Sequencing Systemic Therapy in Hepatocellular Carcinoma

World Health Organization. Cancer. 2022. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed Jun 5 2023.

Surveillance, epidemiology, and end results program,. Cancer stat facts: common cancer sites. 2023. https://seer.cancer.gov/statfacts/html/common.html. Accessed 26 Jul 2023.

Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7(1):6. https://doi.org/10.1038/s41572-020-00240-3.

Article  PubMed  Google Scholar 

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. https://doi.org/10.1056/NEJMoa0708857.

Article  CAS  PubMed  Google Scholar 

Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. https://doi.org/10.1016/s1470-2045(08)70285-7.

Article  CAS  PubMed  Google Scholar 

Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, 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(10126):1163–73. https://doi.org/10.1016/S0140-6736(18)30207-1.

Article  CAS  PubMed  Google Scholar 

•• Cheng A-L, Qin S, Ikeda M, Galle PR, Ducreux M, Kim T-Y et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab <em>vs.</em> sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862-73. https://doi.org/10.1016/j.jhep.2021.11.030. This is the landmark trial that confirms the survival outcome benefits from atezolizumab plus bevacizumab and brought the regimen as the preferred first-line treatment.

•• Abou-Alfa Ghassan K, Lau G, Kudo M, Chan Stephen L, Kelley Robin K, Furuse J et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evidence. 2022;1(8):EVIDoa2100070. https://doi.org/10.1056/EVIDoa2100070. This is the first trial that confirms the overall survival benefit of dual immune checkpoint blockade, specifically durvalumab and tremelimumab, in hepatocellular carcinoma, bringing this regimen into another preferred first-line treatment.

Chan MY, She WH, Dai WC, Tsang SHY, Chok KSH, Chan ACY, et al. Prognostic value of preoperative alpha-fetoprotein (AFP) level in patients receiving curative hepatectomy- an analysis of 1,182 patients in Hong Kong. Transl Gastroenterol Hepatol. 2019;4:52. https://doi.org/10.21037/tgh.2019.06.07.

Article  PubMed  PubMed Central  Google Scholar 

Bristol-Myers S. A study of nivolumab in combination with ipilimumab in participants with advanced hepatocellular carcinoma. 2025. 2025. https://ClinicalTrials.gov/show/NCT04039607. Accessed 26 Jul 2023.

Merle P, Blanc J-F, Edeline J, Le Malicot K, Allaire M, Assenat E, et al. Ipilimumab with atezolizumab-bevacizumab in patients with advanced hepatocellular carcinoma: The PRODIGE 81-FFCD 2101-TRIPLET-HCC trial. Dig Liver Dis. 2023;55(4):464–70. https://doi.org/10.1016/j.dld.2023.01.161.

Article  CAS  PubMed  Google Scholar 

Finn RS, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, et al. LBA34 Primary results from the phase III LEAP-002 study: lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2022;33:S1401. https://doi.org/10.1016/j.annonc.2022.08.031.

Article  Google Scholar 

Kelley RK, Rimassa L, Cheng A-L, Kaseb A, Qin S, Zhu AX, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(8):995–1008. https://doi.org/10.1016/S1470-2045(22)00326-6.

Article  CAS  PubMed  Google Scholar 

Qin S, Chan LS, Gu S, Bai Y, Ren Z, Lin X, et al. LBA35 Camrelizumab (C) plus rivoceranib (R) vs. sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): a randomized, phase III trial. Ann Oncol. 2022;33:S1401–2. https://doi.org/10.1016/j.annonc.2022.08.032.

Article  Google Scholar 

Qin S, Kudo M, Meyer T, Finn RS, Vogel A, Bai Y, et al. LBA36 Final analysis of RATIONALE-301: randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Ann Oncol. 2022;33:S1402–3. https://doi.org/10.1016/j.annonc.2022.08.033.

Article  Google Scholar 

Yau T, Park J-W, Finn RS, Cheng A-L, Mathurin P, Edeline J, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77–90. https://doi.org/10.1016/S1470-2045(21)00604-5.

Article  CAS  PubMed  Google Scholar 

Park J-W, Chen M, Colombo M, Roberts LR, Schwartz M, Chen P-J, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 2015;35(9):2155–66. https://doi.org/10.1111/liv.12818.

Article  PubMed  PubMed Central  Google Scholar 

• D’Alessio A, Fulgenzi CAM, Nishida N, Schönlein M, von Felden J, Schulze K, et al. Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: a real-world study. Hepatology. 2022;76(4):1000–12. https://doi.org/10.1002/hep.32468. This study shows a preliminary data that atezolizumab plus bevacizumab is well-tolerated in patients with Child-Pugh B cirrhosis.

Article  CAS  PubMed  Google Scholar 

Howard SH, Genentech Inc, Rutgers Cancer Institute of New Jersey, Big Ten Cancer Research Consortium. A study of Atezolizumab and Bevacizumab in Hepatocellular Carcinoma. 2024. https://ClinicalTrials.gov/show/NCT04829383. Accessed 26 Jul 2023.

Tison A, Garaud S, Chiche L, Cornec D, Kostine M. Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases. Nat Rev Rheumatol. 2022;18(11):641–56. https://doi.org/10.1038/s41584-022-00841-0.

Article  CAS  PubMed  Google Scholar 

Genentech Inc. Highlights of prescribing information: avastin. 2022. http://www.gene.com/download/pdf/avastin_prescribing.pdf. Accessed 26 Jul 2023.

