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Lenvatinib: A Review in Hepatocellular Carcinoma

Drugs volume 79, pages 665–674 (2019)Cite this article

Abstract

Lenvatinib (Lenvima®) is an oral small molecule inhibitor of multiple receptor tyrosine kinases, and is approved for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) in the USA, EU, Japan and China. The approval of lenvatinib was based on results of the randomized, open-label, multinational, non-inferiority phase III REFLECT trial in patients with unresectable HCC, who had not received treatment for advanced disease. In REFLECT, lenvatinib was non-inferior, but not superior, to sorafenib (current standard of care) for overall survival (OS). However, lenvatinib was associated with significant improvements compared with sorafenib in terms of all secondary endpoints [higher objective response rate (ORR), and longer progression-free survival (PFS) and time to progression (TTP)]. Lenvatinib had a generally manageable tolerability profile in REFLECT, with the most common treatment-emergent adverse events being hypertension, diarrhoea, decreased appetite and decreased weight. Given its non-inferior efficacy to sorafenib and manageable tolerability profile, lenvatinib represents a long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC. Further clinical experience may be required to fully define the position of lenvatinib in this setting.

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References

  1. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236.

    Article  Google Scholar 

  2. National Comprehensive Cancer Network. Hepatobiliary cancer (NCCN clinical practice guidelines in oncology). 2018. http://www.nccn.org/. Accessed 26 Mar 2019.

  3. European Medicines Agency. Assessment report: lenvima (international non-proprietary name: lenvatinib). 2018. http://www.ema.europa.eu. Accessed 26 Mar 2019.

  4. Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014;6:18.

    Article  Google Scholar 

  5. Matsuki M, Hoshi T, Yamamoto Y, et al. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Med. 2018;7(6):2641–53.

    CAS  Article  Google Scholar 

  6. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358–80.

    Article  Google Scholar 

  7. Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv238–55.

    CAS  Article  Google Scholar 

  8. European Medicines Agency. Lenvima (lenvatinib): summary of product characteristics. 2018. http://www.ema.europa.eu/. Accessed 26 Mar 2019.

  9. US FDA. Lenvima® (lenvatinib) US prescribing information. 2018. http://www.fda.gov. Accessed 26 Mar 2019.

  10. Eisai Inc. Lenvima® (lenvatinib): Japanese prescribing information. 2018. http://www.pmda.go.jp/. Accessed 26 Mar 2019.

  11. Eisai Inc. Lenvima® (lenvatinib mesylate) capsules: Chinese product specifications. 2018. http://202.96.26.102/index/detail/id/543. Accessed 26 Mar 2019.

  12. Frampton JE. Lenvatinib: a review in refractory thyroid cancer. Targ Oncol. 2016;11(1):115–22.

    Article  Google Scholar 

  13. Scott LJ. Lenvatinib: first global approval. Drugs. 2015;75(5):553–60.

    CAS  Article  Google Scholar 

  14. 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. https://doi.org/10.1155/2014/638747.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kudo M. Lenvatinib may drastically change the treatment landscape of hepatocellular carcinoma. Liver Cancer. 2018;7(1):1–19.

    CAS  Article  Google Scholar 

  16. Ichikawa K, Miyano SW, Adachi Y, et al. Lenvatinib suppresses angiogenesis through the inhibition of both the VEGFR and FGFR signaling pathways. Glob J Cancer Ther. 2016;2(1):019–25.

    Google Scholar 

  17. Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2008;122(3):664–71.

    CAS  Article  Google Scholar 

  18. Matsui J, Funahashi Y, Uenaka T, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14(17):5459–65.

    CAS  Article  Google Scholar 

  19. Okamoto K, Kodama K, Takase K, et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett. 2013;340(1):97–103.

    CAS  Article  Google Scholar 

  20. Ikeda M, Okusaka T, Mitsunaga S, et al. Safety and pharmacokinetics of lenvatinib in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2016;22(6):1385–94.

    CAS  Article  Google Scholar 

  21. Finn RS, Kudo M, Cheng AL, et al. Analysis of serum biomarkers (BM) in patients (pts) from a phase 3 study of lenvatinib (LEN) vs sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC) [abstract no. LBA30]. Ann Oncol. 2017;28(Suppl 5):617.

    Google Scholar 

  22. Vergote I, Ball DW, Kudo M, et al. Prognostic and predictive role of circulating angiopoietin-2 in multiple solid tumors: an analysis of approximately 500 patients treated with lenvatinib across tumor types [abstract no. 11061]. J Clin Oncol. 2014;32(15 Suppl):11061.

    Article  Google Scholar 

  23. Ogasawara S, Mihara Y, Kondo R, et al. Anti-proliferative effect of lenvatinib on human liver cancer cell lines in vitro and in vivo [abstract no. 1545]. Hepatology. 2018;68(Suppl 1):880A.

    Google Scholar 

  24. He XX, Shi LL, Qiu MJ, et al. Molecularly targeted anti-cancer drugs inhibit the invasion and metastasis of hepatocellular carcinoma by regulating the expression of MMP and TIMP gene families. Biochem Biophys Res Commun. 2018;504(4):878–84.

    CAS  Article  Google Scholar 

  25. Shumaker RC, Zhou M, Ren M, et al. Effect of lenvatinib (E7080) on the QTc interval: results from a thorough QT study in healthy volunteers. Cancer Chemother Pharmacol. 2014;73(6):1109–17.

    CAS  Article  Google Scholar 

  26. Shumaker R, Aluri J, Fan J, et al. Evaluation of the effects of formulation and food on the pharmacokinetics of lenvatinib (E7080) in healthy volunteers. Int J Clin Pharmacol Ther. 2014;52(4):284–91.

