Yilong Wu¹, Keunchil Park², Dongwan Kim³, Ross a. Soo⁴, Cindy Li⁵, 

Huiling Xiong⁵, Christian Ihling⁶, James chih-hsin Yang⁷

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

Background:The combination of the highly selective c-Met inhibitor tepotinib (MSC2156119J) + gefitinib was shown to be well tolerated and have antitumor activity possibly associated with c-Met-positive tumor status in the phase Ib part of this trial, which involved patients (pts) with gefitinib-resistant locally advanced/metastatic c-Met+ NSCLC. A tepotinib dose of 500mg/day was selected for use in the phase II part. The soon to be initiated phase II part of the trial (NCT01982955) is described. Trial design: Eligible pts are Asian adults with histologically or cytologically confirmed, gefitinib-resistant locally advanced/metastatic NSCLC other than predominantly squamous histology. Other inclusion criteria include: ECOG PS 0/1; activating EGFR mutations; T790M status assessed centrally using the therascreen® EGFR RGQ PCR Kit [QIAGEN]); confirmed c-Met+ tumors using immunohistochemistry (2+/3+ c-Met protein overexpression using Dako MET IHC MSC2156119J pharmDx anti-total c-MET [D1C2] rabbit MAb [Dako]). FISH (probe: Dako MET/CEN-7 IQFISH Probe Mix (IUO); c-Met: CEP7 ratio ≥2) will be used to prospectively assess c-Met amplification status. Pts with c-Met+, EGFR T790M– NSCLC (n=136) will be randomized to tepotinib 500mg/day p.o. + gefitinib 250mg/day q3w or cisplatin 75mg/m² + pemetrexed 500mg/m²q3w for up to 6 cycles. Pts with c-Met+, T790M+ NSCLC (n=15) will receive tepotinib 500mg/day p.o. + gefitinib 250mg/day q3w. The primary objective is to determine whether progression-free survival (PFS) with second-line tepotinib + gefitinib is superior to that of pemetrexed + cisplatin in pts with c-Met+, T790M– advanced NSCLC and acquired resistance to first-line gefitinib. An interim analysis is planned when 50% of PFS events have occurred in both arms. Secondary objectives are to evaluate: tolerability; efficacy in pts with c-Met+, T790M- tumors; antitumor activity in pts with c-Met+, T790M+ tumors; and patient-reported outcome in all pts. This randomized phase II trial will provide evidence of whether tepotinib has a role in the treatment of Asian pts with c-Met+, T790M– NSCLC with activating EGFR mutations and acquired resistance to first-line gefitinib.

Key Words: NSCLC