Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies

References

• Eisai Inc., Lenvima (lenvatinib) [prescribing information]. Nutley NJ US: Eisai Inc; 2021.
   Google Scholar
• Suyama K, Iwase H. Lenvatinib: a promising molecular targeted agent for multiple cancers. Cancer Control. 2018;25(1):1073274818789361.
   Web of Science ®Google Scholar
• Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621–630.
   PubMed Web of Science ®Google Scholar
• 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;391:1163–1173.
   PubMed Web of Science ®Google Scholar
• Eisai Co., Ltd., MSK K.K. Lenvima® (lenvatinib) approved for additional indication of unresectable thymic carcinoma in Japan [press release]. Mar 23. Available at: https://www.eisai.com/news/2021/news202120.html [ Accessed December 17, 2021].
   Google Scholar
• Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384:1289–1300.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Lenvima: summary of opinion ( post authorisation). EMA/CHMP/565583/2021. 2021. Available at: https://www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-lenvima-ii-42_en.pdf [ Accessed December 9, 2021].
   Google Scholar
• Makker V, Colombo N, and Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386:437–448.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473–1482.
   PubMed Web of Science ®Google Scholar
• Eisai Europe Limited. Lenvima 4 mg and 10 mg hard capsules [summary of product characteristics]. Hertfordshire UK: Eisai Europe Limited; 2021.
   Google Scholar
• Eisai GmbH. Kisplyx 4 mg and 10 mg hard capsules [summary of product characteristics]. Frankfurt am Main Germany: Eisai GmbH; 2021.
   Google Scholar
• Department of Health and Human Services. NDA 206947/S-003. Supplement approval. 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/206947Orig1s003ltr.pdf [ Accessed December 9, 2021].
   Google Scholar
• Center for Drug Evaluation and Research. Application number: 206947Orig1s000. Summary review. 2015. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206947orig1s000sumr.pdf [ Accessed December 9, 2021].
   Google Scholar
• European Medicines Agency. Lenvima assessment report. EMA/250082/2015. 2015. Available at: https://www.ema.europa.eu/en/documents/assessment-report/lenvima-epar-public-assessment-report_en.pdf [ Accessed December 9, 2021].
   Google Scholar
• European Medicines Agency. Kisplyx: procedural steps taken and scientific information after the authorisation. Available at: https://www.ema.europa.eu/en/documents/procedural-steps-after/kisplyx-epar-procedural-steps-taken-scientific-information-after-authorisation_en-0.pdf [ Accessed December 9, 2021].
   Google Scholar
• Capozzi M, De Divitiis C, Ottaiano A, et al. Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment. Cancer Manag Res. 2019;11:3847–3860.
   PubMed Web of Science ®Google Scholar
• Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23(5):1011–1027.
   PubMed Web of Science ®Google Scholar
• Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13(12):871–882.
   PubMed Web of Science ®Google Scholar
• Katoh M. FGFR inhibitors: effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int J Mol Med. 2016;38(1):3–15.
   PubMed Web of Science ®Google Scholar
• Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol. 2018;9:978.
   PubMed Web of Science ®Google Scholar
• Ott PA, Hodi FS, Buchbinder EI. Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: an overview of rationale, preclinical evidence, and initial clinical data. Front Oncol. 2015;5:202.
   PubMed Web of Science ®Google Scholar
• Fukumura D, Kloepper J, Amoozgar Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15:325–340.
   PubMed Web of Science ®Google Scholar
• Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 2019;14(2):e0212513.
   PubMed Web of Science ®Google Scholar
• Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018;109:3993–4002.
   PubMed Web of Science ®Google Scholar
• Adachi Y, Kamiyama H, Ichikawa K, et al. Inhibition of FGFR reactivates IFNγ signaling in tumor cells to enhance the combined antitumor activity of lenvatinib with anti-PD-1 antibodies. Cancer Res. 2021 canres.2426.2020. [online ahead of print;82:292–306.
   PubMed Web of Science ®Google Scholar
• Ichikawa K, Watanabe Miyano S, Minoshima Y, et al. Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy. Sci Rep. 2020;10:2939.
