EGFR-mutated NSCLC patients treated with EGFR TKI ultimately develop resistance to therapy. Mechanisms of resistance include aberrant signalling of MET, AXL and FGFR. Inhibition of these receptors should thus abrogate their downstream signalling and restore sensitivity to EGFR TKI. S 49076 is a potent ATP-competitive TKI, which targets MET, AXL and FGFR1/2/3 at clinically relevant doses. It showed strong activity in preclinical assays against EGFR mutated MET amplified cell lines to overcome the resistance to EGFR TKI. This study evaluates the relevance of targeting MET and/or AXL dysregulation to overcome acquired non EGFR-T790M-mediated resistance to EGFR-TKI.
The phase I/II is an international, open-label study to evaluate the safety and activity of S 49076 in combination with gefitinib in stage IIIb-IV NSCLC patients who progress on EGFR TKI (1st and 2nd generation), harbouring MET and/or AXL dysregulation without EGFR-T790M mutation. The phase I is a single arm dose-finding part of S 49076 in combination with standard dose of gefitinib. The primary objective is to determine the recommended phase 2 dose (RP2D) based on the dose-limiting toxicities and safety assessments. The secondary objectives are to evaluate the pharmacokinetic profile of both drugs and the anti-tumour activity of the combination. S 49076 and gefitinib are administered orally once daily over a continuous 28-day cycle with doses ranging from 500mg to 600mg. Dose levels are allocated using a modified Bayesian Continual Reassessment Method. This study part is active and recruiting over 5 countries across Asia and Europe. The end of phase I is expected in Q3 2017. A non-randomised and non-comparative phase II part will then evaluate the anti-tumour activity of S 49076 at the RP2D in combination with gefitinib in cohorts of patients with MET and/or AXL dysregulation. The primary objective will be to determine the objective response rate according to RECIST and the secondary objectives will be to evaluate survival rate, progression free survival, clinical benefit rate and response duration as well as safety. An interim analysis will be performed in each cohort for futility.
Clinical trial identification
Legal entity responsible for the study
Institut de Recheches Internationales Servier
Institut de Recherches Internationales Servier
K. Park: Servier study international coordinator and investigator. F. Ciardiello, W. Lim, C-C. Lin: Servier study national coordinator and investigator. T. Hida, H. Murakami, M. Nishio: Servier study investigator. F. Cantero, V. Cattan, C. Gabarroca, E. Gandossi: Servier employee. L. Paz-Ares: Study Servier national coordinator and investigator.