Phase Ii Study of Lenvatinib (Len), a Multi-Targeted Tyrosine Kinase Inhibitor, in Patients (Pts) with All Histologic Subtypes of Advanced Thyroid Cancer (Differentiated, Medullary and Anaplastic)

Takahashi, Shunji; Tahara, Makoto; Kiyota, Naomi; Yamazaki, Tomoko; Chayahara, Naoko; Nakano, Kenji; Inagaki, Risa; Toda, Kazuhisa; Enokida, Tomohiro; Minami, Hironobu; Imamura, Yoshiaki; Sasaki, Tatsuya; Suzuki, Takuya; Fujino, Kiyoshi; Dutcus, Corina E.

doi:10.1093/annonc/mdu340.10

Cited by 21 publications

(10 citation statements)

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“…The current analysis was based on pooled data collected from eight phase 1 studies of lenvatinib in healthy subjects (Eisai data on file) , four phase 1 studies of lenvatinib in patients with solid tumours (Eisai data on file) , two phase 2 studies of lenvatinib in patients with thyroid cancers and the phase 3 SELECT trial of patients with RR‐DTC . All patients signed informed consent forms for participation in the respective trials, which were conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and local regulations, and approved by the independent review boards of each participating centre.…”

Section: Methodsmentioning

confidence: 99%

Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer

Gupta

Jarząb

Capdevila

et al. 2016

Brit J Clinical Pharma

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AIMSLenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans. METHODSThis population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC. RESULTSThe final pooled dataset included data from 779 subjects receiving 3.2-32 mg oral lenvatinib, mainly once daily as tablets or capsules. Lenvatinib PK was best described by a three-compartment model with linear elimination. Lenvatinib absorption was best described by simultaneous first-and zero-order absorption. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h À1 [percent coefficient of variation (%CV) 25.5], and was independent of dose and time. The relative bioavailability of lenvatinib in capsule form was 90% vs. tablets (%CV 30.2). The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liver-function markers [alkaline phosphatase (À11.7%) and albumin (À6.3%)] and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (À7.8%) on lenvatinib CL/F. Lenvatinib PK was unaffected by pH-elevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function. CONCLUSIONSThe significant effects of several covariates on lenvatinib PK variability were small in magnitude, and therefore were not considered clinically relevant, or to warrant any dose adjustment. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacokinetics of lenvatinib have previously been studied only in individual clinical trials with limited sample sizes, or in targeted pharmacokinetic studies of special populations (e.g. subjects with renal or hepatic impairment). WHAT THIS STUDY ADD• The first population pharmacokinetic analysis for lenvatinib provides crucial insight into the intrinsic and extrinsic factors affecting lenvatinib pharmacokinetics.• The study provides useful information on the interaction of lenvatinib with pH-elevating agents commonly used by cancer patients, based on clinical trial data and not as a prospectively designed drug-drug-interaction study.

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Section: Methodsmentioning

confidence: 99%

Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer

Gupta

Jarząb

Capdevila

et al. 2016

Brit J Clinical Pharma

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“…However, several molecular targeted therapies have achieved successful results against ATCs (6)(7)(8). Rosove et al (9) reported an impressive case of an ATC patient successfully treated with a selective BRAF V600E inhibitor, vemurafenib.…”

Section: Introductionmentioning

confidence: 99%

Growth arrest by activated BRAF and MEK inhibition in human anaplastic thyroid cancer cells

Kurata

Onoda

Noda

et al. 2016

International Journal of Oncology

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Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated. Dabrafenib strongly inhibited the viability in BRAF mutated cells by demonstrating G0/G1-arrest via the downregulation of MEK/ERK phosphorylation. Upregulated phosphorylation of MEK was observed in RAS mutated cells after dabrafenib treatment and caused VEGF upregulation, but was not related to the cellular proliferation. Trametinib inhibited the cellular viability to variable degrees in every cell by downregulating ERK phosphorylation. Dual blockade by both inhibitors demonstrated clear cytostatic effect in all the cells. OCUT-4 showed the weakest sensitivity to trametinib, no additional effect of either inhibitor in combination with the other, and an increase of SNAI1 mRNA expression after treatment with inhibitors, suggesting a mechanism for resistance. Our findings demonstrated the efficacy of a mutation-selective BRAF inhibitor and a MEK inhibitor in human ATC cells in a genetic alteration-specific manner.

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“…Lenvatinib was well tolerated at doses from 10 mg BID to 25 mg OD [ 20 – 24 ] and was associated with a reduction in disease activity biomarkers [ 23 ], partial response, and stable disease according to response evaluation criteria in solid tumours [ 21 ]. These findings were further established in phase 2 trials and notably responses were demonstrated in thyroid cancer [ 25 – 27 ].…”

Section: Case Reportmentioning

confidence: 83%

A Case of Lenvatinib-Induced Focal Segmental Glomerulosclerosis (FSGS) in Metastatic Medullary Thyroid Cancer

Fleming

McGuinness

Kipgen

et al. 2018

Case Reports in Oncological Medicine

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We describe a case of lenvatinib (E7080) associated focal segmental glomerulosclerosis (FSGS) encountered during the treatment of metastatic medullary thyroid cancer. Proteinuria is a relatively common side effect of VEGF-targeted treatments and can occasionally result in treatment discontinuation. Here, we describe a patient who developed secondary FSGS necessitating discontinuation of treatment at first but who was subsequently rechallenged with anti-VEGF-targeted treatment without recurrence of proteinuria. Lenvatinib was a novel experimental agent at the time the treatment took place; however, its recent licensing for the treatment of thyroid malignancies in the UK makes reporting of these adverse effects all the more important now.

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Phase Ii Study of Lenvatinib (Len), a Multi-Targeted Tyrosine Kinase Inhibitor, in Patients (Pts) with All Histologic Subtypes of Advanced Thyroid Cancer (Differentiated, Medullary and Anaplastic)

Cited by 21 publications

References 0 publications

Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer

Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer

Growth arrest by activated BRAF and MEK inhibition in human anaplastic thyroid cancer cells

A Case of Lenvatinib-Induced Focal Segmental Glomerulosclerosis (FSGS) in Metastatic Medullary Thyroid Cancer

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