First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors.

PurposeTepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and methodsPatients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsOne hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.ConclusionsTepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials

Abstract 2724: Development of a sensitive assay for measuring pharmacodynamic modulation of c-Met in biopsies

Abstract Introduction: MSC2156119J, a highly selective, potent, reversible, ATP-competitive c-Met inhibitor currently under clinical testing, efficiently inhibits c-Met phosphorylation and downstream signaling in vivo and induces regression of established tumors in xenograft models in preclinical studies (Bladt et al. Clin Cancer Res. 2013;19:2941-51). One initial event following c-Met activation is Y1234/35 phosphorylation in the activation loop of the kinase domain. This results in kinase activation and triggers phosphorylation of tyrosine residues in the c-Met C-terminal tail (eg, Y1349), creating multifunctional docking sites for intracellular adapters. The development of an assay allowing the measurement of these phospho-c-Met epitopes in tumor biopsies will be crucial for establishing an optimal biologic dose for MSC2156119J. Methods: We describe here the development of a highly sensitive Luminex assay that can reliably and reproducibly measure the phosphorylation state of Y1234/35 and Y1349 residues of the c-Met receptor. The high sensitivity of the assay was confirmed by measuring the phospho-c-Met levels in biopsies from patients before and during MSC2156119J treatment. Results: We first assessed the stability of phosphorylated Y1234/35 and Y1349 epitopes in preclinical tumor samples. Analyses revealed that the total c-Met protein is rather stable over time, while the phospho-c-Met epitopes Y1234/35 and Y1349 are relatively unstable; their detection requires rapid processing of tumor samples derived from preclinical tumors or from patients. In tumor samples derived from human xenografts treated with MSC2156119J, Y1349 phosphorylation inhibition varied in different tumor models and did not show strong dose dependence. In contrast, phosphorylation of Y1234/35 residues was effectively inhibited by MSC2156119J in all tumor models tested. Based on these findings, phosphorylation of c-Met Y1234/35 was also assessed in tumor biopsies from patients treated with MSC2156119J in the first-in-man trial (NCT01014936; Falchook et al. J Clin Oncol. 2013;31(suppl):2506). When compared to pretreatment tumor biopsies, on-treatment samples showed effective, dose-dependent inhibition of &amp;gt;90% of c-Met Y1234/35 phosphorylation. Conclusions: We successfully developed an assay capable of detecting phosphorylation of the c-Met Y1234/35 epitope, which is crucial for c-Met activation. Using this assay on tumor samples from xenograft models and on patient-derived tumor biopsies, we demonstrated that MSC2156119J inhibits phosphorylation of c-Met Y1234/35 in a dose-dependent fashion. Therefore, phosphorylation of c-Met Y1234/35 can be used as a pharmacodynamic biomarker of c-Met inhibition and will be an important and valuable element for the selection of the optimal biologic dose of MSC2156119J. Citation Format: Friedhelm Bladt, Frank Jaehrling, Manja Friese-Hamim, Gerald S. Falchook, Hesham M. Amin, Manfred B. Klevesath, Andree Blaukat. Development of a sensitive assay for measuring pharmacodynamic modulation of c-Met in biopsies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2724. doi:10.1158/1538-7445.AM2014-2724</jats:p