Patients (pts) with NSCLC treated with EGFR inhibitors (EGFRi) ultimately develop resistance, often through c-Met activation. Dual EGFR and c-Met inhibition is therefore a rational option to treat c-Met + , EGFRi-resistant NSCLC. Tepotinib is a highly selective c-Met inhibitor with good tolerability and promising efficacy against solid tumors. This phase Ib trial, conducted in Asia, examined tepotinib plus gefitinib in pts with c-Met + /EGFR-mutant NSCLC.
Pts aged ≥18 years were eligible if they had locally advanced/metastatic NSCLC, ECOG PS 0–1, EGFR mutation confirmed by Therascreen EGFR RGQ PCR (Qiagen), and c-Met positivity determined by IHC using CONFIRM anti-c-Met mAb (SP44; Ventana/Roche). A 3 + 3 design was used with expansion at the RP2D. Pts received tepotinib 300 or 500 mg/day plus gefitinib 250 mg/day (T300G250 or T500G250). The primary objective was to determine the RP2D of tepotinib plus gefitinib; secondary objectives included pharmacokinetics (PK), safety, and antitumor activity.
18 pts were enrolled (median age 65 [41–78], male 8). Pts had received a median of 2 (1–8) prior regimens including an EGFRi. 6 received T300G250, 12 T500G250. No dose-limiting toxicities were observed, and tepotinib 500 mg/day was confirmed as the RP2D. T500G250 was associated with treatment-related grade ≥3 increased amylase (n = 2), increased lipase (2), neutropenia (1) and hyperglycemia (1). No evidence of cumulative toxicity was noted. The best overall response was partial response in 5/18 pts, 4 with IHC 3+ tumors treated with T500G250 and 1 with an IHC 2+ tumor (T300G250). 4/18 pts had stable disease (SD) (3 IHC 2+ [1 T300G250, 2 T500G250], 1 IHC 3+ [T500G250]). PK were as expected based on historical comparisons.
Tepotinib was well tolerated in combination with gefitinib; the RP2D of tepotinib in combination with gefitinib in NSCLC is 500 mg/kg/day. Data show evidence of antitumor activity, with responses mainly in pts with c-Met IHC 3+ tumors and SD in pts with IHC 2+ tumors. A phase II trial is randomizing ∼136 pts with T790M–/c-Met+ tumors who have failed first-line gefitinib to tepotinib + gefitinib or cisplatin/pemetrexed.
Clinical trial identification
Legal entity responsible for the study
Global Clinical Development Center Merck Serono (Beijing) Pharmaceutical R&D Co., Ltd
Y-L. Wu: Honoraria in the past two years from Roche, AstraZeneca, Eli Lilly, Sanofi. Research for Roche, AstraZeneca, Eli Lilly, Pfizer, Merck Serono, Novartis, BMS, ACEA Biosciences. R. Soo: Paid honoraria and consulted for AstraZeneca, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche. Conducted research for AstraZeneca, Pfizer, Roche, Taiho, Merck-Serono, Novartis, Servier Bayer. J. Yang: Honoraria from AstraZeneca, Roche, Eli Lilly, Boehringer Ingelheim, Pfizer. Paid consultant to AstraZeneca, Roche/Genentech, Eli Lilly, Boehringer, Clovis, Novartis, Bayer, MSD, Merck, Pfizer, Astellas, Daichi-Sankyo, Celgene. Funder research Boehringer. U. Stammberger: Employee of Merck KGaA. W. Chen, G. Locatelli: Employee of Merck. K. Park: Advisory role for Astra Zeneca, Boehringer Ingeiheim, Clovis, Eli Lilly, Hanmi, ONO, Roche, in the past 2 years. Research for AstraZeneca. All other authors have declared no conflicts of interest.