Yi-long Wu¹, Keunchil Park², Dong-wan Kim³, Ross a. Soo⁴, Cindy Li⁵,  Huiling Xiong⁵, Christian Ihling⁶, James chih-hsin Yang⁷

 ¹Lung Cancer, GuangdongGeneral Hospital (GGH) & Guangdong Academy of Medical Sciences, Guangzhou,China, ²Innovative CancerMedicine Institute, Samsung Medical Center, Sungkyunkwan University School ofMedicine, Seoul, Republic of Korea, ³Department of InternalMedicine, Seoul National University Hospital, Seoul, Republic of Korea, ⁴National UniversityCancer Institute, National University Health System, Singapore, ⁵Merck SeronoPharmaceutical R&D Co., Ltd., Beijing, China, ⁶Merck KGaA, Darmstadt,Germany, ⁷National TaiwanUniversity, Graduate Institute of Oncology, Taipei, Taiwan

Objective:c-Met abnormalities can cause resistanceto EGFR TKIs in EGFR mutant NSCLC patients (pts). The highly selective c-Metinhibitor tepotinib (MSC2156119J) had promising activity in a phase I trial inpts with advanced solid tumors. Phase Ib data from a trial evaluating tepotinib+ gefitinib in pts with Met+ NSCLC (NCT01982955) is reported. Method: Eligibility:Asian adults; locally advanced/metastatic NSCLC, Met+ status (2+/3+ c-Metprotein overexpression using CONFIRM anti-total c-MET [SP44] rabbit MAb[Ventana]; c-Met amplification status was also assessed retrospectively usingFISH [probe: Dako MET/CEN-7 IQFISH Probe Mix (IUO); c-Met:CEP7 ratio ≥2]); ECOGPS 0/1. EGFR mutation status was assessed using the therascreen® EGFR RGQ PCRKit (QIAGEN). A 3+3 design was used; planned recruitment was 15-18 pts. Ptsreceived tepotinib 300 or 500mg p.o. + gefitinib 250mg/d q3w. Primaryobjective: determine the recommended phase II dose of tepotinib for use incombination; secondary objectives: pharmacokinetics, safety, antitumoractivity. Result: 14 pts have been enrolled (median age 65years; male43%; ECOG PS 0/1 2/12; median prior therapy regimens including an EGFR TKI 3.5).3 pts received tepotinib 300mg + gefitinib and 11 tepotinib 500mg + gefitinib.No DLTs were observed; 4 pts had grade 3/4 treatment-related adverse events(amylase increase [n=3], lipase increase [2], decreased neutrophil count [1]).Best overall response(BOR) for the 12 evaluable pts by IHC status was IHC 2+, 5stable disease (SD), 2 disease progression (PD); IHC 3+, 4 partial response(PR), 1 PD; BOR by FISH status: positive 4 PR, 1 SD, 1 PD; negative 3 SD, 2 PD;not valid 1 SD. EGFR mutation status for these 12 pts was T790M (n=2), othermutation (8), no mutation (2). Conclusion: Tepotinib, in combinationwith gefitinib, was well tolerated at a dose of 500 mg/d in pts with advancedNSCLC. Response may be associated with c-Met status. The phase II trial willrandomize ≈136 pts with T790M-/c-Met+ tumors who have failed first-linegefitinib to tepotinib 500mg/d + gefitinib or cisplatin/ pemetrexed.

KeyWords: non-small cell lung cancer