Activity of the c-Met inhibitor tepotinib (MSC2156119J) in combination with gefi
PUBLISHED: 2015-11-26  856 total views, 1 today

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

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