Population pharmacokinetic analysis of tepotinib, an oral MET kinase inhibitor, including data from the VISION study

Abstract

Purpose Tepotinib is a highly selective, potent, mesenchymal–epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping. Objectives of this population pharmacokinetic (PK) analysis were to evaluate the dose–exposure relationship of tepotinib and its major circulating metabolite, MSC2571109A, and to identify the intrinsic/extrinsic factors that are predictive of PK variability. Methods Data were included from 12 studies in patients with cancer and in healthy participants. A sequential modeling approach was used to analyze the parent and metabolite data, including covariate analyses. Potential associations between observed covariates and PK parameters were illustrated using bootstrap analysis-based forest plots. Results A two-compartment model with sequential zero- and first-order absorption, and a first-order elimination from the central compartment, best described the plasma PK of tepotinib in humans across the dose range of 30–1400 mg. The bioavailability of tepotinib was shown to be dose dependent, although bioavailability decreased primarily at doses above the therapeutic dose of 500 mg. The intrinsic factors of race, age, sex, body weight, mild/moderate hepatic impairment and mild/moderate renal impairment, along with the extrinsic factors of opioid analgesic and gefitinib intake, had no relevant effect on tepotinib PK. Tepotinib has a long effective half-life of ~ 32 h. Conclusions Tepotinib shows dose proportionality up to at least the therapeutic dose, and time-independent clearance with a profile appropriate for once-daily dosing. None of the covariates identified had a clinically meaningful effect on tepotinib exposure or required dose adjustments.

Exposure–response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations

“…Graphical and model-based analyses suggest a flat exposure-efficacy relationship for OR, DOR, and PFS in the VISION study. It is in agreement with our dose selection rationale that 500 mg/day regimen of tepotinib is expected to achieve close-to-complete (≥ 95%) intra-tumoral phospho-MET inhibition in the majority (> 90%) of treated patients [14], and renders clinical efficacy independent of individual factors that may influence exposure. At a reduced tepotinib dose of 250 mg/day, which is recommended to manage AEs, targeted sustained nearly-complete MET inhibition (≥ 95%) would still be expected in ≥ 80% of patients.…”

“…This raises important opportunities for PD biomarker and PK/PD model-informed approaches to rational dose selection [ 29 , 30 ]. Tepotinib, a highly selective inhibitor of the MET receptor tyrosine kinase, was developed using a fully biomarker-driven and model-informed approach to dose selection in early development, with the recommended phase 2 dose of 500 mg/day selected to provide sustained maximal target inhibition in tumor tissue, based on integrated modeling of preclinical PK/PD relationships, clinical PK, and tumor PD data evaluating inhibition of tumor MET phosphorylation in the first-in-human study [ 14 , 31 ]. Efficacy and overall benefit/risk of the 500 mg/day dosage for the treatment of NSCLC harboring MET ex14 skipping alterations have been demonstrated in the pivotal phase 2 VISION trial [ 6 ].…”

“…The relationship between tepotinib exposure and the efficacy outcomes, OR, DOR, and PFS was evaluated using tepotinib 24-h area under the concentration–time curve at steady state (AUC τ,ss ) as the exposure metric. Individual tepotinib AUC τ,ss was predicted from a tepotinib population PK model [ 14 ]. Other exposure metrics, AUC 0-24 on day one of treatment and mean daily AUC until the first confirmed best overall response, were explored in an earlier analysis version based on a subset of the patients, but did not result in meaningful differences in the exposure–response association (data on file).…”

“…The exposure metrics for tepotinib and MSC2571109A, used in the graphical analyses and in model-based analysis, were derived from a tepotinib population PK model [14], including individual predictions of longitudinal, time-varying AUC 24h (for the edema TTE and albumin modeling), and steady-state AUC (AUC τ,ss ), AUC 24h immediately preceding the event, the time-averaged AUC 24h during the week prior to the event, or the time-averaged AUC 24h during the 2 weeks prior to the event (for the graphical analyses). Linear, log-linear, and E max (or I max ) models of drug effect (EFF drug ) were evaluated in the exposure-response models, as indicated by the exploratory graphical analysis (Eqs.…”

“…The maximum tolerated dose of tepotinib was not reached in the first-in-human dose ranging study, which evaluated the safety profile of tepotinib at doses between 30 and 1400 mg/day [ 11 ]. A tepotinib dose of 500 mg/day (as hydrochloride hydrate, equivalent to 450 mg/day tepotinib free base) was subsequently established as the recommended phase 2 dose, using a translational modeling approach that integrated clinical and non-clinical pharmacokinetic (PK) and tumor pharmacodynamic (PD) data, and non-clinical efficacy data [ 14 ]. This model suggested that a once daily tepotinib dose of 500 mg will achieve plasma concentrations at or above the PD threshold of close-to-complete tumor phospho-MET inhibition (≥ 95%) in at least 90% of patients.…”