Atezolizumab plus Bevacizumab after first-line multikinase inhibitors for advanced hepatocellular carcinoma: The concept of “drug class change”

Hepatocellular carcinoma (HCC) represents the fifth most frequent cancer and the second leading cause of cancer-related death worldwide, with a constantly increasing trend which is predicted to last over the next 20 years [ [1] Rumgay H. Arnold M. Ferlay J. et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022; 77: 1598-1606 Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar ]. Curative treatment options, such as liver transplantation, hepatic resection or ablation may be available for early stage patients; however - despite the application of surveillance programs [ [2] Garuti F. Neri A. Avanzato F. et al. The changing scenario of hepatocellular carcinoma in Italy: an update. Liver Int. 2021; 41: 585-597 Crossref PubMed Scopus (47) Google Scholar , [3] Singal A.G. Zhang E. Narasimman M. et al. HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: a meta-analysis. J Hepatol. 2022; 77: 128-139 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar ] - the majority of HCC patients are diagnosed at later stages, with a disease burden which is not amenable to curative treatments but only to palliative therapies, such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE) and systemic treatment. In particular, systemic therapy is the treatment of choice in patients with macrovascular invasion or extrahepatic spread, or in those who do not respond or are unsuitable to loco-regional approaches and, since 2008, the oral multikinase inhibitor (MKI) Sorafenib has been used as first line standard of care in these patients [ [4] Llovet J.M. Ricci S. Mazzaferro V. et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359: 378-390 Crossref PubMed Scopus (9271) Google Scholar ]. In 2018, Lenvatinib was found to be non-inferior to Sorafenib in terms of overall survival (OS) and progression free survival (PFS) [ [5] Kudo M. Finn R.S. Qin S. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018; 391: 1163-1173 Abstract Full Text Full Text PDF PubMed Scopus (2722) Google Scholar ], leading to its possible use as alternative first-line systemic treatment in the advanced setting, while several other systemic agents have proven their efficacy in the second line setting [ 6 Bruix J. Qin S. Merle P. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 389: 56-66 Abstract Full Text Full Text PDF PubMed Scopus (2319) Google Scholar , 7 Abou-Alfa G.K. Meyer T. Cheng A.L. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018; 379: 54-63 Crossref PubMed Scopus (1308) Google Scholar , 8 Zhu A.X. Kang Y.K. Yen C.J. et al. REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20: 282-296 Abstract Full Text Full Text PDF PubMed Scopus (927) Google Scholar ], although without reaching a definitive consensus on their sequential use. More recently, the advent of immune checkpoint inhibitors (ICIs), particularly antibodies targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, has dramatically changed the landscape of HCC therapy, particularly in the advanced stage; in 2020, the combination of Atezolizumab and Bevacizumab showed a significantly better OS and PFS compared to Sorafenib in systemic treatment-naïve advanced HCC patients [ [9] Finn R.S. Qin S. Ikeda M. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020; 382: 1894-1905 Crossref PubMed Scopus (2552) Google Scholar ] and more recently, a new ICI combination (Tremelimumab plus Durvalumab) improved OS versus sorafenib in advanced HCC [ [10] Abou-Alfa G.K. Lau G. Kudo M. et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022; 1EVIDoa2100070https://doi.org/10.1056/EVIDoa2100070 Crossref Google Scholar ]. Atezolizumab plus bevacizumab in advanced hepatocellular carcinoma after treatment failure with multikinase inhibitorsDigestive and Liver DiseasePreviewData on the effectiveness of atezolizumab plus bevacizumab (atezo-bev) after failure of multikinase inhibitor (MKI) therapy in patients with advanced hepatocellular carcinoma are scarce. Full-Text PDF