Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models

Okamoto, Kiyoshi; Kodama, Kotaro; Takase, Kazuma; Sugi, Naoko Hata; Yamamoto, Yuji; Iwata, Masao; Tsuruoka, Akihiko

doi:10.1016/j.canlet.2013.07.007

Cited by 253 publications

(178 citation statements)

References 26 publications

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“…[20][21][22][23]) that has recently been approved for the treatment of radioiodine-refractory DTC (RR-DTC) on the basis of the results of the SELECT phase III trial (24). Preclinical and phase I evidence of antitumor efficacy in a variety of solid tumor types, including thyroid cancer (25)(26)(27)(28), prompted the initiation of a phase II trial in advanced, unresectable progressive MTC and RR-DTC, stratified by histology (29).…”

Section: Introductionmentioning

confidence: 99%

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Schlumberger

Jarząb

Cabanillas

et al. 2016

Clinical Cancer Research

219

162

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Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC).Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review.Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%-89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction.Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.

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Section: Introductionmentioning

confidence: 99%

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Schlumberger

Jarząb

Cabanillas

et al. 2016

Clinical Cancer Research

219

162

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“…Lenvatinib mesylate is a multityrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, platelet-derived growth factor receptor b, rearranged during transfection, and KIT (Matsui et al, 2008a,b;Okamoto et al, 2013). In a phase I study, lenvatinib was shown to have favorable PK properties, and its metabolic fate was investigated (Boss et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Oxidative Metabolic Pathway of Lenvatinib Mediated by Aldehyde Oxidase

et al. 2014

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Lenvatinib is a multityrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors, and is being developed as an anticancer drug. P450s are involved in one of the elimination pathways of lenvatinib, and mono-oxidized metabolites, such as N-oxide (M3) and desmethylated metabolite (M2), form in rats, dogs, monkeys, and humans. Meanwhile, two other oxidative metabolites are produced only in monkey and human liver S9 fractions, and their structures have been identified using high-resolution mass spectrometry as a quinolinone form of lenvatinib (M39) and a quinolinone form of desmethylated lenvatinib (M29). The formation of M39 from lenvatinib occurred independently of NADPH and was effectively inhibited by typical inhibitors of aldehyde oxidase, indicating the involvement of aldehyde oxidase, but not P450s, in this pathway. M29 was a dioxidized metabolite arising from a combination of monooxidation and desmethylation and could only be produced from M2 in a NADPH-independent manner; M29 could not be generated from M3 or M39. These results suggested that M29 is formed from lenvatinib by a unique two-step pathway through M2. Although both lenvatinib and M2 were substrates for aldehyde oxidase, an enzyme kinetic study indicated that M2 was a much more favorable substrate than lenvatinib. No inhibitory activities of lenvatinib, M29, or M39 and no significant inhibitory activities of M2 or M3 on aldehyde oxidase were observed, suggesting a low possibility of drug-drug interactions in combination therapy with substrates of aldehyde oxidase.

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“…Clinical evidence suggests that sorafenib blocks thyroid cancer growth through both antiproliferative and antiangiogenic mechanisms . Lenvatinib inhibits VEGFR1-3, fibroblast growth factor receptors 1-4, RET, c-KIT, and PDGFRβ [Matsui et al 2008;Okamoto et al 2013].…”

Section: Targeted Systemic Therapies For Rairefractory Thyroid Cancermentioning

confidence: 99%

Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer

Worden

2014

Ther Adv Med Oncol

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Until recently, no truly effective treatment options have existed for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), a serious disease with poor prognosis. In November 2013, the targeted multikinase inhibitor, sorafenib, was approved for use in these patients based on substantially improved progression-free survival compared with placebo. A number of other targeted agents, including lenvatinib, are being investigated in phase II and phase III trials. With the advent of these new treatment options, practitioners are faced with making important decisions in determining which patients are candidates for systemic treatment and the optimal timing for treatment initiation. Since patients may remain asymptomatic for a protracted period of time, tumor size and growth rate are the primary considerations for making these choices. Proactive management of side effects is also critical in optimizing the effectiveness of treatment. Here we review targeted systemic agents that are either in use or are under investigation for RAI-refractory DTC and provide recommendations on the rationale for initiating systemic treatment and on managing adverse events. Four illustrative case studies are provided.

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Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models

Cited by 253 publications

References 26 publications

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Oxidative Metabolic Pathway of Lenvatinib Mediated by Aldehyde Oxidase

Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer

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