Landon L. Chan , Stephen L. Chan
Abstract
Emergence of multi-targeted kinase inhibitors (MTIs) and immune checkpoint inhibitors (ICI) have changed the landscape of management in hepatocellular carcinoma (HCC). Combination therapy involving ICI has superseded sorafenib as the first-line treatment option for advanced HCC due to their superior response rates and survival benefits based on recently published phase III trials. However, the role of first-line lenvatinib remains uncertain as no prospective trials have compared its efficacy with ICI in advanced HCC. Several retrospective studies have shown that first-line lenvatinib may not be inferior to ICI combination. Indeed, a growing body of evidence suggests that ICI treatment is associated with inferior treatment outcome in non-viral HCC patients, questioning the supremacy of ICI treatment in all patients and rendering first-line lenvatinib as a potential preferred treatment option. Furthermore, in high-burden intermediate-stage HCC, accumulating evidence supports first-line lenvatinib, or in combination with transarterial chemoembolization (TACE), as a preferred treatment option over TACE alone. In this Review, we describe the latest evidence surrounding the evolving role of first-line lenvatinib in HCC. (Clin Mol Hepatol. 2023; 29: 909–923)
Keywords: hepatocellular carcinoma; antineoplastic agents; immune checkpoint inhibitor.
About the Author
Landon L. Chan 1 , Stephen L. Chan 21 Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong
2 Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong; State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong SAR,
References
1. Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.
2. Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90.
3. Johnson PJ, Qin S, Park JW et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 2013;31:3517-24.
4. Cheng AL, Kang YK, Lin DY et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013;31:4067-75.
5. Cainap C, Qin S, Huang WT et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015;33:172-9.
6. Zhu AX, Rosmorduc O, Evans TR et al. SEARCH: a phase III, randomized, double-blind, placebocontrolled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2015;33:559-66.
7. Kudo M, Finn RS, 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;391:1163-73.
8. Bruix J, Qin S, Merle P, Granito A 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.
9. Abou-Alfa GK, Meyer T, Cheng AL et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54-63.
10. Zhu AX, Kang YK, Yen CJ et al. 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;20:282-96.
11. Finn RS, Qin S, Ikeda M et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-905.
12. 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;44(4 Suppl.):379.
13. Rittmeyer A, Barlesi F, Waterkamp D et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-65.
14. 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;76:862-73.
15. Tohyama O, Matsui J, Kodama K et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res 2014;2014:638747.
16. Vogel A, Qin S, Kudo M et al. Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol 2021;6:649-58.
17. Luo J, Gao B, Lin Z et al. Efficacy and safety of lenvatinib versus sorafenib in first-line treatment of advanced hepatocellular carcinoma: A meta-analysis. Front Oncol 2022;12:1010726.
18. Kudo M. Durvalumab plus tremelimumab in unresectable hepatocellular carcinoma. Hepatobiliary Surg Nutr 2022;11:592-6.
19. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158-68.
20. Brahmer JR, Abu-Sbeih H, Ascierto PA et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitorrelated adverse events. J Immunother Cancer 2021;9: e002435.
21. Tison A, Garaud S, Chiche L et al. Immunecheckpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases. Nat Rev Rheumatol 2022;18:641-56.
22. Toniutto P, Fumolo E, Fornasiere E, Bitetto D. Liver transplantation in patients with hepatocellular carcinoma beyond the milan criteria: A comprehensive review. J Clin Med 2021;10:3932.
23. Mazzaferro V, Regalia E, Doci R et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9.
24. Au KP, Chok KSH. Immunotherapy after liver transplantation: Where are we now? World J Gastrointest Surg 2021;13:1267-78.
25. Jiang J, Huang H, Chen R et al. Immunotherapy for hepatocellular carcinoma recurrence after liver transplantation, can we harness the power of immune checkpoint inhibitors? Front Immunol 2023;14:1092401.
26. Weinmann A, Niederle IM, Koch S et al. Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Dig Liver Dis 2012;44:432-7.
27. Sposito C, Mariani L, Germini A et al. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol 2013;59:59-66.
28. Alsina AE, Makris A, Nenos V et al. Can sorafenib increase survival for recurrent hepatocellular carcinoma after liver transplantation? A pilot study. Am Surg 2014;80:680-4.