   PubMed Web of Science ®Google Scholar
• 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;7:2641–2653.
   PubMed Web of Science ®Google Scholar
• Hoshi T, Watanabe Miyano S, Watanabe H, et al. Lenvatinib induces death of human hepatocellular carcinoma cells harboring an activated FGF signaling pathway through inhibition of FGFR-MAPK cascades. Biochem Biophys Res Commun. 2019;513:1–7.
   PubMed Web of Science ®Google Scholar
• Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651–668.
   PubMed Web of Science ®Google Scholar
• Grünwald V, Powles T, Choueiri TK, et al. Lenvatinib plus everolimus or pembrolizumab versus sunitinib in advanced renal cell carcinoma: study design and rationale. Future Oncol. 2019;15:929–941.
   PubMed Web of Science ®Google Scholar
• Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology. 2017;93(1):147–159.
   PubMed Web of Science ®Google Scholar
• Yonucu S, Yiotalmaz D, Phipps C, et al. Quantifying the effects of antiangiogenic and chemotherapy drug combinations on drug delivery and treatment efficacy. PLoS Comput Biol. 2017;13:1005724.
   PubMed Web of Science ®Google Scholar
• Une N, Takano-Kasuya M, Kitamura N, et al. The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors. Med Oncol. 2021;38:60.
   PubMed Web of Science ®Google Scholar
• Bruheim S, Kristian A, Uenaka T, et al. Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts. Int J Cancer. 2011;129:742–750.
   PubMed Web of Science ®Google Scholar
• Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.
   PubMed Web of Science ®Google Scholar
• Bailly C, Thuru X, Quesnel B. Combined cytotoxic chemotherapy and immunotherapy of cancer: modern times. NAR Cancer. 2020;2:zcaa002.
   PubMedGoogle Scholar
• Matsuki M, Adachi Y, Ozawa Y, et al. Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus. Cancer Sci. 2017;108:763–771.
   PubMed Web of Science ®Google Scholar
• Leonetti A, Leonardi F, Bersanelli M, et al. Clinical use of lenvatinib in combination with everolimus for the treatment of advanced renal cell carcinoma. Ther Clin Risk Manag. 2017;13:799–806.
   PubMed Web of Science ®Google Scholar
• Mitsuhashi K, Kimura T, and Hoshi T, et al. Effects of lenvatinib mesilate in combination with everolimus on VEGF and FGF-driven angiogenesis and tumor growth. [ abstract]. Cancer Res. 2016;76(14 doi:https://doi.org/10.1158/1538-7445.AM2016-3262): abstract.
   Google Scholar
• Boss DS, Glen H, Beijnen JH, et al. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer. 2012;106:1598–1604.
   PubMed Web of Science ®Google Scholar
• 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;76:1153–1161.
   PubMed Web of Science ®Google Scholar
• Hong DS, Kurzrock R, Wheler JJ, et al. Phase I dose-escalation study of the multikinase inhibitor lenvatinib in patients with advanced solid tumors and in an expanded cohort of patients with melanoma. Clin Cancer Res. 2015;21:4801–4810.
   PubMed Web of Science ®Google Scholar
• Yamada K, Yamamoto N, Yamada Y, et al. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res. 2011;17(8):2528–2537.
   PubMed Web of Science ®Google Scholar
• Cabanillas ME, Takahashi S. Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer. Semin Oncol. 2019;46:57–64.
   PubMed Web of Science ®Google Scholar
• Cabanillas ME, Hu MI, Durand JB, et al. Challenges associated with tyrosine kinase inhibitor therapy for metastatic thyroid cancer. J Thyroid Res. 2011;2011:985780.
   PubMedGoogle Scholar
• Brose MS, Frenette CT, Keefe SM, et al. Management of sorafenib-related adverse events: a clinician’s perspective. Semin Oncol. 2014;41(2):S1–S16.
   PubMedGoogle Scholar
• Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639–3646.
   PubMed Web of Science ®Google Scholar
• Vaklavas C, Lenihan D, Kurzrock R, et al. Anti-vascular endothelial growth factor therapies and cardiovascular toxicity: what are the important clinical markers to target? Oncologist. 2010;15:130–141.
