Tepotinib + gefitinib (TEP+GEF) in MET+/epidermal growth factor receptor (EGFR)-mutant non-small lung cancer (NSCLC): Phase II data

Abstract

Background: MET amplification (amp) may cause acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR‐mutant NSCLC; dual Met/EGFR inhibition has potential in EGFR TKI‐resistant NSCLC. We report ph2 data from a randomized ph1b/2 trial of TEP (potent, selective Met TKI) + GEF vs chemotherapy (CT: pemetrexed + cisplatin/carboplatin) in Asian patients (pts) with MET+/EGFR+T790M‐ NSCLC and a single‐arm cohort of TEP+GEF in Chinese pts with MET+/EGFR+T790M+ NSCLC. Methods: Pts with advanced EGFR+ and MET + (IHC2+/3+, gene amp) NSCLC, acquired resistance to 1L EGFR TKI and ECOG PS 0‐1 were randomized to receive TEP+GEF 500/250 mg QD or CT. Primary endpoint: PFS (investigator). Secondary endpoints: safety, objective response rate, PFS (IRC; randomized). Results: Low recruitment halted enrolment. To 12 June 2017, 55/156 planned MET+ T790Mpts (TEP+GEF n = 31; CT n = 24) were randomized and 15 MET+ T790M+ pts included (28/70 men, median age 60.4 [range 42, 82] y). Median TEP+GEF treatment duration: randomized 21.4 (range 4.6, 91.9) wks; single‐arm 6.3 (3, 40) wks. In MET+ T790M‐ pts, a numeric trend favored TEP+GEF vs CT for PFS (HR: 0.71 [90% CI 0.36, 1.39]; Table). High IHC (IHC3+:0.35 [0.17, 0.74]) and MET amp (0.17 [0.05, 0.57]) favored improved PFS. Antitumor activity was limited in the single‐arm MET+ T790M+ group (median PFS 1.4 months [90% CI 1.4, 4.9] BOR SD in 40% pts). In randomized pts (MET+ T790M‐), 3 (TEP+GEF) vs 1 (CT) had treatment‐emergent adverse events (TEAEs) leading to permanent treatment discontinuation, 1 vs 0 had TEAEs leading to death (0 trial drug‐related), 5 vs 7 had serious trial‐drug related TEAEs, 16 vs 12 had Grade ≥3 trial‐drug related TEAEs, 4 vs 2 had a trialdrug related TEAE of special interest (lipase/amylase increase ≥3). Safety in the single‐arm group was similar. MET+: Met overexpression by immunohistochemistry (IHC2+ or 3+) and/or MET gene amplification and/or increased gene copy number (GCN ≥5 or MET/CEP7 ratio ≥2) by in‐situ hybridization IRC, independent review committee; OR, odds ratio; ORR, objective response rate; PFS, progression‐free survival. Conclusions: TEP+GEF has promising antitumor activity in Met protein overexpression and gene‐amp MET+/EGFR+T790M‐NSCLC pts and was generally well‐tolerated. (Table Presented) .