Phase II study of tepotinib + gefitinib (TEP+GEF) in MET-positive (MET+)/epidermal growth factor receptor (EGFR)-mutant (MT) non-small cell lung cancer (NSCLC)

Abstract

Background: NSCLC can acquire resistance to EGFR tyrosine kinase inhibitors (EGFR TKIs) via MET activation; dual MET/EGFR inhibition may have potential in EGFR TKI‐resistant NSCLC. TEP is a potent, selective MET TKI. We report randomized phase 2 data from a phase 1b/2 signal detection trial of TEP+GEF vs chemotherapy (pemetrexed +cisplatin/carboplatin) in patients (pts) with MET+/EGFR+T790MNSCLC (NCT01982955). Methods: Asian pts with advanced MET+(IHC2+, IHC3+, gene amplification) NSCLC, acquired resistance to 1st‐line EGFR TKI and ECOG performance status 0‐1 were eligible. Tumors had an EGFR‐activating mutation (T790M‐). Pts received TEP+GEF 500/250mg once‐daily. Primary endpoint: progression‐free survival (PFS by investigator). Secondary endpoints: safety, antitumor activity, pharmacokinetics. Results: Due to low recruitment, enrolment was halted after 55 pts were randomized to TEP+GEF (n=31) or chemotherapy (n=24): male n=23, median age 60.4 (range 42‐82) years. There was a numeric trend towards TEP+GEF on PFS in the intent‐totreat analysis set (hazard ratio [HR]: 0.71 [0.36, 1.39]), driven by the IHC3+(HR: 0.35 [0.17, 0.74]) and gene‐amplified (HR: 0.17 [0.05, 0.57]) pts (Table) confirming these as predictive biomarkers as indicated by phase 1b data. All pts had treatment‐related (TR) treatment‐emergent adverse events (TEAEs). In the TEP+GEF vs chemotherapy arms, respectively, 9.7 vs 4.3% had TEAEs leading to permanent discontinuation, 3.2 vs 0% had TEAEs leading to death (none were TRTEAEs), 16.1 vs 30.4% had serious TRTEAEs, 51.6 vs 52.2% had Grade ≥3 TRTEAEs, 12.9 vs 8.7% had a TRTEAE of special interest (lipase/amylase increase≥3). Conclusions: TEP+GEF shows promising antitumor activity in pts with MET protein overexpression (IHC3+) and gene amplification EGFR‐MT NSCLC and was generally well‐tolerated. This positive signal warrants further exploration in this pt population. (Table Presented) .