   PubMed Web of Science ®Google Scholar
• Kandula P, Agarwal R. Proteinuria and hypertension with tyrosine kinase inhibitors. Kidney Int. 2011;80:1271–1277.
   PubMed Web of Science ®Google Scholar
• Rimassa L, Danesi R, Pressiani T, et al. Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma. Cancer Treat Rev. 2019;77:20–28.
   PubMed Web of Science ®Google Scholar
• Keizer RJ, Gupta A, Mac Gillavry MR, et al. A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080. J Pharmacokinet Pharmacodyn. 2010;37:347–363.
   PubMed Web of Science ®Google Scholar
• Gupta A, Koetz B, Hanekom W, et al. Population pharmacokinetics (PK) and exposure/response relationships of the receptor tyrosine kinase inhibitor E7080 in phase I studies [abstract]. Eur J Cancer Suppl. 2010 Abstract 453;8:143.
   Web of Science ®Google Scholar
• LiverTox.Clinical and research information on drug-induced liver injury [internet]. Lenvatinib.Bethesda MD:National Institute of Diabetes and Digestive and Kidney Diseases.2012. updated June 1, 2017.
   Google Scholar
• Ikeda M, Okusaka T, Mitsunaga S, et al. Safety and pharmacokinetics of lenvatinib in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2016;22:1385–1394.
   PubMed Web of Science ®Google Scholar
• Ikeda K, Kudo M, Kawazoe S, et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol. 2017;52:512–519.
   PubMed Web of Science ®Google Scholar
• 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;57:1138–1147.
   PubMed Web of Science ®Google Scholar
• 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;81:1124–1133.
   PubMed Web of Science ®Google Scholar
• Hayato S, Shumaker R, Ferry J, et al. Exposure-response analysis and simulation of lenvatinib safety and efficacy in patients with radioiodine-refractory differentiated thyroid cancer. Cancer Chemother Pharmacol. 2018;82:971–978.
   PubMed Web of Science ®Google Scholar
• Brose MS, Panaseykin Y, Konda B, et al. A randomized study of lenvatinib 18 mg vs 24 mg in patients with radioiodine-refractory differentiated thyroid cancer. J Clin Endocrinol Metab. 2021. online ahead of print https://doi.org/10.1210/clinem/dgab1731.
   Google Scholar
• Sato J, Satouchi M, Itoh S, et al. Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial. Lancet Oncol. 2020;21:843–850.
   PubMed Web of Science ®Google Scholar
• Taylor MH, Lee CH, Makker V, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 2020;38:1154–1163.
   PubMed Web of Science ®Google Scholar
• Arora S, Balasubramaniam S, Zhang W, et al. FDA approval summary: pembrolizumab plus lenvatinib for endometrial carcinoma, a collaborative international review under Project Orbis. Clin Cancer Res. 2020;26:5062–5067.
   PubMed Web of Science ®Google Scholar
• Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38:2981–2992.
   PubMed Web of Science ®Google Scholar
• Makker V, Aghajanian C, Cohn A, et al. Lenvatinib and pembrolizumab in advanced endometrial carcinoma (EC): long-term efficacy and safety update from a phase 1b/2 study [abstract]. J Immunother Cancer. 2021;9(Suppl 2):A381. Abstract 354.
   Web of Science ®Google Scholar
• Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22:946–958.
   PubMed Web of Science ®Google Scholar
• Molina AM, Hutson TE, Larkin J, et al. A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother Pharmacol. 2014;73:181–189.
   PubMed Web of Science ®Google Scholar
• Pal SK, Puente J, Heng DYC, et al. Phase 2 trial of lenvatinib at 2 starting doses + everolimus in renal cell carcinoma (RCC) [abstract]. Kidney Cancer J. 2020;18(4 Suppl):34–35. Abstract CTR142.
   Google Scholar
• Food and Drug Administration, American Association for Cancer Research. Oncology Dose Finding Workshop. June 13, 2016; Washington DC US. Available at: https://www.aacr.org/wp-content/uploads/2019/11/6.13.16-FDA-AACR-Dose-Finding-for-Online.pdf [ Accessed 2021 Dec 9].