29. Chen YY, Chen CL, Lin CC et al. Efficacy and Safety of Lenvatinib in Hepatocellular Carcinoma Patients with Liver Transplantation: A Case-Control Study. Cancers (Basel) 2021;13:4584.
30. Bang K, Casadei-Gardini A, Yoo C et al. Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation. Cancer 2023;12:2572-9.
31. Mazzarelli C, Zavaglia C, Cesarini L et al. Lenvatinib for treatment of recurrence hepatocellular carcinoma after liver transplantation: A case series. Dig Liver Dis 2023;55 (Suppl 1):S68.
32. de Franchis R, Bosch J, Garcia-Tsao G et al; Baveno VII Faculty. Baveno VII – Renewing consensus in portal hypertension. J Hepatol 2022;76:959-74.
33. Thabut D, Kudo M. Treatment of portal hypertension in patients with HCC in the era of Baveno VII. J Hepatol 2023;78:658-62.
34. Hidaka H, Uojima H, Nakazawa T et al. Portal hemodynamic effects of lenvatinib in patients with advanced hepatocellular carcinoma: A prospective cohort study. Hepatol Res 2020;50:1083-90.
35. Allaire M, Rudler M, Thabut D. Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses... Liver Int 2021;41:1734-43.
36. Maesaka K, Sakamori R, Yamada R et al. Therapeutic efficacy of lenvatinib in hepatocellular carcinoma patients with portal hypertension. Hepatol Res 2020;50:1091-100.
37. Fang P, Hu JH, Cheng ZG et al. Efficacy and safety of bevacizumab for the treatment of advanced hepatocellular carcinoma: a systematic review of phase II trials. PLoS One 2012;7:e49717.
38. Chuma M, Uojima H, Hiraoka A et al. Analysis of efficacy of lenvatinib treatment in highly advanced hepatocellular carcinoma with tumor thrombus in the main trunk of the portal vein or tumor with more than 50% liver occupation: A multicenter analysis. Hepatol Res 2021;51:201-15.
39. Kuzuya T, Ishigami M, Ito T et al. Sorafenib vs. Lenvatinib as first-line therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Anticancer Res 2020; 40: 2283-2290.
40. Breder V, Vogel A, Merle P et al. IMbrave150: Exploratory efficacy and safety results of hepatocellular carcinoma (HCC) patients (pts) with main trunk and/or contralateral portal vein invasion (Vp4) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in a global Ph III study. J Clin Oncol 2021;39(15 Suppl.):4073.
41. Kim BK, Cheon J, Kim H et al. Atezolizumab/Bevacizumab vs. Lenvatinib as first-line therapy for unresectable hepatocellular carcinoma: A real-world, multi-center study. Cancers (Basel) 2022;14:1747.
42. Casadei-Gardini A, Rimini M, Tada T et al. Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population. Eur J Cancer 2023;180:9-20.
43. Kuo YH, Lu SN, Chen YY et al. Realworld lenvatinib versus sorafenib in patients with advanced hepatocellular carcinoma: A propensity score matching analysis. Front Oncol 2021;11:737767.
44. Burgio V, Iavarone M, Di Costanzo GG et al. Real-life clinical data of lenvatinib versus sorafenib for unresectable hepatocellular carcinoma in Italy. Cancer Manag Res 2021;13:9379-89.
45. Rimini M, Shimose S, Lonardi S et al. Lenvatinib versus Sorafenib as first-line treatment in hepatocellular carcinoma: A multi-institutional matched case-control study. Hepatol Res 2021;51:1229-41.
46. Tovoli F, Ielasi L, Casadei-Gardini A et al. Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients. J Hepatol 2019;71:1175-1183.
47. Casadei Gardini A, Scarpi E, Foschi FG et al. Impact of physician experience and multidisciplinary team on clinical outcome in patients receiving sorafenib. Clin Res Hepatol Gastroenterol 2019;43:e76-e78.
48. Finn RS, Kudo M, Merle P 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(Suppl. 7):S1401.
49. Targeted Oncology Staff. Finn Reviews Phase 3 Trials of Lenvatinib in Advanced HCC. Targeted Oncology web site. URL: https://www.targetedonc.com/view/finn-reviews-phase-3-trials-of-lenvatinib-in-advanced-hcc. Accessed 8 May 2023.
50. Chan LL, Mo FK, Law ALY et al. P-108: Impact of dose adjustment on clinical outcome of lenvatinib-treated patients with advanced hepatocellular carcinoma (HCC). Paper presented at: International Liver Cancer Association Conference; 2022; Madrid, Spain.
