Reference Detail

Ref Type

PMID

Authors

Gerald Steven Falchook , Razelle Kurzrock , Hesham M. Amin , Siqing Fu , Sarina Anne Piha-Paul , Filip JankuHongxia Zheng , Barbara Sarholz , Andreas Johne , David S. Hong

Title

Efficacy, safety, biomarkers, and phase II dose modeling in a phase I trial of the oral selective c-Met inhibitor tepotinib (MSC2156119J).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	33	no. 15_suppl

URL

https://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.2591

Abstract Text

Background: Tumor c-Met overexpression is associated with tumor aggression and poor prognosis, making it a target for therapy. This phase I study (NCT01014936) in patients (pts) with advanced solid tumors provided data that allowed determination of a recommended phase II dose (RP2D) for the selective oral c-Met inhibitor tepotinib (MSC2156119J). Methods: Primary objectives were to determine the MTD and RP2D. Secondary endpoints included antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics. Pts received tepotinib according to one of three 3-weekly regimens (R): 30–230 mg/d d1–14 followed by 7-d rest (R1); 30–115 mg/d 3x/week (R2); or 300–1400mg/d d1–21 (R3). Interim PK and biomarker data were analyzed using a population modeling approach. Using these data and the exposure/target inhibition relationship established in mice, a human population PK model was developed to simulate c-Met inhibition profiles in humans and determine the biologically active dose of tepotinib. Results: As of 9/30/2014,143 pts had been enrolled (R1 = 42; R2 = 45; R3 = 56). The MTD was not reached at ≤ 1400 mg/day d1–21 (R3). Among the 56 pts treated with R3 (c-Met overexpressing 12; amplified 4; overexpressing and amplified 3), treatment-related adverse events (trAEs) were observed in 61%. Of these, > 75% experienced trAEs of worst grade 1/2. Seven pts (13%) experienced trAEs of worst grade ≥ 3: fatigue (2), peripheral edema (2), ALT increase (1), AST increase (1), hyponatremia (1), edema (1), and thrombocytopenia (1). Of the 56pts treated with R3, 2 had a PR and 7 had SD as their best overall response. Patients with PRs had tumors with c-Met overexpression or amplification, as did 2/7 pts with SD. A biologically active dose of 500 mg/d was selected as the RP2D based on a translational modeling approach, with simulations indicating that ≥ 95% pMET inhibition was required for tumor regression. Human population PK simulations suggested that tepotinib 500 mg daily could achieve continuous pMET inhibition of ≥ 95% in 90% of the population. Conclusions: Tepotinib is well tolerated and shows antitumor activity, particularly in pts with c-Met overexpressing/amplified tumors. Clinical trial information: NCT01014936.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References