Phase Ib study of tepotinib in EGFR-mutant/c-Met-positive NSCLC: Final data and long-term responders.
8547 Background: Patients (pts) with NSCLC that is initially responsive to EGFR tyrosine kinase inhibitors (EGFR TKI) typically develop resistance, often associated with aberrant c-Met activity. Dual inhibition of EGFR and c-Met is therefore a rational option to treat c-Met+ EGFR TKI-resistant NSCLC. Tepotinib is a highly selective c-Met inhibitor with good tolerability and promising activity against solid tumors. We report final data from a phase Ib trial of tepotinib + gefitinib in pts with c-Met+/EGFR-mutant NSCLC conducted in Asia. Methods: Eligible pts were adults with locally advanced/metastatic NSCLC and ECOG PS 0–1. Tumors had to express EGFR with an activating mutation be resistant to EGFR TKI therapy and be c-Met+ by IHC. Pts received tepotinib 300 or 500 mg QD combined with gefitinib 250 mg QD (T300G250 or T500G250). The primary objective was to determine the recommended phase II dose (RP2D) of tepotinib in combination with gefitinib; secondary objectives included pharmacokinetics (PK), safety, and antitumor activity. Results: 18 pts were enrolled (median age 65 [41–78]; 8 male); 6 received T300G250, 12 T500G250. No dose-limiting toxicities were observed, and tepotinib 500 mg QD was confirmed as the RP2D. 17 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), mostly grade ≤2 and most commonly diarrhea (12), rash (8), and amylase increase (6). Grade ≥3 TRTEAEs were increased amylase (n = 4), increased lipase (3), neutropenia (1), and hyperglycemia (1). The best overall response was partial response in 6 pts; 4/7 pts with IHC 3+ tumors responded (all treated with T500G250) vs 2/11 with IHC 2+ tumors. Response durations of pts with PR were 4.2–12.5 months. 4/18 pts (IHC 2+, n = 3) had stable disease. 8 pts experienced progression free survival > 5 months, 3 pts > 10 months. PK were as expected from previous studies. Conclusions: Tepotinib in combination with gefitinib was well tolerated. The RP2D of tepotinib for use in combination with gefitinib in NSCLC is 500 mg QD. T500G250 showed signs of activity against c-Met+ tumors. A phase II trial is randomizing ≈156 pts with c-Met+/T790M– tumors who have failed first-line EFGR TKI 2:1 to tepotinib + gefitinib or pemetrexed + cisplatin/carboplatin. Clinical trial information: NCT02864992.