Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024. https://doi.org/10.3322/caac.21834

Article  PubMed  Google Scholar 

Zheng RS, Chen R, Han BF, Wang SM, Li L, Sun KX, et al. Cancer incidence and mortality in China, 2022. Zhonghua Zhong Liu Za Zhi. 2024;46:221–231. https://doi.org/10.3760/cma.j.cn112152-20240119-00035

Article  CAS  PubMed  Google Scholar 

Wu D, Jia B, Jia M, et al. Comparative efficacy and safety of systemic therapy for advanced hepatocellular carcinoma: a systematic review and network meta-analysis. Front Oncol. 2023;13:1274754. https://doi.org/10.3389/fonc.2023.1274754

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cappuyns S, Corbett V, Yarchoan M, Finn RS, Llovet JM. Critical appraisal of guideline recommendations on systemic therapies for advanced hepatocellular carcinoma: a review. JAMA Oncol. 2023. https://doi.org/10.1001/jamaoncol.2023.2677

Article  Google Scholar 

Bruix J, Qin S, Merle P, Granito A, Huang Y-H, Bodoky G, 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. https://doi.org/10.1016/S0140-6736(16)32453-9

Article  CAS  PubMed  Google Scholar 

Fung AS, Tam VC, Meyers DE, Sim H-W, Knox JJ, Zaborska V, et al. Second-line treatment of hepatocellular carcinoma after sorafenib: characterizing treatments used over the past 10 years and real-world eligibility for cabozantinib, regorafenib, and ramucirumab. Cancer Med. 2020;9:4640–4647. https://doi.org/10.1002/cam4.3116

Article  CAS  PubMed  PubMed Central  Google Scholar 

Abou-Alfa GK, Meyer T, Cheng A-L, El-Khoueiry AB, Rimassa L, Ryoo B-Y, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63. https://doi.org/10.1056/NEJMoa1717002

Article  CAS  PubMed  PubMed Central  Google Scholar 

Llovet JM, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, 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. https://doi.org/10.1016/S1470-2045(23)00469-2

Article  CAS  PubMed  Google Scholar 

Peng Z, Fan W, Zhu B, Wang G, Sun J, Xiao C, et al. Lenvatinib combined with transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma: a phase III, randomized clinical trial (LAUNCH). J Clin Oncol. 2023;41:117–127. https://doi.org/10.1200/JCO.22.00392

Article  CAS  PubMed  Google Scholar 

Finn RS, Kudo M, Klümpen H-J, Lim HY, Merle P, Ikeda M, et al. Regorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in routine clinical practice: exploratory analysis of overall survival (OS) in the prospective, observational REFINE study. J Clin Oncol. 2022;40:433. https://doi.org/10.1200/JCO.2022.40.4_suppl.433

Article  Google Scholar 

Li B-K, Yuan Y, Qiao L, He W, Wang G, Chen H, et al. 949P Regorafenib combined with immunotherapy versus regorafenib as second-line therapy in patients with advanced hepatocellular carcinoma: a multicenter real-world study. Ann Oncol. 2023;34:S596. https://doi.org/10.1016/j.annonc.2023.09.2095

Article  Google Scholar 

Guan R, Mei J, Li S, Lin W, Deng M, Wei W, et al. Comparative efficacy of PD-1 inhibitors plus lenvatinib and regorafenib after lenvatinib failure for advanced hepatocellular carcinoma: a real-world study. Hepatol Int. 2023. https://doi.org/10.1007/s12072-022-10470-0

Article  PubMed  Google Scholar 

Yoo C, Cheon J, Ryoo B-Y, Ryu M-H, Kim H-D, Kim K-P, et al. Second-line regorafenib in patients (pts) with unresectable hepatocellular carcinoma (uHCC) after progression on first-line atezolizumab plus bevacizumab (Atezo-Bev): phase 2 REGONEXT trial. J Clin Oncol. 2024;42:477. https://doi.org/10.1200/JCO.2024.42.3_suppl.477

Article  Google Scholar 

Carr BI, Cavallini A, Lippolis C, D’Alessandro R, Messa C, Refolo MG, et al. Fluoro-sorafenib (regorafenib) effects on hepatoma cells: growth inhibition, quiescence, and recovery. J Cell Physiol. 2013;228:292–297. https://doi.org/10.1002/jcp.24148

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jiang L, Li L, Liu Y, Lu L, Zhan M, Yuan S, et al. Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma. Front Pharmacol. 2023;14:1097277. https://doi.org/10.3389/fphar.2023.1097277

