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

Abstract

Purpose: Tepotinib 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 Methods: Patients 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. Results: One hundred and forty-nine patients received tepotinib (R1: n ¼ 42; R2: n ¼ 45; R3: n ¼ 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. Conclusions: Tepotinib 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.

Tepotinib Efficacy in a Patient with Non-Small Cell Lung Cancer with Brain Metastasis Harboring an HLA-DRB1-MET Gene Fusion

“…Tepotinib was very well tolerated by the patient even at 1,000 mg daily, and she did not have any related adverse events. Doses of up to 1,400 mg daily were previously shown to be well tolerated in phase I studies [20]. This efficacy is in line with interim data from the ongoing phase II VISION trial in patients with NSCLC with MET ex14 mutations, in which tepotinib 500 mg daily was shown to have durable clinical activity and a favorable safety profile, and patients with brain metastases at baseline benefitted equally from treatment [15].…”

HGF/c-Met Axis: The Advanced Development in Digestive System Cancer

“…Tepotinib is an effective and highly selective c-Met inhibitor, and its c-Met selectivity exceeds that of most kinase inhibitors with a cell-based 50% inhibitory concentration (IC50) of 1.7 nM (Falchook et al, 2020). In contrast, highly selective c-Met inhibitors have little effect on other targets and are expected to produce less toxicity.…”

Open-label, single-center, phase I trial to investigate the mass balance and absolute bioavailability of the highly selective oral MET inhibitor tepotinib in healthy volunteers

“…In this study, a single 500 mg dose of tepotinib was well tolerated by healthy volunteers; although 75% experienced TEAEs, most were mild and resolved rapidly. Tepotinib has also been found to be well tolerated in phase I/Ib and phase II clinical trials in patients with solid tumors, which have further characterized its side-effect profile [9,17,18,21,35,36]. Ongoing phase II trials in NSCLC and hepatocellular carcinoma will add further insight into the side-effect profile and efficacy of tepotinib [16-18, 20-22, 35].…”

“…At the current recommended phase I dose of tepotinib of 500 mg/ day [9,30], and using the tablet formulation being administered in ongoing clinical phase II trials, tepotinib had a geometric mean absolute bioavailability of 72% (range, 62-81%), with low interindividual variability (geometric CV, 10.8%).…”

“…Tepotinib (MSC2156119J) is an oral, highly selective, potent adenosine triphosphate-competitive inhibitor of MET, with >1000-fold selectivity for MET over 236 out of 241 other kinases tested, and >200-fold selectivity over the other five [8]. In the first-in-man trial, tepotinib doses of up to 1400 mg/ day were administered in patients with solid tumors without reaching the maximum tolerated dose; 500 mg once daily was subsequently established as the recommended phase II dose (RP2D) based on a translational modeling approach [9]. Tepotinib alone or in combination has been shown to be active in various preclinical tumor models [8,[10][11][12][13][14][15][16].…”