Translational pharmacokinetic-pharmacodynamic modeling of preclinical and clinical data of the oral MET inhibitor tepotinib to determine the recommended phase II dose

Abstract

Tepotinib is a highly selective and potent MET inhibitor in development for the treatment of patients with solid tumors. Given the favorable tolerability and safety profiles up to the maximum tested dose in the first-in-human (FIH) trial, an efficacy-driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/target inhibition/tumor growth inhibition relationship, a subcutaneous KP-4 pancreatic cell-line xenograft model in mice with sensitivity to MET pathway inhibition was selected as a surrogate tumor model. Further clinical PK and target inhibition data (derived from predose and postdose paired tumor biopsies) from a FIH study were integrated with the longitudinal PKs and target inhibition profiles from the mouse xenograft study to establish a translational PK/pharmacodynamic (PD) model. Preclinical data showed that tumor regression with tepotinib treatment in KP-4 xenograft tumors corresponded to 95% target inhibition. We therefore concluded that a PD criterion of sustained, near-to-complete (>95%) phospho-MET inhibition in tumors should be targeted for tepotinib to be effective. Simulations of dose-dependent target inhibition profiles in human tumors that exceeded the PD threshold in more than 90% of patients established an RP2D of tepotinib 500 mg once daily. This translational mathematical modeling approach supports an efficacy-driven rationale for tepotinib phase II dose selection of 500 mg once daily. Tepotinib at this dose has obtained regulatory approval for the treatment of patients with non-small cell lung cancer harboring MET exon 14 skipping.

FIGURE 1

Workflow of model development. The effects of tepotinib and MSC2571109A, the major human circulating metabolite of tepotinib, on KP‐4 tumors in BALB/c mice were determined in a short‐term (1–4 day) pharmacokinetic/pharmacodynamic (PK/PD) study and longer‐term (10–16 day) efficacy studies. In the preclinical PK/PD study, target inhibition was assessed according to phospho‐MET modulation in xenograft tumors; in tumor growth inhibition studies, tumor size was measured. Longitudinal PK and PD measurements from KP‐4 tumor‐bearing mice in these studies, and clinical PD assessments based on paired biopsies (pretreatment and on‐treatment) from patients in a first‐in‐human study were then integrated into mathematical models. CLX, cell line xenograft; EC₉₀, effective concentration 90%; RP2D, recommended phase II dose

FIGURE 2

Tumor growth inhibition in cell‐line xenograft tumors. Observed versus predicted tumor volumes after fitting the pharmacokinetic/efficacy model to tumor volume data (means from two independent experiments) from the KP‐4 (a), Hs746T (b), and NIH3T3/TPR (c) xenograft efficacy studies. (d) Efficacy study of metabolite MSC2571109A in KP‐4 cell‐line xenograft tumors. Panel a, adapted from Falchook G, Kurzrock R, Amin HM, Xiong W, Fu S, Phia‐Paul SA, et al. First‐in‐Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors. Clin Cancer Res 2020;26(6):1237–46. Copyright 2020 American Association for Cancer Research. Reproduced with permission of the authors

FIGURE 3

Inhibition of phosphorylated MET. (a) Sustained high level of phospho‐MET inhibition is required for efficacy. Simulation of phospho‐MET inhibition using the established pharmacokinetic/pharmacodynamic (PK/PD) model after repeated treatment with tepotinib at doses that caused tumor regression indicates that high and sustained levels of phospho‐MET inhibition must be maintained. A daily dose of tepotinib 77 mg/kg was predicted to achieve tumor stasis in mice with KP‐4 cell line xenografts, corresponding to continuous greater than 90% phospho‐MET inhibition based on simulation from the PK/PD model. (b) Correlation of efficacy (% T/C) to PD modulation phospho‐MET inhibition (Y^1234−1235) in the KP‐4 xenograft tumor model. Near‐complete inhibition (≥95%) of phospho‐MET is required for tumor stasis or regression. Using the PK/PD model, phospho‐MET modulation was simulated under daily treatment conditions and at the doses tested in the efficacy experiments (5–200 mg/kg). The average phospho‐MET over time was then calculated and plotted against % TGI. The black line represents the fit to the data and shows that tumor regression (% T/C > 0) is achieved when mean phospho‐MET is greater than 95% over the treatment period. The % T/C represents the tumor volume of treated groups in relation to control and is calculated according to: %∆T/∆C = (TVf − TVi/TVfCtrl – TViCtrl) × 100%; where, TV = tumor volume, f = final, i = initial, and Ctrl = control. TGI, tumor growth inhibition. Panel (b), Falchook G, Kurzrock R, Amin HM, Xiong W, Fu S, Phia‐Paul SA, et al. First‐in‐Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors. Clin Cancer Res 2020;26(6):1237–46. Copyright 2020 American Association for Cancer Research. Reproduced with permission

FIGURE 4

Statistical regression of phopho‐MET to tepotinib exposure. The shape icons represent the observed percentage phospho‐MET inhibition relative to baseline marked with tepotinib dose level (mg/day). The solid, dashed, and dotted curves represent the regression lines with linear, maximum effect (E_max) and sigmoid E_max models, respectively. The horizontal line represents the PD threshold of 95% phospho‐MET inhibition. The vertical line and the shade area represent the population median and 90% prediction interval of steady state AUC (AUC_τ,SS) at 500 mg once daily dose, respectively. AUC, area under the concentration curve; PD, pharmacodynamic

FIGURE 5

Simulation of dose‐dependent phospho‐MET inhibition (relative to baseline) in humans and of tepotinib plasma concentration. Left to right and top to bottom: tepotinib 1000 mg, 700 mg, 500 mg, and 250 mg once daily, respectively. (a) The solid black line represents the median prediction of percentage phospho‐MET inhibition relative to baseline, and the shaded area represents a simulation‐based 10%–90% prediction interval for phospho‐MET inhibition relative to baseline. The dashed lines indicate the PD threshold of 5% phospho‐MET corresponding to 95% phospho‐MET inhibition. (b) The solid black line represents the median tepotinib plasma concentration, and the shaded area represents a simulation‐based 10%–90% prediction interval for tepotinib plasma concentration. The dashed lines indicate the free fraction‐corrected effective concentration 90% (EC₉₀) or EC 95% (EC₉₅) of 390 or 823 ng/ml in the preclinical tumor growth inhibition model. PD, pharmacodynamic