J Liver Cancer.  2023 Sep;23(2):262-271. 10.17998/jlc.2023.07.17.

The role of lenvatinib in the era of immunotherapy of hepatocellular carcinoma

Affiliations
  • 1Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong Faculty of Medicine, Shatin, Hong Kong, China
  • 2State Key Laboratory of Translational Oncology, State Key Lab & Research Institutes, Hong Kong Cancer Institute, The Chinese University of Hong Kong Faculty of Medicine, Shatin, Hong Kong, China

Abstract

Hepatocellular carcinoma (HCC) frequently presents as advanced stage with poor prognosis and high mortality. Systemic treatment is the treatment of choice for advanced disease. In 2007, the first multi-kinase inhibitor (MKI) sorafenib was approved and shown to modestly prolong overall survival (OS). The progress of systemic therapy has been slow afterwards until 2018 when lenvatinib, another MKI, was shown to be non-inferior to sorafenib on median OS as the first-line therapy for HCC. Since then, remarkable progress has been achieved on the treatment of advanced HCC, including the development of second-line targeted treatment, including regorafenib, cabozantinib and ramucirumab from 2017 to 2019. A growing focus has been placed on immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4. These ICIs have proven their potency in treating HCC as both initial and subsequent line of therapy. At present, both regimens of atezolizumab combined with bevacizumab, as well as the combination of tremelimumab and durvalumab, are recommended as the first-line treatments based on positive phase III clinical trials. With the advancement of ICIs, it is anticipated that the role of MKIs in the treatment of HCC will evolve. In this article, lenvatinib, one of the most commonly used MKIs in HCC, is chosen to be reviewed.