Article  CAS  PubMed  PubMed Central  Google Scholar 

Granito A, Forgione A, Marinelli S, Renzulli M, Ielasi L, Sansone V, et al. Experience with regorafenib in the treatment of hepatocellular carcinoma. Ther Adv Gastroenterol. 2021;14:17562848211016960. https://doi.org/10.1177/17562848211016959

Article  CAS  Google Scholar 

Xie L, Liu M, Cai M, Huang W, Guo Y, Liang L, et al. Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis in hepatocellular carcinoma. Biomed Pharmacother. 2023;159: 114254. https://doi.org/10.1016/j.biopha.2023.114254

Article  CAS  PubMed  Google Scholar 

Yan T, Huang C, Peng C, Duan X, Ji D, Duan Y, et al. A multi-center retrospective study on the efficacy and safety of regorafenib vs. regorafenib combined with PD-1 inhibitors as a second-line therapy in patients with advanced hepatocellular carcinoma. Ann Transl Med. 2023;11:109. https://doi.org/10.21037/atm-22-6614

Article  PubMed  PubMed Central  Google Scholar 

Stefanini B, Ielasi L, Chen R, Abbati C, Tonnini M, Tovoli F, et al. TKIs in combination with immunotherapy for hepatocellular carcinoma. Expert Rev Anticancer Ther. 2023;23:279–291. https://doi.org/10.1080/14737140.2023.2181162

Article  CAS  PubMed  Google Scholar 

Lim HY, Merle P, Finn RS, Frenette C, Masi G, Ikeda M, et al. Regorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in routine clinical practice: Interim analysis of the prospective, observational REFINE trial. J Clin Oncol. 2020;38:542. https://doi.org/10.1200/JCO.2020.38.4_suppl.542

Article  Google Scholar 

Finn RS, Merle P, Granito A, Huang Y-H, Bodoky G, Pracht M, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase III RESORCE trial. J Hepatol. 2018;69:353–358. https://doi.org/10.1016/j.jhep.2018.04.010

Article  CAS  PubMed  Google Scholar 

Zhang W, Zhao Y, Ma G, Zhang Y, Guo Y, Chen Z. Efficacy and safety of regorafenib alone or in combinations in the second-line setting for advanced hepatocellular carcinoma: a multicenter real-world study. J Clin Oncol. 2023;41:e16172–e16172. https://doi.org/10.1200/JCO.2023.41.16_suppl.e16172

Article  Google Scholar 

Zhai J, Liu J, Fu Z, Bai S, Li X, Qu Z, et al. Comparison of the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma: a retrospective cohort study. J Gastrointest Oncol. 2022;13:1278–1288. https://doi.org/10.21037/jgo-22-404

Article  PubMed  PubMed Central  Google Scholar 

Kuo HY, Khan KA, Kerbel RS. Antiangiogenic—immune-checkpoint inhibitor combinations: lessons from phase III clinical trials. Nat Rev Clin Oncol. 2024;21(6):468–482. https://doi.org/10.1038/s41571-024-00886-y

Article  CAS  Google Scholar 

Shigeta K, Matsui A, Kikuchi H, Klein S, Mamessier E, Chen IX, et al. Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2020-001435

Article  PubMed  PubMed Central  Google Scholar 

Wang H, Xiao W, Han Y, Cao S, Zhang Z, Chen G, et al. Study on efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with regorafenib and PD-1 antibody versus continued TACE combined with regorafenib in patients with hepatocellular carcinoma after failed second-line treatment with regorafenib. J Gastrointest Oncol. 2022;13:1907–1914. https://doi.org/10.21037/jgo-22-626

Article  PubMed  PubMed Central  Google Scholar 

Huang J, Guo Y, Huang W, Hong X, Quan Y, Lin L, et al. Regorafenib combined with PD-1 blockade immunotherapy versus regorafenib as second-line treatment for advanced hepatocellular carcinoma: a multicenter retrospective study. J Hepatocell Carcinoma. 2022;9:157–170. https://doi.org/10.2147/JHC.S353956

Article  PubMed  PubMed Central  Google Scholar 

Finn RS, Merle P, Ikeda M, Klümpen H-J, Masi G, Granito A, et al. Real-world dosing of regorafenib in patients with unresectable hepatocellular carcinoma (uHCC): Final analysis of the prospective, observational REFINE study. J Clin Oncol. 2023;41:518. https://doi.org/10.1200/JCO.2023.41.4_suppl.518