDF PubMed Scopus (475) Google Scholar , 3 Abou-Alfa GK Lau G Kudo M et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evidence. 2022; 1: 8 Crossref Google Scholar the clinical implications of the combination of ICIs plus TKIs remain less clear. The phase 3 LEAP-002 4 Llovet JM Kudo M Merle P et al. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023; 24: 1399-1410 Summary Full Text Full Text PDF PubMed Google Scholar trial showed negative results for the combination of the multi-TKI lenvatinib with pembrolizumab. By contrast, CARES-310 5 Qin S Chan SL Gu S et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023; 402: 1133-1146 Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar was positive for the combination of camrelizumab and rivoceranib; however, the trial recruited mainly in Asia, and rivoceranib is highly VEGFR2 specific, unlike the multi-TKIs currently approved for hepatocellular carcinoma. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 studyFirst-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals. Full-Text PDF