• Huynh J, Cho MT, Kim EJ-H, Ren M, Robbins C, Amaya-Chanaga C et al. Post hoc analysis in patients (pts) with unresectable hepatocellular carcinoma (uHCC) who progressed to Child-Pugh B (CPB) liver function in the phase III REFLECT study of lenvatinib (LEN). J Clin Oncol. 2021;39(3_suppl):298-. https://doi.org/10.1200/JCO.2021.39.3_suppl.298. Lenvatinib is less tolerated in patients with Child-Pugh B cirrhosis compared to those with Child-Pugh A.

Marrero JA, Kudo M, Venook AP, Ye SL, Bronowicki JP, Chen XP, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol. 2016;65(6):1140–7. https://doi.org/10.1016/j.jhep.2016.07.020.

Article  CAS  PubMed  Google Scholar 

Kumar V, Shinagare AB, Rennke HG, Ghai S, Lorch JH, Ott PA, et al. The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature. Oncologist. 2020;25(6):505–14. https://doi.org/10.1634/theoncologist.2019-0659.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Invernizzi F, Iavarone M, Zavaglia C, Mazza S, Maggi U, Cesarini L et al. Experience with early sorafenib treatment with mTOR inhibitors in hepatocellular carcinoma recurring after liver transplantation. Transplantation. 2020;104(3).

Kang SH, Cho H, Cho EJ, Lee JH, Yu SJ, Kim YJ et al. Efficacy of sorafenib for the treatment of post-transplant hepatocellular carcinoma recurrence. J Korean Med Sci. 2018;33(45):e283. https://doi.org/10.3346/jkms.2018.33.e283.

Rajendran L, Ivanics T, Claasen MPAW, Muaddi H, Sapisochin G. The management of post-transplantation recurrence of hepatocellular carcinoma. Clin Mol Hepatol. 2022;28(1):1–16. https://doi.org/10.3350/cmh.2021.0217.

Article  PubMed  Google Scholar 

Bang K, Casadei-Gardini A, Yoo C, Iavarone M, Ryu M-H, Park SR, et al. Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation. Cancer Med. 2023;12(3):2572–9. https://doi.org/10.1002/cam4.5123.

Article  CAS  PubMed  Google Scholar 

Chen Y-Y, Chen C-L, Lin C-C, Wang C-C, Liu Y-W, Li W-F, et al. Efficacy and safety of lenvatinib in hepatocellular carcinoma patients with liver transplantation: a case-control study. Cancers. 2021. https://doi.org/10.3390/cancers13184584.

Article  PubMed  PubMed Central  Google Scholar 

Kim BK, Cheon J, Kim H, Kang B, Ha Y, Kim DY et al. Atezolizumab/bevacizumab vs. lenvatinib as first-line therapy for unresectable hepatocellular carcinoma:a real-world, Multi-Center Study. Cancers (Basel). 2022;14(7). https://doi.org/10.3390/cancers14071747.

Su CW, Teng W, Lin PT, Jeng WJ, Chen KA, Hsieh YC, et al. Similar efficacy and safety between lenvatinib versus atezolizumab plus bevacizumab as the first-line treatment for unresectable hepatocellular carcinoma. Cancer Med. 2023;12(6):7077–89. https://doi.org/10.1002/cam4.5506.

Article  CAS  PubMed  Google Scholar 

Hiraoka A, Kumada T, Tada T, Hirooka M, Kariyama K, Tani J, et al. Does first-line treatment have prognostic impact for unresectable HCC?-Atezolizumab plus bevacizumab versus lenvatinib. Cancer Med. 2023;12(1):325–34. https://doi.org/10.1002/cam4.4854.

Article  CAS  PubMed  Google Scholar 

Niizeki T, Tokunaga T, Takami Y, Wada Y, Harada M, Shibata M, et al. Comparison of efficacy and safety of atezolizumab plus bevacizumab and lenvatinib as first-line therapy for unresectable hepatocellular carcinoma: a propensity score matching analysis. Target Oncol. 2022;17(6):643–53. https://doi.org/10.1007/s11523-022-00921-x.

Article  PubMed  PubMed Central  Google Scholar 

•• Casadei-Gardini A, Rimini M, Tada T, Suda G, Shimose S, Kudo M, et al. Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population. Eur J Cancer. 2023;180:9–20. https://doi.org/10.1016/j.ejca.2022.11.017. This is the largest retrospective study that compared atezolizumab plus bevacizumab and lenvatinib as first-line regimen. It showed the discrepancy of overall survival benefit between viral and non-viral related HCC.

Article  CAS  PubMed  Google Scholar 

Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19(3):151–72. https://doi.org/10.1038/s41571-021-00573-2.

Article  CAS  PubMed  Google Scholar 

Lim CJ, Lee YH, Pan L, Lai L, Chua C, Wasser M, et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut. 2019;68(5):916–27. https://doi.org/10.1136/gutjnl-2018-316510.

Article  CAS  PubMed  Google Scholar 

Kasprowicz V, Schulze zur Wiesch J, Kuntzen T, Nolan Brian E, Longworth S, Berical A et al. High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome. J Virol. 2008;82(6):3154-60. https://doi.org/10.1128/jvi.02474-07.

Franceschini D, Paroli M, Francavilla V, Videtta M, Morrone S, Labbadia G, et al. PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Investig. 2009;119(3):551–64. https://doi.org/10.1172/JCI36604.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592(7854):450–6. https://doi.org/10.1038/s41586-021-03362-0.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Verset G, Borbath I, Karwal M, Verslype C, Van Vlierberghe H, Kardosh A, et al. Pembrolizumab monotherapy for previously untreated advanced hepatocellular carcinoma: data from the open-label, phase II KEYNOTE-224 trial. Clin Cancer Res. 2022;28(12):2547–54. https://doi.org/10.1158/1078-0432.CCR-21-3807.

Article  CAS 

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