    CAS  Article  Google Scholar 

  27. Gupta A, Jarzab B, Capdevila J, et al. Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer. Br J Clin Pharmacol. 2016;81(6):1124–33.

    CAS  Article  Google Scholar 

  28. Shumaker RC, Aluri J, Fan J, et al. Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults. Clin Drug Investig. 2014;34(9):651–9.

    CAS  Article  Google Scholar 

  29. Dubbelman AC, Rosing H, Nijenhuis C, et al. Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas. Invest New Drugs. 2015;33(1):233–40.

    CAS  Article  Google Scholar 

  30. Tamai T, Hayato S, Hojo S, et al. Dose finding of lenvatinib in subjects with advanced hepatocellular carcinoma based on population pharmacokinetic and exposure-response analyses. J Clin Pharmacol. 2017;57(9):1138–47.

    CAS  Article  Google Scholar 

  31. 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(10126):1163–73.

    CAS  Article  Google Scholar 

  32. Nakamichi S, Nokihara H, Yamamoto N, et al. A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2015;76(6):1153–61.

    CAS  Article  Google Scholar 

  33. Shumaker R, Aluri J, Fan J, et al. Effects of ketoconazole on the pharmacokinetics of lenvatinib (E7080) in healthy participants. Clin Pharmacol Drug Dev. 2015;4(2):155–60.

    CAS  Article  Google Scholar 

  34. Hudgens S, Copher R, Meier G. Longitudinal analysis of adjusted EQ-5D utility score at baseline, progression-free survival, and progression for lenvatinib versus sorafenib [abstract no. PCN151]. Value Health. 2018;21(Suppl 1):35.

    Google Scholar 

  35. Hudgens S, Copher R, Meier G. Evaluation of the disease-specific items on the eortc in hepatocellular carcinoma patients treated with lenvatinib or sorafenib [abstract no. PCN162]. Value Health. 2018;21(Suppl 1):37.

    Article  Google Scholar 

  36. Hudgens S, Misurski D, Meier G. Detrimental impact of toxicity on quality of life in hepatocellular carcinoma patients treated with lenvatinib or sorafenib [abstract no. PCN2]. Value Health. 2017;20(9):A411–2.

    Article  Google Scholar 

  37. Ikeda K, Kudo M, Kawazoe S, et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol. 2017;52(4):512–9.

    CAS  Article  Google Scholar 

  38. Launay-Vacher V, Deray G. Hypertension and proteinuria: a class-effect of antiangiogenic therapies. Anticancer Drugs. 2009;20(1):81–2.

    CAS  Article  Google Scholar 

  39. Eisai Inc. Eisai to present results of post-hoc analyses of Lenvima® (lenvatinib) phase III REFLECT study in hepatocellular carcinoma at 2019 grastrointestinal cancers symposium [media release]. 15 Jan 2019. https://www.eisai.com/news/2019/news201903.html.

  40. The ASCO Post. Lenvatinib mesylate approved in Japan for unresectable HCC. 2018. http://www.ascopost.com/News/58662. Accessed 26 Mar 2019.

  41. Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017;11(4):317–70.

    Article  Google Scholar 

  42. Hiraoka A, Kumada T, Kariyama K, et al. Clinical features of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions: multicenter analysis. Cancer Med. 2019;8(1):137–46.

    CAS  Article  Google Scholar 

  43. Hiraoka A, Kumada T, Kariyama K, et al. Therapeutic potential of lenvatinib for unresectable hepatocellular carcinoma in clinical practice: multicenter analysis. Hepatol Res. 2019;49(1):111–7.

    CAS  PubMed  Google Scholar 

  44. Finn RS, Kudo M, Cheng AL, et al. Final analysis of serum biomarkers in patients (pts) from the phase III study of lenvatinib (LEN) vs sorafenib (SOR) in unresectable hepatocellular carcinoma (uHCC) [REFLECT] [abstract no. 59PD]. Ann Oncol. 2018;29(Suppl 8):viii17–8.

    Google Scholar 

  45. Myojin Y, Shiode Y, Kodama K, et al. In vivo high-throughput screen to identify oncogenic biomarkers determining efficacy of molecular target therapy in hepatocellular carcinoma [abstract no. 351]. Hepatology. 2018;68(Suppl 1):212A.

    Google Scholar 

  46. Kobayashi M, Kudo M, Izumi N, et al. Cost-effectiveness analysis of lenvatinib treatment for patients with unresectable hepatocellular carcinoma (uHCC) compared with sorafenib in Japan. J Gastroenterol. 2019. https://doi.org/10.1007/s00535-019-01554-0.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

During the peer review process, the manufacturer of lenvatinib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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  1. Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand

    Zaina T. Al-Salama, Yahiya Y. Syed & Lesley J. Scott

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  1. Zaina T. Al-Salama
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  3. Lesley J. Scott
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Correspondence to Zaina T. Al-Salama.

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Funding

The preparation of this review was not supported by any external funding.

Conflicts of interest

Zaina T. Al-Salama, Yahiya Y. Syed and Lesley J. Scott are salaried employees of Adis/Springer, are responsible for the article content and declare no relevant conflicts of interest

Additional information

The manuscript was reviewed by: G. G. Di Costanzo, Department of Transplantation, Liver Unit, Cardarelli Hospital, Naples, Italy; M. Fukudo, Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical University, Hokkaido, Japan.

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Al-Salama, Z.T., Syed, Y.Y. & Scott, L.J. Lenvatinib: A Review in Hepatocellular Carcinoma. Drugs 79, 665–674 (2019). https://doi.org/10.1007/s40265-019-01116-x

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