   Google Scholar
• Al-Huniti N, Feng Y, Yu JJ, et al. Tumor growth dynamic modeling in oncology drug development and regulatory approval: past, present, and future opportunities. CPT Pharmacometrics Syst Pharmacol. 2020; 9: 419–427.
   PubMedGoogle Scholar
• Tahara M, Brose MS, Wirth LJ, et al. Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer. 2019;106:61–68.
   PubMed Web of Science ®Google Scholar
• Robinson B, Schlumberger M, Wirth LJ, et al. Characterization of tumor size changes over time from the phase 3 study of lenvatinib in thyroid cancer. J Clin Endocrinol Metab. 2016;101:4103–4109.
   PubMed Web of Science ®Google Scholar
• Wirth LJ, Tahara M, Robinson B, et al. Treatment-emergent hypertension and efficacy in the phase 3 Study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT). Cancer. 2018;124:2365–2372.
   PubMed Web of Science ®Google Scholar
• Okusaka T, Ikeda K, Kudo M, et al. Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT. J Gastroenterol. 2021;56:570–580.
   PubMed Web of Science ®Google Scholar
• Sung MW, Finn RS, Qin S, et al. Association between overall survival and adverse events with lenvatinib treatment in patients with hepatocellular carcinoma (REFLECT) [abstract]. J Clin Oncol. 2019Suppl): Abstract 317; 374: https://doi.org/10.1200/JCO.2019.37.4_suppl.317
   Google Scholar
• Nishio M, Peled N, Zer A, et al. Phase 3 LEAP-006 safety run-in (Part 1): first-line pembrolizumab + chemotherapy with lenvatinib for metastatic NSCLC. Presented at: European Socity for Medical Oncology (ESMO); September 19–21, 2020; virtual congress
   Google Scholar
• Colombo N, Lorusso D, Santin AD, et al. Characterization of adverse reactions in patients with advanced endometrialv cancer (AEC) receiving lenvatinib + pembrolizumab (study 309/KEYNOTE-775) [abstract]. Int J Gynecol Cancer. 2021;31(Suppl 3):A78. Abstract 145.
   PubMed Web of Science ®Google Scholar
• Jones A, Robbins C, Amaya-Chanaga C, et al. Patient education and management of adverse reactions in patients with unresectable hepatocellular carcinoma (uHCC) treated with lenvatinib: nurse practitioners’ perspective. Presented at: The Oncology Nursing Society’s Annual Conference; April 20–29, 2021; virtual congress.
   Google Scholar
• Villa G, Colombo N, Zale M, et al. Characterization of adverse reactions in patients with advanced endometrial cancer receiving lenvatinib + pembrolizumab (study 309/KEYNOTE-775): nurse roles in patient education and adverse-reaction management. Presented at: Annual Navigation & Survivorship Conference; November 17–21, 2021; virtual congress.
   Google Scholar
• Motzer R, George S, Merchan JR, et al. Characterization and management of adverse reactions (ARs) in patients with advanced renal cell carcinoma (aRCC) receiving lenvatinib + pembrolizumab (CLEAR study) [abstract]. Int Kidney Cancer Symp. 2021: Abstract CTR14.
   Google Scholar
• Taylor MH, Schmidt EV, Dutcus C, et al. The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Future Oncol. 2021;17:637–648.
   PubMed Web of Science ®Google Scholar
• Gaspar N, Campbell-Hewson Q, Gallego Melcon S, et al. Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)(). ESMO Open. 2021;6:100250.
   PubMed Web of Science ®Google Scholar
• Gaspar N, Venkatramani R, Hecker-Nolting S, et al. Lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma (ITCC-050): a multicentre, open-label, multicohort, phase 1/2 study. Lancet Oncol. 2021;22:1312–1321.
   PubMed Web of Science ®Google Scholar
• Dela Cruz FS, Fox E, Muscal JA, et al. A phase I/II study of lenvatinib (LEN) plus everolimus (EVE) in recurrent and refractory pediatric solid tumors, including CNS tumors [abstract]. J Clin Oncol. 2020;38(15):Suppl): Abstract 10527.
   Web of Science ®Google Scholar