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

Purpose: Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the maximum tolerated dose (MTD) of tepotinib to determine the recommended phase II dose (RP2D). Experimental Design: 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 x /week; or R3, 300-1400 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 (TEAEs). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects. Results: 149 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 (1000, 1400 mg), the MTD was not reached at the highest tested dose of 1400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modelling 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.