Lenvatinib (E7080)

Lenvatinib (E7080) is an inhibitor of multiple RTK with IC50 values of 22nM, 4nM, 5.2nM, 39nM and 35nM on VEGFR-1, VEGFR-2, VEGFR-3, PDGFRβ and RET, respectively [1].

Lenvatinib is presently under investigation both as monotherapy and in combination with cytotoxic agents for multiple types of solid tumor, including thyroid carcinoma and hepatocellular carcinoma (in Phase III trials), and melanoma, renal carcinoma, non-small cell lung carcinoma, glioblastoma multiforme, and ovarian and endometrial carcinoma (Phase I and II trials) [1].

When used as an inhibitor of RET kinase, Lenvatinib cause growth inhibition in TPC-1 cells and LC-2/ad cells. The GI50 values are 27nM and 48nM. It is also reported that Lenvatinib can inhibit RET (rearranged during transfection) gene fusion kinases, and inhibit oncogenic signaling of RET gene fusions. Lenvatinib has been demonstrated to exert antitumor activities in RET gene fusion-driven tumor models [2].

References:
[1] Neda Stjepanovic, Jaume Capdevila. Multikinase inhibitors in the treatment

of thyroid cancer: specific role of lenvatinib. Biologics: Targets and Therapy. 2014 (8): 129-139.

[2] Kiyoshi Okamoto, Kotaro Kodama, Kazuma Takase, Naoko Hata Sugi, Yuji Yamamoto, Masao Iwata, Akihiko Tsuruoka. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Letters. 2013 July（340）：97-103.

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment.[Pubmed:25913680]

Cancer. 2015 Aug 15;121(16):2749-56.

BACKGROUND: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor alpha (PDGFRalpha), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC). METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed. RESULTS: After >/=14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%-82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%). CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749-2756. (c) 2015 American Cancer Society.

Phase 1b study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma.[Pubmed:26503473]

Oncotarget. 2015 Dec 15;6(40):43127-34.

OBJECTIVE AND METHODS: In this phase 1b study, patients with stage 4 or unresectable stage 3 melanoma were treated with escalating doses of lenvatinib (once daily) and temozolomide (TMZ) (days 1-5) in 28-day cycles, to determine the maximum tolerated dose (MTD) of the combination. Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2. Adverse events (AEs) were recorded and tumor response assessed per RECIST 1.0. RESULTS: Dose-limiting toxicity occurred in 1 of 32 treated patients (DL1); MTD was not reached. The highest dose administered was lenvatinib 24 mg + TMZ 150 mg/m2. Most common treatment-related AEs included fatigue (56.3%), hypertension (53.1%), and proteinuria (46.9%). Overall objective response rate was 18.8% (6 patients), all partial response; (DL1, n = 1; DL3, n = 5). Stable disease (SD) >/= 16 weeks was observed in 28.1% of patients (DL1 and DL2, n = 1 each; DL3, n = 7); 12.5% of patients had SD >/= 23 weeks. Single and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration. CONCLUSIONS: Lenvatinib 24 mg/day + TMZ 150 mg/m2/day (days 1-5) demonstrated modest clinical activity, an acceptable safety profile, and was administered without worsening of either lenvatinib- or TMZ-related toxicities in this patient group.

Effects of Ketoconazole on the Pharmacokinetics of Lenvatinib (E7080) in Healthy Participants.[Pubmed:26097795]

Clin Pharmacol Drug Dev. 2015 Mar;4(2):155-160.

BACKGROUND: Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p-glycoprotein. METHODS: In this Phase I, single-center, randomized, open-label, two-period, crossover study, healthy adults (18-55 years; N = 18) were randomized to one of two sequences (ketoconazole --> placebo or vice versa). Ketoconazole (400 mg) or placebo was administered orally once daily for 18 days; a 5 mg dose of lenvatinib was orally administered on Day 5 of each treatment period. Blood samples were collected over 14 days and lenvatinib plasma concentrations measured by high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Systemic exposure to lenvatinib increased slightly (15-19%) with coadministration of ketoconazole. Although the 90% confidence interval (CI) for area under the plasma concentration-time curve (AUC) was within the prespecified bioequivalence interval of 80-125%, Cmax slightly exceeded the 125% CI bound (134%). No changes in tmax, tlag, or t(1/2) were observed. Thirteen subjects (72%) experienced treatment-emergent adverse events (11 mild, 2 moderate), most commonly headache (22%) and diarrhea (17%). CONCLUSIONS: Lenvatinib exposure was slightly increased by ketoconazole; however, the magnitude of the change was relatively small, and likely not clinically meaningful.

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer.[Pubmed:26311725]

Clin Cancer Res. 2016 Jan 1;22(1):44-53.

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.

Lenvatinib (E7080) is an oral, multi-targeted tyrosine kinase inhibitor that inhibits VEGFR1-3, FGFR1-4, PDGFR, KIT, and RET, shows potent antitumor activities.

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