The price and value of therapeutic synergy in liver cancer

Over the past 5 years, breakthroughs in the delivery of systemic therapy have transformed advanced hepatocellular carcinoma, a disease with a typical life expectancy of 6 months following diagnosis, 1 Giannini EG Farinati F Ciccarese F et al. Prognosis of untreated hepatocellular carcinoma. Hepatology. 2015; 61: 184-190 Crossref PubMed Scopus (152) Google Scholar into an oncological indication in which more effective therapies and optimal sequencing have extended patients' survival to contemporary estimates ranging from 16 to 22 months in randomised trials 2 Fulgenzi CAM Scheiner B Korolewicz J et al. Efficacy and safety of frontline systemic therapy for advanced HCC: a network meta-analysis of landmark phase III trials. JHEP Rep. 2023; 5100702 Google Scholar and in routine practice. 3 Fulgenzi CAM Cheon J D'Alessio A et al. Reproducible safety and efficacy of atezolizumab plus bevacizumab for HCC in clinical practice: results of the AB-real study. Eur J Cancer. 2022; 175: 204-213 Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar Although PD-1 pathway inhibition did not show superior efficacy over sorafenib, 4 Yau T Park JW Finn RS et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022; 23: 77-90 Summary Full Text Full Text PDF PubMed Scopus (295) Google Scholar its use in combination with VEGF 5 Finn RS Qin S Ikeda M et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020; 382: 1894-1905 Crossref PubMed Scopus (2753) Google Scholar and CTLA-4 6 Abou-Alfa GK Chan SL Kudo M et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022; 40: 379 Crossref Google Scholar inhibitors has led to the approval of novel standards of care in advanced disease, making long-term survival an achievable aim in some patients. The capacity to selectively inhibit multiple oncogenic pathways involved in hepatocellular carcinoma progression, paired with shown monotherapy activity and convenient oral administration, has made tyrosine-kinase inhibitors (TKIs) a rational choice as combination partner for immunotherapy. However, unlike renal cell carcinoma, in which TKI doublet 7 Rini BI Plimack ER Stus V et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019; 380: 1116-1127 Crossref PubMed Scopus (1914) Google Scholar and triplet combinations 8 Motzer R Alekseev B Rha SY et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021; 384: 1289-1300 Crossref PubMed Scopus (679) Google Scholar have led to greater and more durable benefit compared with TKI monotherapy or immune-checkpoint inhibitors (ICIs), the optimal TKI combination partner has not yet emerged in advanced hepatocellular carcinoma. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 studyCamrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. Full-Text PDF