Keyword

Lenvatinib; Immune checkpoint inhibitors; Carcinoma, hepatocellular

Reference

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68:394–424.
2. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359:378–390.
3. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 noninferiority trial. Lancet. 2018; 391:1163–1173.
4. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018; 379:54–63.
5. Bruix J, Qin S, Merle P, Granito A, Huang YH, 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.
6. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020; 382:1894–1905.
7. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, 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; 20:282–296.
8. Abou-Alfa GK, Chan SL, Kudo M, Lau G, Kelley RK, Furuse J, 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 Suppl 4:379.
9. Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 2020; 6:e204564.
10. 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 Suppl 7:S1401–S1402.
11. National Comprehensive Cancer Network (NCCN). NCCN guidelines: hepatocellular carcinoma [Internet]. Plymouth Meeting (US): NCCN; [cited 2023 May 1]. Available from: https://www.nccn.org/ professionals/physician_gls/pdf/hcc.pdf.
12. Gordan JD, Kennedy EB, Abou-Alfa GK, Beg MS, Brower ST, Gade TP, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol. 2020; 38:4317–4345.
13. Vogel A, Martinelli E; ESMO Guidelines Committee. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO clinical practice guidelines. Ann Oncol. 2021; 32:801–805.
14. Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B. Systemic treatment of hepatocellular carcinoma: an EASL position paper. J Hepatol. 2021; 75:960–974.
15. Korean Liver Cancer Association (KLCA); National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol. 2022; 28:583–705.
16. Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022; 76:862–873.
17. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022; 1:1–12.
18. 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.
19. Fulgenzi CAM, Cheon J, D'Alessio A, Nishida N, Ang C, Marron TU, 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.
20. Haanen J, Obeid M, Spain L, Carbonnel F, Wang Y, Robert C, et al. Management of toxicities from immunotherapy: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022; 33:1217–1238.
21. Reiss KA, Yu S, Mamtani R, Mehta R, D'Addeo K, Wileyto EP, et al. Starting dose of sorafenib for the treatment of hepatocellular carcinoma: a retrospective, multi-institutional study. J Clin Oncol. 2017; 35:3575–3581.
22. Alghamdi MA, Amaro CP, Lee-Ying R, Sim HW, Samwi H, Chan KK, et al. Effect of sorafenib starting dose and dose intensity on survival in patients with hepatocellular carcinoma: results from a Canadian Multicenter Database. Cancer Med. 2020; 9:4918–4928.
23. Chan LL, Mo FKF, Law ALY, Shum TCY, Tai AYP, Lee AS, et al. Impact of dose adjustment on clinical outcome of lenvatinib-treated patients with advanced hepatocellular carcinoma (HCC) [Internet]. Shatin (CN): The Chinese University of Hong Kong Faculty of Medicine; [cited 2023 May 1]. Available from: https://www.postersessiononline.eu/173580348_eu/congresos/ILCA2022/aula/-P_108_ILCA2022.pdf.
24. Tison A, Garaud S, Chiche L, Cornec D, Kostine M. Immunecheckpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases. Nat Rev Rheumatol. 2022; 18:641–656.
25. Kawashima S, Joachim K, Abdelrahim M, Abudayyeh A, Jhaveri KD, Murakami N. Immune checkpoint inhibitors for solid organ transplant recipients: clinical updates. Korean J Transplant. 2022; 36:82–98.
26. Roayaie S, Schwartz JD, Sung MW, Emre SH, Miller CM, Gondolesi GE, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl. 2004; 10:534–540.
27. d'Izarny-Gargas T, Durrbach A, Zaidan M. Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: a systematic review. Am J Transplant. 2020; 20:2457–2465.
28. Li Z, Gao J, Zheng S, Wang Y, Xiang X, Cheng Q, et al. Therapeutic efficacy of sorafenib in patients with hepatocellular carcinoma recurrence after liver transplantation: a systematic review and meta-analysis. Turk J Gastroenterol. 2021; 32:30–41.
29. Bang K, Casadei-Gardini A, Yoo C, Iavarone M, Ryu MH, Park SR, et al. Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation. Cancer Med. 2023; 12:2572–2579.
30. Yoo C, Kim JH, Ryu MH, Park SR, Lee D, Kim KM, et al. Clinical outcomes with multikinase inhibitors after progression on firstline atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: a multinational multicenter retrospective study. Liver Cancer. 2021; 10:107–114.
31. Gile J, Palmer ME, Storandt MH, Bekaii-Saab TS, Tran NH, Mahipal A. Outcome of receiving lenvatinib following immunotherapy in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2023; 41 Suppl 4:507.
32. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, GarciaCriado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022; 76:681–693.
33. Arizumi T, Minami T, Chishina H, Kono M, Takita M, Yada N, et al. Time to transcatheter arterial chemoembolization refractoriness in patients with hepatocellular carcinoma in Kinki criteria stages B1 and B2. Dig Dis. 2017; 35:589–597.
34. Peck-Radosavljevic M, Kudo M, Raoul JL, Lee HC, Decaens T, Heo J, et al. Outcomes of patients (pts) with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE): global OPTIMIS final analysis. J Clin Oncol. 2018; 36 Suppl 15:4018.
35. Kudo M. A new treatment option for intermediate-stage hepatocellular carcinoma with high tumor burden: initial lenvatinib therapy with subsequent selective TACE. Liver Cancer. 2019; 8:299–311.
36. Kudo M, Ueshima K, Chan S, Minami T, Chishina H, Aoki T, et al. Lenvatinib as an initial treatment in patients with intermediatestage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh A liver function: a proof-of-concept study. Cancers (Basel). 2019; 11:1084.
37. Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, 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.
38. Li X, Feng GS, Zheng CS, Zhuo CK, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol. 2004; 10:2878–2882.
39. Sergio A, Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A, et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol. 2008; 103:914–921.
40. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005; 307:58–62.
41. Jiang H, Meng Q, Tan H, Pan S, Sun B, Xu R, et al. Antiangiogenic therapy enhances the efficacy of transcatheter arterial embolization for hepatocellular carcinomas. Int J Cancer. 2007; 121:416–424.
42. Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, et al. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial. Gut. 2020; 69:1492–1501.
43. Fu Z, Li X, Zhong J, Chen X, Cao K, Ding N, et al. Lenvatinib in combination with transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma (uHCC): a retrospective controlled study. Hepatol Int. 2021; 15:663–675.
44. Ueshima K, Ishikawa T, Saeki I, Morimoto N, Aikata H, Tanabe N, 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 Suppl 4:417.
45. 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.
46. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021; 384:1289–1300.
47. Makker V, Colombo N, Herráez AC, Santin AD, Colomba E, Miller DS, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022; 386:437–448.
48. Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumorassociated macrophage and activation of the interferon pathway. PLoS One. 2019; 14:e0212513.
49. Kimura T, Kato Y, Ozawa Y, Kodama K, Ito J, Ichikawa K, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018; 109:3993–4002.
50. Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020; 38:2960–2970.
51. 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 Suppl 7:S1401.
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