51. Kelley RK, Rimassa L, Cheng AL et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2022;23:995-1008.
52. Pfister D, Núñez NG, Pinyol R et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021;592:450-6.
53. Rimini M, Rimassa L, Ueshima K et al. Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis. ESMO Open 2022;7:100591.
54. Han SK, Baik SK, Kim MY. Non-alcoholic fatty liver disease: Definition and subtypes. Clin Mol Hepatol 2023;29 (Suppl.):S5-S16.
55. Chan AW, Wong GL, Chan HY et al. Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B. J Gastroenterol Hepatol 2017;32:667-76.
56. Peng Z, Fan W, Zhu B 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;41:117-27.
57. Zhang S, Zhong BY, Zhang L et al. Transarterial chemoembolization failure/refractoriness: A scientific concept or pseudo-proposition. World J Gastrointest Surg 2022;14:528-37.
58. Liu K, Min XL, Peng J et al. The changes of HIF-1α and VEGF expression after TACE in patients with hepatocellular carcinoma. J Clin Med Res 2016;8:297-302.
59. Sergio A, Cristofori C, Cardin R et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 2008;103:914-21.
60. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018;391:1301-14.
61. Reig M, Forner A, Rimola J et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76:681-93.
62. Arizumi T, Minami T, Chishina H et al. Time to transcatheter arterial chemoembolization refractoriness in patients with hepatocellular carcinoma in kinki criteria stages B1 and B2. Dig Dis 2017;35:589-97.
63. Marrero JA, Kudo M, Venook AP et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. J Hepatol 2016;65:1140-7.
64. Ganten TM, Stauber RE, Schott E et al. Sorafenib in patients with hepatocellular carcinoma – results of the observational INSIGHT study. Clin Cancer Res 2017;23:5720-8.
65. Iavarone M, Cabibbo G, Piscaglia F et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology 2011;54:2055-63.
66. Kudo M, Ueshima K, Chan S et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and child-pugh a liver function: A proof-of-concept study. Cancers (Basel) 2019;11:1084.
67. Kudo M. Lenvatinib may drastically change the treatment landscape of hepatocellular carcinoma. Liver Cancer 2018;7:1-19.
68. Mazzaferro V, Llovet JM, Miceli R et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10:35-43.
69. Ueshima K, Ishikawa T, Saeki I et al. Transcatheter arterial chemoembolization therapy in combination strategy with lenvatinib in patients with unresectable hepatocellular carcinoma (TACTICS-L) in Japan: Final analysis. J Clin Oncol 2022;40(4 Suppl):417.
70. Kudo M, Guo Y, Hua Y et al. TALENTACE: A phase III, open-label, randomized study of on-demand transarterial chemoembolization combined with atezolizumab + bevacizumab or on-demand transarterial chemoembolization alone in patients with untreated hepatocellular carcinoma. J Clin Oncol 2022;40(4 suppl):TPS487.
71. Foerster F, Kloeckner R, Reig M et al. ABC-HCC: A phase IIIb, randomized, multicenter, open-label trial of atezolizumab plus bevacizumab versus transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma. J Clin Oncol 2022;40(4 suppl):TPS498.
72. Kudo M. Atezolizumab plus bevacizumab followed by curative conversion (ABC Conversion) in patients with unresectable, TACE-unsuitable intermediate-stage hepatocellular carcinoma. Liver Cancer 2022;11:399-406.
73. Yoo C, Kim JH, Ryu MH et al. Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: A multinational multicenter retrospective study. Liver Cancer 2021;10:107-14.
74. Gile J, Palmer ME, Storandt MH et al. Outcome of receiving lenvatinib following immunotherapy in patients with advanced hepatocellular carcinoma. J Clin Oncol 2023;41(4 Suppl.):507.
75. Llovet JM, Vogel A, Madoff DC et al. Randomized phase 3 LEAP-012 study: Transarterial chemoembolization with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma not amenable to curative treatment. Cardiovasc Intervent Radiol 2022;45:405-12.
For citation:Chan L.L., Chan S.L. The evolving role of lenvatinib at the new era of first-line hepatocellular carcinoma treatment. Clinical review for general practice. 2024; 5 (7): 24–36. (In Russ.). DOI: 10.47407/kr2024.5.7.00445
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