EGFR TKI resistance in pts with NSCLC with activating EGFR mutations (mt) is often due to c-Met abnormalities. The highly selective c-Met inhibitor tepotinib (MSC2156119J) had activity in a phase I trial in pts with advanced solid tumors. We report phase Ib data from a trial of tepotinib + gefitinib (Gef) in pts with Met+ NSCLC.
Asian adults with locally advanced/metastatic NSCLC and ECOG PS 0/1 were eligible. All pts had Met+ tumors (IHC 2 + /3+ overexpression using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana]). C-Met amplification was assessed retrospectively using FISH (Dako MET/CEN-7 IQFISH Probe Mix (IUO); c-Met:CEP7 ratio ≥2). Tumor EGFR mt status was assessed retrospectively using therascreen® EGFR RGQ PCR Kit (QIAGEN). The phase Ib part had a 3 + 3 design; planned recruitment was 15-18 pts, who received tepotinib 300 or 500 mg/d p.o. + Gef 250 mg/d q3w. Primary objective: determine the RP2D of tepotinib for use with Gef; secondary objectives: PK, safety, and antitumor activity.
As of 28/02/15, 15 pts had been enrolled: median age 63 years; male 40%; ECOG PS 0/1 2/13; median prior therapy regimens including an EGFR TKI 2. 3 pts received tepotinib 300 mg + Gef and 12 tepotinib 500 mg + Gef. 4 pts remain on treatment with tepotinib 500 mg + Gef. No DLTs were observed. 11 pts had tepotinib-related adverse events; the most common were asymptomatic amylase increase (n = 5), diarrhea (4), decreased appetite (4), dyspepsia (3). Grade 3/4 treatment-related adverse events included asymptomatic amylase (n = 3) or lipase increase (2), decreased neutrophil count (1), hyperglycemia (1). 3 and 2 of 6 pts with IHC 3+ tumors had a PR or SD, vs 1 and 5 of 8 pts with IHC 2+ tumors. The only pt with c-Met:CEP7 ratio ≥2 had a PR; 3 and 1 of 6 pts with ≥5 Met copies in >50% of cells had a PR or SD. 3/6 pts with c-Met:CEP7 ratio <2 had SD. EGFR mt status for 12 pts was T790M and L858R mt (n = 2), L858R mt alone (4), exon 19 deletion (2), no mt detected using therascreen® kit (2).
The RP2D of tepotinib with Gef in advanced NSCLC is 500 mg/day. Antitumor activity of the combination was observed in EGFR TKI-pretreated c-Met+ NSCLC. The phase II part will randomize ≈136 pts with T790M-/c-Met+ tumors who have failed first-line Gef to tepotinib 500 mg/d + Gef or cisplatin/pemetrexed.
Clinical trial identification
R. Soo: consultancy/advisory role with AstraZeneca. Research funding from Merck Serono. J.C.-H. Yang: consultancy/advisory role and received honoraria from AstraZeneca; consultancy/advisory role with Merck Serono. K. Park: consultancy/advisory role with and received research funding from AstraZeneca
U. Stammberger, C. Ihling: employee of Merck KGaA. H. Xiong: employee of Merck Serono Pharmaceutical R&D Co., Ltd, Beijing, China. Y.-L. Wu: consultancy/advisory role with Merck Serono; honoraria from AstraZeneca. All other authors have declared no conflicts of interest.